Two Different Motor Systems are Needed to Generate Human Speech

Two Different Motor Systems are Needed to GenerateHuman Speech

Gert Holstege* and Hari H. Subramanian

Asia-Pacific Centre for Neuromodulation, Queensland Brain Institute, The University of Queensland, Brisbane 4072, Australia

Vocalizations such as mews and cries in cats or crying

and laughter in humans are examples of expression of

emotions. These vocalizations are generated by the

emotional motor system, in which the mesencephalic

periaqueductal gray (PAG) plays a central role, as dem-

onstrated by the fact that lesions in the PAG lead to

complete mutism in cats, monkeys, as well as in

humans. The PAG receives strong projections from

higher limbic regions and from the anterior cingulate,

insula, and orbitofrontal cortical areas. In turn, the PAG

has strong access to the caudal medullary nucleus ret-

roambiguus (NRA). The NRA is the only cell group that

has direct access to the motoneurons involved in vocal-

ization, i.e., the motoneuronal cell groups innervating

soft palate, pharynx, and larynx as well as diaphragm,

intercostal, abdominal, and pelvic floor muscles.

Together they determine the intraabdominal, intratho-

racic, and subglottic pressure, control of which is nec-

essary for generating vocalization. Only humans can

speak, because, via the lateral component of the voli-

tional or somatic motor system, they are able to modu-

late vocalization into words and sentences. For this

modulation they use their motor cortex, which, via its

corticobulbar fibers, has direct access to the motoneur-

ons innervating the muscles of face, mouth, tongue, lar-

ynx, and pharynx. In conclusion, humans generate

speech by activating two motor systems. They generate

vocalization by activating the prefrontal-PAG-NRA-

motoneuronal pathway, and, at the same time, they

modulate this vocalization into words and sentences by

activating the corticobulbar fibers to the face, mouth,

tongue, larynx, and pharynx motoneurons. J. Comp.

Neurol. 524:1558–1577, 2016.

VC 2015 Wiley Periodicals, Inc.

INDEXING TERMS: emotional motor system; volitional or somatic motor system; motor cortex; periaqueductal gray;

laughter; nucleus retroambiguus

Once oculomotor system researchers told us that

during electrophysiological experiments in cats, in order

to reach the oculomotor nucleus, they passed their nee-

dles through the ventrolateral periaqueductal gray

(PAG), it unintentionally elicited vocalizations like mews,

howls, and hisses. More specific studies in cats demon-

strated that electrical as well as neurochemical stimula-

tion in the PAG indeed generated vocalizations (Kanai

and Wang, 1962; Carrive et al., 1987; Bandler and Car-

rive, 1988; Zhang et al., 1994; Subramanian et al.,

2008). Moreover, bilateral lesions in the PAG resulted

in complete mutism in cat (Kelly et al., 1946; Adametz

and O’Leary, 1959), dog (Skultety, 1962), as well as in

monkey (J€urgens and Pratt, 1979). The role of the PAG

in sound production was not only demonstrated in cat

(Kanai and Wang, 1962; Zhang et al., 1995) and mon-

key (J€urgens et al., 1967; J€urgens and Pratt, 1979; Lar-

son, 1985, 1988, 1991), but also in humans (Steriade

et al., 1961; Botez and Barbeau, 1971; Esposito et al.,

1999). Vocalization not only can be elicited by stimula-

tion in the PAG, but in cat and monkey also by electri-

cal stimulation in the hypothalamus (J€urgens et al.,

1967a; Baxter, 1967; Altafullah et al., 1988), amygdala

(J€urgens et al., 1967b), bed nucleus of the stria termi-

nalis (J€urgens, 1976), orbitofrontal cortex (Myers,

1976), and anterior cingulate cortex (Hunsperger and

Bucher, 1967). All these regions have direct and strong

access to the PAG (Hopkins and Holstege, 1978; Hol-

stege et al., 1985; Holstege, 1987a, 1991; Kuipers

et al., 2006), but sound production in these regions

was only possible when the PAG was intact (Adametz

and O’Leary, 1959; Skultety, 1962; J€urgens and Pratt,

*CORRESPONDENCE TO: Gert Holstege, Asia-Pacific Centre for Neuro-modulation, Queensland Brain Institute, The University of Queensland,Brisbane 4072, Australia. E-mail: [email protected]

Received March 23, 2015; Revised September 3, 2015;Accepted September 3, 2015.DOI 10.1002/cne.23898Published online November 17, 2015 in Wiley Online Library(wileyonlinelibrary.com)VC 2015 Wiley Periodicals, Inc.

1558 The Journal of Comparative Neurology | Research in Systems Neuroscience 524:1558–1577 (2016)

REVIEW

1979). However, stimulation in the motor or premotor

cortex in monkey, regions that do not project to the

PAG (Kuypers and Lawrence, 1967), cannot produce

vocalization (J€urgens, 1974; Kirzinger and J€urgens,

1982). Also, in humans, stimulation in the ventral

sensory-motor cortex did not generate sound produc-

tion (Breshears et al., 2015).

These results emphasize the central role of the PAG

in the production of vocalization in animals as well as

in humans. This coordinating role in generating vocaliza-

tion is also demonstrated by the fact that at levels cau-

dal to the PAG only partial vocalizations can be

generated in the nucleus retroambiguus (Zhang et al.,

1992, 1994; Schadt et al., 2006; Subramanian and Hol-

stege, 2009; Subramanian et al., 2015).

There exist different kinds of vocalization. In cats,

mews and hisses are vocalizations with different mean-

ings (Yeon et al., 2011) and the PAG is able to produce

such different vocalizations, depending on where in the

PAG the stimulation takes place (Zhang et al., 1994;

Subramanian et al., 2015). A certain kind of vocalization

is a specific modulation of basic sound production.

Laryngeal muscles narrowing the glottis opening pro-

duce sound, but these same muscles, together with the

pharyngeal, palatal, tongue, and facial muscles, are also

involved in modulating this basic sound into a particular

vocalization that represents a specific message. Spe-

cific vocalizations also exist in humans. Examples are

screaming, shouting, and yelling, as well as laughter

and crying, which will be discussed in a separate

paragraph.

Human speech is also a sound modulation, but a

completely different one. For modulating sound into

speech, humans need another motor system, the voli-

tional or somatic motor system, located in the motor

and premotor cortex. The reason is that in order to vol-

untarily produce words and sentences by the motor

cortex, a large amount of memory is required, which

involves a large number of neurons, many of which are

located in Broca’s area (Brodmann’s areas [BA] 44 and

45) just rostral to the mouth, tongue, pharynx, and lar-

ynx part in the most lateral motor cortex.

In this article we will review the two descending sys-

tems that produce speech. Since human speech is a

product of both the emotional and volitional or somatic

motor systems (Holstege, 1996), these two systems

(Fig. 1) will be discussed first. Next the muscles

involved in producing speech will be reviewed, followed

by their motoneurons and premotor interneurons.

Special attention will be given to the premotor inter-

neurons located in the nucleus retroambiguus (NRA),

since they play a crucial role in vocalizations such as

crying and laughter as well as in the production of

speech. Subsequently, the afferent projections to the

NRA will be discussed. Also, the premotor interneurons

involved in modulating vocalization will be reviewed as

well as their afferents originating in the PAG and higher

structures of the limbic system. Successively, the motor

cortex and Broca’s area as parts of the volitional or

somatic motor system will be discussed, and finally the

cortex region involved in the initiation of speech.

TWO MOTOR SYSTEMS

Not even four decades ago the common opinion in

neurology and neuroscience was that in humans the

corticobulbospinal tract controls all movements. This

notion was supported by the clinical finding that inter-

ruption of this descending pathway led to major loss of

the motor capacity of the patient. For example, a lesion

in the facial part of the motor cortex (BA 4) led to loss

of oral movement control contralateral to the lesion

(Myers, 1976). Remarkably, however, these patients,

when told a joke or a funny story, were able to smile

by using the same mouth muscles on the contralateral

side of the lesion that they could not contract voluntar-

ily (J€urgens and Pratt). This phenomenon remained

unexplained, because pathways causing motor activa-

tion induced by emotional stimulation were not known.

Abbreviations

BC brachium coniunctivumBP brachium pontisC1 first cervical spinal segmentCN cochlear nucleiCU cuneate nucleusDGNA dorsal group of the nucleus ambiguusECU external cuneate nucleusG gracile nucleusIC inferior colliculusIO inferior oliveIVN inferior vestibular nucleusKF K€olliker-Fuse nucleusLVN lateral vestibular nucleusMesV mesencephalic trigeminal tractMLF medial longitudinal fasciculusMVN medial vestibular nucleusNRA nucleus retroambiguusNRM nucleus raphe magnusNRP nucleus raphe pallidusNRTP nucleus reticularis tegmenti pontisnV trigeminal nerveP pyramidal tractPBL lateral parabrachial nucleusRB restiform bodyRN red nucleusRST rubrospinal tractRTN retrotrapezoid nucleusS solitary complexSO superior olivary complexVm motor trigeminal nucleusVpr principal trigeminal nucleusVprinc principal trigeminal nucleusVsp spinal trigeminal nucleusVspin caud spinal trigeminal nucleus pars caudalisVII facial nucleusXd dorsal vagal nucleusXII hypoglossal nucleus

Two Different Motor Systems in Human Speech

The Journal of Comparative Neurology | Research in Systems Neuroscience 1559

At that time, many psychiatrists were of the opinion

that most emotional illnesses did not have a basis in

aberrant brain function, but had to be cured by careful

personal attention.

In the meantime it has become clear that those brain

regions that are involved in emotional functions have

their own hardware, such as specific fiber pathways to

brainstem and spinal cord taking part in the emotional

motor system (EMS) (Holstege, 1992; Holstege et al.,

1996a). One of the reasons for the EMS not to have

been detected earlier was that its pathways did not

show up using retro- and anterograde lesion-

degeneration fiber tracing techniques (Nauta and

Gygax, 1951; Fink and Heimer, 1967). Since then,

many new retrograde tracing techniques as horseradish

peroxidase (HRP), wheat germ agglutinin horseradish

peroxidase (WGA-HRP), Fluoro-Gold and choleratoxin

beta (CTB), and anterograde tracing techniques, such

as autoradiography, Phaseolous vulgaris-leucoagglutin

(PHA-L), and several others, demonstrated that struc-

tures belonging to or strongly connected with the limbic

system have their own descending motor output sys-

tems. These newly discovered pathways were brought

together in the concept of the emotional motor system

(Holstege, 1991, 1992; Holstege et al., 1996a). In order

to distinguish this motor system from the well-known

descending motor system originating in the motor and

premotor cortex, the latter descending system was

called the volitional or somatic motor system.

VOLITIONAL OR SOMATIC MOTORSYSTEM, MEDIAL AND LATERALCOMPONENTS

Both the volitional and emotional motor systems con-

sist of a medial and a lateral component (Fig. 1). Of the

volitional or somatic motor system, the pathways

directly or indirectly controlling the motoneurons inner-

vating axial and proximal body musculature, regulating

body posture, as well as the motoneurons of neck and

external eye musculature, determining the direction of

the visual field, represent the medial component. They

originate not only in the motor and premotor cortex,

but also in brainstem structures such as the caudal

pontine and medullary dorsomedial tegmentum, the

vestibular nuclei, deep tectal layers, interstitial nucleus

of Cajal, and the rostral interstitial nucleus of the MLF

(Holstege and Kuypers, 1982; B€uttner-Ennever et al.,

1982; Holstege, 1988; Holstege and Cowie, 1989). The

descending pathways that control the motoneurons

innervating distal body muscles, i.e., arm, hand, leg,

feet, as well as the mouth opening, oral, tongue, phar-

ynx, larynx, and soft palate muscles represent the lat-

eral component. Examples of descending systems

belonging to the lateral component of the volitional or

somatic motor system are the rubrospinal tract, albeit

this pathway is of minor importance in humans (Mas-

sion, 1988), and the corticobulbospinal tracts originat-

ing in the motor and premotor cortex (Kuypers, 1981;

Holstege, 1991, 1996b). In rats, cats, monkey, and

humans these corticobulbospinal tracts terminate on

premotor interneurons in caudal pons, medulla, and spi-

nal cord, in monkey, and especially in humans also

directly on motoneurons, albeit not on all motoneurons

(Kuypers, 1958a,b,c).

EMOTIONAL MOTOR SYSTEM, MEDIALAND LATERAL COMPONENTS

Medial component of the EMSThe medial component of the EMS consists of path-

ways to neuronal cell groups in the brainstem that in

turn project to all parts of the spinal cord gray matter

or caudal brainstem (Holstege and Kuypers, 1982).

Examples are the caudal raphe nuclei and adjoining

ventromedial tegmentum, containing neurons using

serotonin, leucine-enkephalin, substance P, and many

other neurotransmitters and neuromodulators (Holstege,

1991). These raphe nuclei and their adjoining ventrome-

dial tegmentum are subdivided into different cell

groups, of which the caudal region (raphe magnus, pal-

lidus, and obscurus with adjoining tegmentum) project

caudally and the rostral raphe nuclei (raphe dorsalis

and centralis) project rostrally, in order to supply

Figure 1. The motor system consists of two subsystems, the voli-

tional or somatic and the emotional motor system. Both subsys-

tems have access to premotor interneurons and motoneurons.

G. Holstege and H.H. Subramanian

1560 The Journal of Comparative Neurology |Research in Systems Neuroscience

almost all parts of the central nervous system with

serotonin and several other neurotransmitters and neu-

romodulators. The same is true for the noradrenergic

neurons in the locus coeruleus and other noradrenergic

cell groups in the caudal brainstem. They have a similar

projection pattern as the raphe nuclei. For example,

neurons in the rostral part of the locus coeruleus pro-

ject rostrally to mes-, di-, and telencephalon and neu-

rons in the caudal part of this cell group project

caudally to caudal brainstem and spinal cord (Holets

et al., 1988).

Another example of the medial component of the

emotional motor system is the dopaminergic A11 cell

group in the rostral mesencephalon, which, similar to

the noradrenergic and the serotonergic cell groups,

projects to all parts of the spinal gray matter through-

out the length of the spinal cord (Holstege et al.,

1996b). Because of the extremely diffuse projections of

all these pathways, the raphe nuclei with adjoining teg-

mentum, locus coeruleus, and A11 neurons are not

involved in specific motor activities, but in setting the

general level of activation of all the neurons they have

access to. This is the reason why the medial compo-

nent of the EMS is called the level-setting system (Fig.

3) (Holstege, 1991). These descending level-setting sys-

tems not only involve motor, but also the sensory sys-

tems, because they also have access to the dorsal

horn, where they have a diffuse effect on incoming

nociceptive information (Mason, 2006). The raphe

nuclei and adjoining areas as well as the other level-

setting systems are under strong control of the PAG

(Fig. 3, left) and higher limbic levels such as the medial

orbitofrontal cortex.

Lateral component of the EMSThe lateral component of the EMS consists of the

pathways that control specific emotional motor activ-

ities. Examples are the projections from the PAG to pre-

motor interneuronal cell groups involved in the control

of blood pressure, heart rate, micturition, respiration,

and mating behavior (Fig. 3) (Subramanian et al., 2008;

Holstege, 2014). Vocalization is another example of a

lateral component of the EMS. The PAG, in turn,

receives strong projections from the central nucleus of

the amygdala (Hopkins and Holstege, 1978), lateral bed

nucleus of the stria terminalis (Holstege et al., 1985),

lateral hypothalamus (Holstege, 1987a), and in cat the

infralimbic cortex (Kuipers et al., 2006), which is equiv-

alent to the anterior cingulate cortex in monkey (An

et al., 1998; Saleem et al., 2008). By way of their

descending pathways, these limbic areas control the

PAG motor output, but, in order to generate higher level

emotional motor output not controlled by the PAG,

these limbic areas also have their own access to the

caudal pontine and medullary lateral tegmentum, con-

taining the premotor interneurons of the motoneurons

of the chewing, tongue, facial, soft palate, pharynx, and

larynx muscles. An example of the emotional output of

these projections in humans is illustrated in Figure 2.

Figure 2. A lesion in the volitional or somatic motor system, i.e., in the left motor cortex controlling face movements (A) results in the

inability to show teeth on the right side (B), but the patient is still able to smile (C), because the emotional motor system is still intact

(Holstege, 2002).



MUSCLES INVOLVED IN GENERATINGVOCALIZATION

Vocalization includes sound production, for the gen-

eration of which increased intra-abdominal and intra-

thoracic pressure is necessary in order to generate

airflow through a narrow glottis. The muscles that

determine abdominal pressure are the costal dia-

phragm, forming the roof of the abdominal cavity (Sub-

ramanian and Holstege, 2011), and the abdominal

muscles transversus, obliquus internus, and obliquus

externus, establishing the lateral and anterior borders

of the abdominal-pelvic cavity. The pelvic floor, the bot-

tom of this cavity, is also involved in abdominal-pelvic

pressure control (Fig. 4). In case an increase of

abdominal-pelvic pressure is necessary in the context

of vomiting, coughing, sneezing, or child delivery, the

larynx or glottis has to be closed in order to prevent

air to escape from the thorax. During sound production,

air is pushed through the narrowed glottis. The muscles

that close or narrow the larynx by adducting the vocal

folds are the lateral cricoarytenoid, thyroarytenoid, and

interarytenoid. During childbirth not only the larynx, but

also the upper part of the alimentary tract has to be

closed in order to prevent gastric contents entering the

mouth. Muscles involved in closing the esophagus are

the striated muscles of the upper esophagus and lower

pharynx.

In conclusion, each motor activity that involves an

increase in abdominal-pelvic pressure requires a differ-

ent combination of muscle activation. For example, dur-

ing childbirth all muscles mentioned above are

activated, but the pelvic floor muscles are relaxed, with

the exception of the anal and urethral sphincters. Dur-

ing vomiting all these muscles are activated except the

upper esophagus and pharynx. During forced expiration,

including coughing and sneezing, all muscles are

involved except those larynx and pharynx muscles that

close the upper airway. During vocalization many of

these muscles are activated, albeit that the larynx

muscles that normally close the glottis only narrow it.

Generating vocalization in animals and humans, or

speech in humans, requires various combinations of

activation of mouth opening, face, tongue, soft palate,

and certain pharynx and larynx muscles. For the precise

mechanics of laryngeal, oral, and respiratory muscles

and how they integrate during positive and negative

vocalizations in the cat, see the article by Subramanian

et al. (2015, this volume).

MOTONEURONS INNERVATING THEMUSCLES GENERATING VOCALIZATIONAND SPEECH

The motoneurons innervating the costal diaphragm

are located in the phrenic nucleus, which in cats is

Figure 3. The PAG not only controls sound production and vocalization, but also many other motor systems.



located in the C4–C6 (Rikard-Bell and Bystrzycka,

1980) and in humans in the C3–C5 spinal segments

(Routal and Pal, 1999). The motoneurons innervating

the abdominal muscles in cat are located laterally in

the ventral horn of the T5–L3 spinal cord (Holstege

et al., 1987) and those innervating the pelvic floor in

the nucleus of Onuf in the S1–S2 sacral cord (Sato

et al., 1978; Schroder, 1981; Blok et al., 1996; Vander-

horst and Holstege, 1997b). The motoneurons innervat-

ing the upper esophagus, pharynx, larynx, and soft

palate are not located in the spinal cord, but in the

nucleus ambiguus in the lateral tegmental field of the

medulla. In cat the nucleus ambiguus extends from the

level of the caudal facial nucleus until the level just

caudal to the obex. In Nissl-stained sections, only one

part of the nucleus ambiguus can be distinguished as a

motoneuronal cell group. In cat this is the so-called dor-

sal group of Taber (Taber, 1961), located a few milli-

meters caudal to the facial nucleus. The rostral and the

caudal extensions of the nucleus ambiguus do not form

a distinct nucleus, but lie scattered in the ventrolateral

part of the lateral tegmental field (Holstege et al.,

1983). Moreover, most transverse sections contain only

a small number of ambiguus motoneurons. This is the

reason for its name, nucleus ambiguus, because it was

“ambiguous,” i.e., unclear, indefinite, or uncertain

whether or not in Nissl-stained sections a certain cell is

an ambiguus motoneuron. Another problem was that the

nucleus ambiguus not only contains somatic motoneur-

ons innervating pharynx and larynx, but also parasympa-

thetic motoneurons innervating the gastrointestinal tract,

heart, and lungs via the vagal nerve. These parasympa-

thetic motoneurons have no relation to the somatic moto-

neurons innervating the striated muscles, but both send

fibers through the vagal nerve. The dorsal group of the

nucleus ambiguus in cat contains motoneurons innervat-

ing soft palate and upper, middle, and lower pharynx (Hol-

stege et al., 1983). Some of the motoneurons innervating

the pharynx are located scattered in the area of the retro-

facial nucleus, but only very few in the caudal nucleus

ambiguus. The motoneurons innervating the cricothyroid

and upper esophagus muscles are located in the rostral

nucleus ambiguus (Fig. 5), i.e., in the area of the retrofa-

cial nucleus rostral to the dorsal group. The motoneurons

innervating the laryngeal adductor muscles as thyroaryte-

noid, lateral cricoarytenoid, posterior cricoarytenoid, and

interarytenoid are situated in the nucleus ambiguus cau-

dal to the dorsal group (Fig. 5), where they lie rather

Figure 4. The PAG–NRA–motoneuronal system controls the intraabdominal pressure (Holstege, 2014).



scattered throughout the lateral tegmental field (Yoshida

et al., 1982; Holstege et al., 1983; Davis and Nail, 1984;

Hisa et al., 1984).

Muscles involved in modulating vocalization are the pro-

truder and retractor tongue and geniohyoid muscles. Their

motoneurons are located in the hypoglossal nucleus

around the level of the obex (Holstege et al., 1983; Yoshida

et al., 1983; Dobbins and Feldman, 1995). The perioral and

lower face muscle motoneurons are located in the lateral

part of the facial nucleus. In the facial nucleus in monkey

(Welt and Abbs, 1990), and in all likelihood even more pro-

nounced in humans, the perioral motoneurons are more

numerous and occupy longer columns than the other facial

motoneuronal cell groups. The mouth opening muscles are

the anterior digastric and mylohyoid. Their motoneurons

are located in the ventrolateral part of the motor trigeminal

nucleus (Yoshida et al., 1983; Holstege et al., 1983).

PREMOTOR INTERNEURONS

All motoneurons, autonomic and somatic, receive their

afferent fibers from so-called premotor interneurons that

belong to the basic motor system (Fig. 1). There are

exceptions to this rule, such as direct rubromotoneuronal

projections in cat (Holstege, 1987b) and monkey (Hol-

stege et al., 1988; Ralston et al., 1988) and corticomoto-

neuronal projections in primates (Kuypers, 1981) as well

as projections belonging to the medial component of the

emotional motor system (level-setting systems).

In the spinal cord the premotor interneurons are

located in the intermediate zone bordering the moto-

neuronal cell groups (Rustioni et al., 1971), and in the

caudal brainstem in the lateral tegmental field, also

called parvocellular reticular formation, which is the ros-

tral extension of the spinal intermediate zone (Fig. 5,

right). The motor trigeminal, facial, ambiguus, and hypo-

glossal motoneuronal cell groups are located within this

lateral tegmental field (Holstege et al., 1977). Premotor

interneurons not only excite the motoneurons of spe-

cific agonist muscles, but at the same time also excite

the premotor interneurons that in turn inhibit the moto-

neurons innervating the antagonist muscles.

Although most premotor interneurons are situated

close to their motoneurons, some are located at a

Figure 5. On the left, the rostrocaudal extent of the nucleus ambiguus, with the various motoneuronal cell groups innervating the various

muscles, is indicated. On the right, the caudal brainstem with the lateral tegmental field as the rostral extension of the spinal intermediate

zone. Similar to the spinal cord it contains motoneuronal cell groups as well as their premotor interneurons.



much larger distance. For example, the premotor inter-

neurons of the motoneurons innervating the pelvic

organs are located in the dorsolateral pontine tegmen-

tum (Beckel and Holstege, 2014). Also, the premotor

interneurons for the diaphragm, abdominal, internal

intercostal, and pelvic floor motoneurons are not

located in the spinal cord, but in the NRA in the caudal

medulla. The reason is that the diaphragm motoneurons

in the phrenic nucleus can only function properly when

their premotor interneurons are informed about blood-

stream pO2 and pCO2, blood pressure, and lung exten-

sion. This information does not enter the spinal cord,

but enters the caudal medulla via the vagal nerve. The

same is true for the abdominal and pelvic floor muscle

motoneurons as far as they play a role in abdominal

pressure control. With regard to the premotor interneur-

ons involved in vocalization and speech, those involved

in generating vocalization and those involved in the

modulation of vocalization will be discussed separately.

PREMOTOR INTERNEURONS GENERATINGVOCALIZATION

Vocalization is the result of air pushed from the

thorax through the narrow glottis opening. The airflow

is generated by increased abdominal pressure caused

by contraction of certain muscles of the diaphragm,

and of the internal intercostal, abdominal, and pelvic

floor muscles. These muscles not only play a role in

controlling abdominal pressure, but also in other motor

activities such as inspiration, posture control, micturi-

tion, defecation, and parturition.

With regard to abdominal pressure control, the pre-

motor interneurons are located in the NRA (Holstege,

1989), because the NRA is the only cell group in the

central nervous system that has direct access to all the

motoneurons specifically involved in thoracic and

abdominal pressure control (Fig. 4) (Holstege and

Kuypers, 1982; Holstege, 1991; Vanderhorst et al.,

2000a). In transverse sections the NRA has a small

diameter (�0.5 mm), but a relatively long rostrocaudal

extent, �7 mm in cats (Berman, 1968) and �9 mm in

humans (Olszewski and Baxter, 1954; Paxinos and

Huang, 1995). Olszewski and Baxter were the first to

define the NRA in their human brain atlas and Merrill

(1970), using electrical stimulation in cat, was the first

to demonstrate involvement of the NRA in respiration.

The NRA premotor interneurons send fibers that cross

at the level of the caudal brainstem to descend in the

contralateral spinal cord to project bilaterally, but

mainly contralaterally to the phrenic nucleus, to all

internal intercostal muscle motoneurons in the thoracic

cord, to all oblique and transverse abdominal muscle

motoneurons in the thoracolumbar cord, and to the pel-

vic floor motoneurons in Onuf’s nucleus in the sacral

cord (Holstege and Kuypers, 1982; Holstege and Tan,

1987) (Figs. 4 and 6). The specificity of the descending

NRA projections is also demonstrated by the fact that

the rectus abdominis muscle motoneurons, not being

involved in abdominal pressure control, do not receive

NRA projections (Holstege, 1989, 1991). Electron

microscopic studies revealed that the projections to

abdominal oblique and pelvic floor muscle motoneurons

are direct and excitatory (Vanderhorst et al., 2000a;

Boers et al., 2006). Moreover, in golden hamster, cat,

and monkey, and probably many other mammals, the

NRA also contains premotor interneurons that project

to those lower limb muscle motoneurons that generate

the posture necessary for mating behavior (Vanderhorst

and Holstege, 1997a; Gerrits and Holstege, 1999; Van-

derhorst et al., 2000a). How far mating posture also

involves abdominal pressure changes remains to be

determined.

According to our concept, each NRA-interneuron proj-

ects to a group of motoneurons involved in a specific

task, although this still has to be verified. It has been

established, however, that in cat the rostral NRA neu-

rons have access to the more rostrally located moto-

neurons in the medulla innervating pharynx, larynx,

cricothyroid, and to the diaphragm motoneurons in the

cervical cord, while neurons in the caudal NRA project

to the more caudally located motoneurons in the spinal

cord innervating abdominal (Fig. 6) and pelvic floor

muscles (Holstege and Kuypers, 1982; Holstege and

Tan, 1987; Holstege, 1989). These observations fit the

physiological findings in cat that neurochemical stimula-

tion in the rostral NRA activates the cricothyroid and

laryngeal adductor muscles, as well as the diaphragm,

while neurons in the caudal NRA activate abdominal

muscles (Fig. 4) (Zhang et al., 1995; Subramanian and

Holstege, 2009).

Anterograde tracing techniques show that the NRA

also projects very strongly to the dorsal group of the

nucleus ambiguus (Figs. 6 and 7) (Holstege, 1989),

which in cat contains pharynx and soft palate moto-

neurons (Holstege et al., 1983). It has to be empha-

sized that most injection sites in these anterograde

tracing studies not only involved the NRA itself, but

also parts of the NRA surrounding the lateral tegmental

field. This is important because in the case in which

the injection site only involved the NRA, projections

were found to the nucleus ambiguus motoneurons

almost exclusively contralaterally (Fig. 7). These results

indicate that, with the exception of the few NRA neu-

rons projecting back to the PAG (Klop et al., 2002), the

NRA itself contains premotor interneurons that



Figure 6. Darkfield photomicrographs of the brainstem and spinal cord in a cat with an injection of 3H-leucine in the nucleus retroambi-

guus. Note the very strong projection to the nucleus ambiguus on the contralateral side as well as to the motoneurons of the intercostal

and abdominal muscles. Note also the strong bilateral projections to the lateral parabrachial and K€olliker-Fuse nuclei (Holstege, 1989).

Figure 7. In a case in which the 3H-leucine injection was mainly in the white matter of the dorsolateral funiculus, the injection site just

extended in the most lateral part of the caudal NRA, not involving any neurons located in the lateral tegmental field adjoining the NRA.

The only ascending projection was to the contralateral dorsal group of the nucleus ambiguus and not to the ipsilateral NA. The descending

projections to the spinal cord were also contralateral but partly recrossed at the level of the motoneurons they terminated on (Boers

et al., 2005). Scale bars 5 1 mm in A; 0.5 mm in B.



innervate motoneurons involved in defining the intraab-

dominal, intrathoracic, and infraglottic pressure. These

results demonstrate that the NRA neurons are not

heavily interconnected with the structures involved in

vocal pattern generation, as stated in certain reviews

(Hage, 2010). However, the lateral tegmental field

adjoining the NRA contains neurons that project to

other neurons in the lateral tegmental field, but these

neurons do not project to the motoneurons that receive

afferents from the NRA.

Regarding the afferents to the nucleus ambiguus,

those from the NRA are by far the strongest (Boers

et al., 2005) (Fig. 8). Moreover, electron microscopic

studies (Boers et al., 2002, 2006) have demonstrated

that the NRA projections to the cricothyroid, soft pal-

ate, and pharynx muscle motoneurons are direct and

excitatory. It is important to emphasize that these

strong NRA projections not only play a role in vocaliza-

tion, but also in motor activities such as sneezing (Wal-

lois et al., 1995), coughing (Gestreau et al., 1997), and

vomiting (Miller et al., 1995). Studies concerning NRA

projections to the laryngeal adductor muscle motoneur-

ons are difficult to perform, because these motoneur-

ons lie scattered in the lateral tegmental field caudal to

the dorsal group of the nucleus ambiguus. However,

NRA projections to these motoneurons almost certainly

exist, because neurochemical stimulation in the rostral

NRA elicited partial vocalizations, i.e., contraction of the

laryngeal adductor muscles (Zhang et al., 1995; Subra-

manian and Holstege, 2009; Subramanian et al., 2015).

In conclusion, the NRA not only maintains direct projec-

tions to phrenic, internal intercostal, abdominal, and

pelvic floor motoneurons, but also to the motoneurons

innervating larynx, pharynx, soft palate, and the striated

muscles of the upper esophagus.

Since the NRA is the only cell group that has exclu-

sive access to the motoneurons of a complete set of

thoracic and abdominal pressure control muscles,

including larynx and pharynx, all motor systems that

require specific abdominal, thoracic, or laryngeal pres-

sure changes must have direct or indirect (e.g., via the

PAG) access to the NRA premotor interneurons.

AFFERENT PROJECTIONS TO THE NUCLEUSRETROAMBIGUUS

As indicated above, the NRA plays a crucial role in

all motor systems that involve changes in intrathoracic

and intraabdominal pressure, such as vocalization,

sneezing, coughing, vomiting, childbirth, and, at least in

golden hamster, cat, and monkey, even posture during

sexual intercourse (Vanderhorst and Holstege, 1997a;

Gerrits and Holstege, 1999; Vanderhorst et al., 2000a).

Laughter and crying are also examples of human vocal-

izations for which NRA activation is needed to produce

the accompanying intrathoracic, intraabdominal, and

subglottic pressure changes. For each of all these

motor systems a different range of NRA neurons is

stimulated, which brings up the question which brain

regions have direct access to the NRA.

In cats and monkeys (Holstege, 1989; Vanderhorst

et al., 2000b) (Figs. 9 and 10), and in all likelihood also

in humans, the strongest projections to the NRA origi-

nate in the PAG and its laterally adjoining tegmentum.

Figure 8. Overview of the premotor interneuronal projections to

the dorsal group of the nucleus ambiguus in the cat. Note that

the strongest projection originates from the nucleus retroambi-

guus. Shading represents the lateral tegmental field in pons and

medulla and the intermediate zone in the spinal cord (Boers

et al., 2005).



As mentioned above, the PAG is the central pattern

generator for vocalization, because neurochemical stim-

ulation in the PAG generates vocalization, while lesions

in the PAG may result in complete mutism in animals

(Adametz and O’Leary, 1959) as well as in humans

(Steriade et al., 1961; Botez and Barbeau, 1971; Espo-

sito et al., 1999).

Other regions projecting to the NRA are the ventro-

lateral parabrachial and K€olliker-Fuse nuclei, as well as

neurons in the so-called retrotrapezoid nucleus ventro-

lateral to the facial nucleus, the retrofacial nucleus, and

the ventrolateral medullary tegmentum caudal to it

(Gerrits and Holstege, 1996). Further caudally, at the

level of the hypoglossal nucleus, neurons in the solitary

nucleus and adjoining lateral tegmental field also pro-

ject to the NRA (Fig. 11). Neurons in these same lateral

tegmental regions not only project to the NRA, but also

to the motoneurons in the motor trigeminal, facial,

ambiguus, and hypoglossal nuclei (Holstege et al.,

1977, 1983; Holstege and Kuypers, 1977). In all likeli-

hood, the central pattern generators for sneezing,

coughing, and vomiting are located in these lateral teg-

mental regions. Indeed, neurons in the retrofacial

nucleus are thought to serve as the central pattern gen-

erator for vomiting (Koga et al., 1998), gagging (Fukuda

and Koga, 1997), and sneezing (Nonaka et al., 1990).

Other cells in this same region are thought to be

involved in respiratory rhythmogenesis (Richter et al.,

1992). Based on these findings, one might conclude

that the central pattern generators for vocalization are

in the PAG (Figs. 9 and 10), and those for vomiting,

respiratory rhythmogenesis, gagging, and sneezing in

the ventrolateral part of the lateral tegmental field.

They all have access to the NRA and use it as a tool to

generate the necessary changes in the intrathoracic

and intraabdominal pressures or, in simple terms, the

NRA is the piano, the central pattern generators are

the piano players.

PREMOTOR INTERNEURONS MODULATINGVOCALIZATION

Although the NRA plays a central role in producing

vocalization, other premotor interneurons play a role in

Figure 9. After an injection of a retrograde tracer (WGA-HRP) in the nucleus retroambiguus and adjoining tegmentum. Note the many ret-

rogradely labeled neurons in the caudal half of the lateral and ventrolateral PAG (Holstege, 1989).



modulating vocalization, i.e., those innervating tongue,

perioral, lower face, and mouth opening muscles as well

as pharynx and soft palate. Of the laryngeal muscles the

thyroarytenoid, lateral cricoarytenoid, and interarytenoid

muscles are involved in both generating as well as modu-

lating vocalization, while the other laryngeal muscles only

play a role in modulating vocalization.

The motoneurons of the muscles mentioned above as

well as their premotor interneurons are located in the

caudal pontine and medullary lateral tegmental field

(Fig. 5, right). For example, the premotor interneurons

projecting to the mouth-opening motoneurons in the

ventromedial motor trigeminal nucleus are located in

the lateral tegmental field at the level of the hypoglos-

sal nucleus, probably because tongue- and mouth-

opening movements are coordinated by these systems

(Cowie and Holstege, 1992). The premotor interneurons

innervating the pharynx and soft palate motoneurons,

located in the dorsal group of the nucleus ambiguus,

originate in the NRA and a smaller number in other

parts of the lateral tegmentum, including the parabra-

chial nuclei (Fig. 8) (Boers et al., 2005).

An interesting example of a cell group that modulates

sound in the monkey is in the ventrolateral pons (Han-

nig and J€urgens, 2006), which, in all likelihood, corre-

sponds to the region ventrally adjoining the K€olliker-

Fuse nucleus in cats. This region in the pontine lateral

tegmental field indeed projects to the motor trigeminal

nucleus, the lateral facial nucleus, and the hypoglossal

nucleus, but only to a very limited extent to the nucleus

ambiguus (Fig. 8) (Boers et al., 2005). Interestingly,

blocking this pontine region with the glutamate antago-

nist kynurenic acid did not stop vocalization, but

stopped only a characteristic frequency modulation (4

kHz / 25 ms) of vocalization (J€urgens, 2000). This find-

ing illustrates that the function of this ventrolateral pon-

tine tegmental region is not involved in generating, but

in modulating vocalization.

PAG GENERATES VOCALIZATION

In cats, chemical stimulation in the PAG produces four

different types of vocalization, mews, howls, cries, and

hisses, depending on where in the PAG the stimulation

takes place. Mews can be elicited in the lateral PAG and

howls in the ventrolateral PAG. Cries can be elicited in

the dorsolateral as well as in the caudal ventrolateral sub-

tentorial PAG, while hisses only in the central parts of the

ventrolateral PAG (Subramanian et al., 2008, 2015). In

adult squirrel monkeys, bilateral electrolytic lesions in

the ventral PAG eliminated nearly the entire production

of spontaneous isolation calls, although other calls

appeared to be unaffected (Newman and Maclean,

1982). Apparently, the PAG projections from the lateral

and ventrolateral PAG differ from those originating in the

more central parts of the PAG, albeit both regions have

direct access to the NRA (Fig. 9). Electrical stimulation of

the PAG–NRA pathway in the pontine and medullary lat-

eral tegmental field, caudal to the PAG, can also result in

vocalization (De Lanerolle, 1988), but neurochemical

stimulation in this region does not generate vocalization,

indicating that neurons in this area are not involved in

generating vocalization.

The PAG in cat, unlike what is stated elsewhere in

monkey (J€urgens and Pratt, 1979), does not project to

Figure 10. Darkfield photomicrographs showing that an injection

of 3H-leucine in the lateral and ventrolateral PAG in a cat (top)

(Holstege, 1991) resulted in a very strong and specific bilateral

projection to the nucleus retroambiguus.



either the nucleus ambiguus (Fig. 12) or to any other

motoneuronal cell group (Holstege, 1991), but it does

project to premotor interneurons in the lateral tegmental

field. In all likelihood, different PAG cells project to differ-

ent combinations of neurons in the NRA as well as to dif-

ferent premotor interneurons in the lateral tegmental

field. In cats only four different vocalizations can be eli-

cited by neurochemical stimulation in the PAG, while

stimulation at higher brain levels produces more elabo-

rate vocalizations such as growls, wails, and screams.

REGIONS ROSTRAL TO THE PAGMODULATE VOCALIZATION

Vocalization can also be generated in limbic regions

such as amygdala, bed nucleus of the stria terminalis,

lateral hypothalamus, and infralimbic cortex or anterior

cingulate cortex in monkey. In these regions very

diverse vocalizations can be elicited (J€urgens, 1976). All

these regions not only have direct and strong access to

the PAG, but they also project to almost all parts of the

lateral tegmental field of caudal pons and medulla

except the NRA (Fig. 13) (Hopkins and Holstege, 1978;

Holstege et al., 1985; Holstege, 1987a; Kuipers et al.,

2006). As mentioned above, the lateral tegmental field

(Fig. 5, right) contains the premotor interneurons

involved in modulating vocalization (Boers et al., 2005).

To put it briefly, the same limbic regions rostral to the

PAG, that can generate vocalization via their access to

the PAG–NRA–motoneuronal pathway, can also modu-

late these vocalizations through their projections to the

premotor interneurons in the lateral tegmental field.

Figure 11. Schematic overview of the pontine and medullary cell groups projecting to the nucleus retroambiguus. The dark regions project

stronger to the NRA than the lighter areas (Gerrits and Holstege, 1996).



MOTOR PATHWAYS FOR CRYING ANDLAUGHTER IN HUMANS

Examples of vocalizations in humans are laughter and

crying (Von Cramon and J€urgens, 1983; Seifritz et al.,

2003; Wattendorf, 2015; Provine, 2015). In human

anencephalic infants, i.e., infants born without any brain

tissue above the mesencephalon, were still able to cry,

similar to normal babies (Nielsen and Sedgwick, 1949;

Barnet et al., 1966). This means that also in humans

the mesencephalon is able to generate vocalizations

like crying. Also in cats, neurochemical stimulation in

the PAG can generate crying (Zhang et al., 1994; Subra-

manian and Holstege, 2009; Subramanian et al., 2015).

Although there are no studies about which regions ros-

tral to the PAG are involved in generating crying, animal

studies strongly suggest that the anterior cingulate

gyrus is involved (Newman, 2007). Since the anterior

cingulate gyrus has strong access to the PAG (An et al.,

1998), in all likelihood the anterior cingulate–PAG–

NRA–motoneuronal pathway is the motor pathway for

crying.

Laughter is another example of a lateral component

of the emotional motor system in humans, because this

vocalization is not generated voluntarily, but only emo-

tionally (Provine, 2015). Since laughter is a product of

the abdominal, pelvic floor, diaphragm, and larynx, one

might expect that the PAG–NRA pathway plays a crucial

role in generating laughter. Indeed, a recent positron

emission tomography (PET) scan study (Wattendorf

et al., 2013) demonstrated that in humans voluntary

and involuntary laughter activated the PAG, and did not

when laughter was inhibited. According to this same

study, also the lateral hypothalamus, amygdala, parietal

operculum, and right cerebellum were activated during

laughter. According to the same research group (Wat-

tendorf, 2015) the posterior and mid-portions of the

insular cortex are activated during ticklish and voluntary

laughter. Since the insula has direct connections with

the PAG (An et al., 1998), one might assume that the

insula–PAG–NRA–motoneuronal pathway is the motor

system of laughter.

MOTOR CORTEX AND BROCA’S AREAMODULATING VOCALIZATION IN HUMANS

The lateral part of the human motor cortex contains

the neurons that have direct connections with the pre-

motor interneurons and motoneurons in the pontine

and medullary lateral tegmental field (Kuypers, 1958b).

By way of these projections this part of the motor cor-

tex has access to the motoneurons of the larynx, phar-

ynx, perioral, tongue, mouth-opening, and mouth-closing

muscles. This cortico-motoneuronal pathway not only

exists in humans but also in monkey and chimpanzee

(Kuypers, 1958c; Morecraft et al., 2014), albeit direct

projections to motoneurons are scarce or even absent

in other mammals, such as cat (Kuypers, 1958a).

Yet the motor cortex cannot produce vocalization.

Electrical stimulation in this part of the motor system

does not result in vocalization or sound production (Bre-

shears et al., 2015), because it has no access to the

NRA. As indicated above, also in humans vocalization is

generated by the PAG, as demonstrated by the fact

that lesions in the PAG in humans may result in abso-

lute mutism (Steriade et al., 1961; Botez and Barbeau,

Figure 13. Darkfield photograph of the caudal medulla of a cat

with an injection in the bed nucleus of the stria terminalis. Note

the strong projection to the lateral tegmental field including the

solitary complex as well to lamina I of the trigeminal nucleus, but

the absence of projections to the nucleus retroambiguus (Hol-

stege et al., 1985).

Figure 12. Darkfield photomicrograph of the medulla oblongata

after a 3H-leucine-injection in the lateral and ventrolateral PAG.

Note the strong projections to the ventromedial medullary teg-

mentum, but the absence of PAG-projections to the dorsal group

of the nucleus ambiguus with motoneurons innervating cricothy-

roid, soft palate and upper, middle and lower pharynx.



1971; Esposito et al., 1999), i.e., without the PAG

humans cannot produce sound. The motor cortex,

therefore, does not produce vocalization, but modulates

vocalization into words and sentences. In order to per-

form such a complicated motor task, the motor cortex

requires a large number of neurons in adjoining parts of

the motor cortex. This part of the prefrontal cortex

serves as the memory for how to generate such compli-

cated movements of the various muscles in order to

produce words and sentences, i.e., speech. These lan-

guage memory neurons are located in Broca’s area

(Brodmann’s areas 44 and 45, on the left side of the

cortex). Lesions in Broca’s area cause so-called motor

aphasia, the inability to produce words and sentences.

However, these patients still can vocalize. In all likeli-

hood, animals such as cats, dogs, and monkey also use

their corticobulbar system to modulate vocalization pro-

duced by the PAG, albeit in a rudimentary way, because

they lack the large number of memory neurons, present

in Broca’s area in humans. However, the intonation of

human speech is not determined by the motor cortex,

but by the various limbic system and prefrontal projec-

tions to the PAG, which change the basic vocalization.

INITIATION OF SPEECH

Although the modulation of vocalization into speech

is produced by Broca’s area and the adjoining motor

cortex, the initiation of speech is in another cortical

region, the supracallosal medial frontal cortex (Barris

and Schuman, 1953) or anterior cingulate cortex (Wat-

tendorf et al., 2013). This area can be divided into

three functional areas, of which the ventral region proj-

ects to the limbic system, including the PAG, an ante-

rior dorsal region which projects to the lateral

prefrontal systems, and a posterior dorsal area that

projects to Broca’s area and adjoining motor cortex

(Warburton et al., 1996; Crosson et al., 1999). Figure

14 represents a schematic overview, which shows the

organization of how speech is produced by the supra-

callosal medial frontal cortex. Since speech needs pre-

cise motor activities of the mouth, face, throat, and

tongue, the motor cortex and its memory (Broca’s area)

play a crucial role. Nevertheless, speech is a modula-

tion of basic vocalization, which in animals as well as in

humans is produced via the anterior cingulate–PAG–

NRA pathway. PET scan results in humans confirm this

concept, because during voiced speech the PAG and

the paramedian cortices were activated, while during

unvoiced speech this was not the case (Schulz et al.,

2005).

RECOGNIZING THE IMPORTANT ROLE OFTHE NRA IN THE GENERATION OFVOCALIZATION AND SPEECH

As described above, the NRA plays a crucial role in

the production of speech. However, in several recent

review articles concerning the basic systems of speech

(J€urgens, 2009; Barlow, 2010; Simonyan and Horwitz,

2011; Ackermann et al., 2014), the NRA is not men-

tioned at all. The problem started in 1989 when it was

demonstrated that the PAG has very strong circum-

scribed access to the NRA, and that the NRA, in turn,

has strong direct access to specifically those motoneur-

ons that determine the subglottic, thoracic, abdominal,

and pelvic pressure (Holstege, 1989). A few years later

these findings were confirmed physiologically (Zhang

et al., 1992, 1994, 1995). Remarkably, this was not

accepted by some study groups, which proposed vari-

ous ideas in order to negate the NRA to be a crucial

cell group for generating vocalization. For example,

regarding the projections of the NRA to the intercostal

and abdominal muscle motoneurons it was claimed that

the majority of the NRA neurons “is connected with the

motoneurons indirectly via spinal interneurons in layers

V-VIII” (J€urgens, 2002). However, as demonstrated in

Figures 6 and 7, these projections are direct and do

not access the motoneurons via spinal premotor inter-

neurons. Moreover, electron microscopic studies con-

firmed that these projections were direct and revealed

that they were excitatory (Vanderhorst et al., 2000a;

Boers et al., 2006). Another remarkable statement was

that the neurons around the NRA receive the same

input from the PAG as the NRA itself (J€urgens, 2002).

As demonstrated in Figure 10 of this review, the PAG

projections to the NRA are very strong and specific.

Only a limited number of PAG fibers terminated in the

surroundings of the NRA and most of these fibers were

fibers of passage on their way to the spinal cord (Mou-

ton and Holstege, 1994).

Another idea was that the NRA is not directly

involved in the vocal pattern-generating process, but

that it would modulate “different pattern generators” by

NRA-projections to these vocal pattern generators

(Hage, 2010). Apart from the fact that the location of

these vocal pattern generators is not precisely known,

Figure 7 of this review shows that NRA neurons project

to motoneurons exclusively (Holstege, 1989; Boers

et al., 2005), and not to other premotor interneurons

possibly involved in generating vocalization. Only some

feedback projections from the NRA to the PAG also

originate in the NRA itself (Klop et al., 2002).

In several review articles, the NRA is replaced by the

term “reticular formation.” In all likelihood, by “reticular



formation” is meant the caudal pontine and medullary

lateral tegmental field, the rostral extension of the spi-

nal intermediate zone (Fig. 5, right). Different parts of

this lateral tegmental field have different functions (Hol-

stege et al., 1983; Cowie and Holstege, 1992), related

to the movements of the muscles innervated by the

motoneurons in the motor trigeminal, facial, ambiguus,

and hypoglossal nuclei. Examples are mouth-closing

and -opening, chewing, facial expression, and swallow-

ing. Vocalization and speech are also examples. How-

ever, they can only be generated when the activation of

these brainstem motoneurons is combined with activa-

tion of the motoneurons controlling the pressure in the

abdominal cavity that produce the airflow necessary for

generating vocalization and speech. The only premotor

cell group that has specific access to these abdominal

pressure motoneurons is the NRA.

In conclusion, generation of vocalization requires

direct and specific control of the laryngeal and abdomi-

nal pressure. The only neuronal cell group that

Figure 14. Summary figure of the pathways involved in the generation of speech. On the left the pathways belonging to the emotional

motor system, on the right the pathways belonging to the volitional or somatic motor system.



maintains direct and specific connections with all the

motoneurons involved in determining abdominal and

laryngeal pressure is the NRA. Generating vocalization

and/or speech requires access to this cell group.

CONFLICT OF INTEREST

Neither author has any conflict of interest, including

any financial, personal, or other relationships with other

people or organizations.

ROLE OF AUTHORS

Both authors had full access to all the data in the

study and take responsibility for the integrity of the

data and the accuracy of the data analysis. Study con-

cept and design: Gert Holstege. Acquisition of data:

Gert Holstege and Hari H. Subramanian. Drafting of the

article: Gert Holstege. Critical revision of the article for

important intellectual content: Hari H. Subramanian.

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Two Different Motor Systems are Needed to Generate Human Speech

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