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Behavioural Brain Research 92 (1998) 119125

The central nervous system control of micturition in cats and humans


Bertil F.M. Blok *, Gert Holstege
Department of Anatomy and Embryology, Faculty of Medical Sciences, Uni6ersity of Groningen, Oostersingel 69,
9713 EZ Groningen, The Netherlands
Abstract
Recent ndings concerning the central control of micturition in cats are compared to ndings obtained from dynamic imaging
studies in humans. In the cat, three areas in the brainstem and diencephalon are specically implicated in the control of
micturition: (1) Barringtons nucleus or the pontine micturition center in the dorsomedial pontine tegmentum directly excites
bladder motoneurons and indirectly inhibits, via inhibitory interneurons in the medial sacral cord, urethral sphincter motoneu-
rons; (2) the periaqueductal grey receiving bladder lling information; and (3) the pre-optic area of the hypothalamus possibly
involved in determining the beginning of micturition. According to PET-scan studies, in humans the same supraspinal regions are
active during micturition. In the cat another area, located in the ventrolateral pontine tegmentum and is called the L-region, which
controls the motoneurons of the pelvic oor, including the external urethral sphincter. This region might be considered as the
pontine storage center. In humans the L-region is especially active in volunteers who tried but did not succeed to micturate. The
results suggest that in cats and humans at the brainstem and diencephalic levels micturition is organized in the same way. 1998
Elsevier Science B.V. All rights reserved.
Keywords: Pontine micturition center; Periaqueductal grey; Hypothalamus; Urge incontinence
1. Introduction
The kidneys produce urine continuously, which, for
practical reasons, is rst collected in the bladder where
it is stored until disposal is possible. Since the individ-
ual animal is relatively vulnerable during the release of
urine, micturition only takes place when the environ-
ment is relatively safe. Furthermore, in many animals
urine is used as a marker for territorial demarcation or
sexual attraction (a female lets the males know that she
is in estrus by leaving a scent trace). Thus, micturition
does not take place at random, but is part of a rather
complicated behavior, directly related to the survival of
the individual or species. This means that spinal cord
micturition control must be under the emotional motor
system regulation [5,16]. This paper will discuss the
bladder and bladder sphincter regulation by the sacral
cord and will give an overview of how the sacral cord
centers are regulated by emotional motor system cen-
ters in the brainstem, diencephalon and cortex. Micturi-
tion depends on the co-ordinated action between the
smooth (detrusor) muscle of the bladder and the stri-
ated external urethral sphincter (EUS), which closes the
bladder. During the storage of urine, the detrusor mus-
cle remains relaxed and the EUS is tonically contracted.
When micturition takes place, this activation pattern is
reversed: the EUS relaxes and the bladder contracts,
resulting in the expulsion of urine.
The motoneurons of both bladder and EUS are
located in the sacral spinal cord. However, the co-ordi-
nation between these two motoneuronal cell groups in
adult animals seems not to take place in the spinal
cord, but in the pontine tegmentum in the brainstem.
Interruption of the descending bers from the pons to
the sacral cord, e.g. in patients with a transection of the
spinal cord, results in dyssynergic micturition. In such
patients the contraction of the bladder is accompanied
Abbre6iations: PAG, periaqueductal grey; PET, positron emission
tomography; PMC, pontine micturition center; rCBF, regional cere-
bral blood ow.
* Corresponding author. Tel.: +31 50 3632460; fax: +31 50
3632461; e-mail: b.f.m.blok@med.rug.nl
0166-4328/98/$19.00 1998 Elsevier Science B.V. All rights reserved.
PII S0166-4328(97)00184-8
B.F.M. Blok, G. Holstege / Beha6ioural Brain Research 92 (1998) 119125 120
Fig. 1. Schematic drawing of the location of the nucleus of Onuf in various mammals. Note the motoneurons in the rat innervating the external
urethral (U) and anal (A) sphincters are located at different sites in the ventral horn, while they are present in the same nucleus in cat, dog,
monkey and man. In the pig the anal sphincter motoneurons are not located in the ventral horn but dorsolateral from the central canal. The
species and the spinal segments, in which the nucleus of Onuf is present, are indicated below the drawings.
by the simultaneous contraction of the sphincter. This
means that, in order to expel urine through the toni-
cally closed urethral sphincter, the bladder has to pro-
duce an extremely high intravesical pressure. The result
is a thick bladder wall and a small bladder capacity, the
so-called overow bladder. Patients with brain lesions
rostral to the pons never show bladder-sphincter
dyssynergia. However, such patients might suffer from
urge incontinence, i.e. hyperactivity of the bladder and
an inability to delay voiding.
Apparently, centres in the pons co-ordinate micturi-
tion as such, but centers rostral to the pons determine
the beginning of micturition act.
2. Efferent systems
2.1. Micturition motoneurons
The smooth detrusor muscle of the bladder is inner-
vated by parasympathetic postganglionic bers, of
which the ganglion cells are located in the bladder wall.
The parasympathetic preganglionic motoneurons reside
in the sacral intermediolateral cell group in the sacral
cord segments and their axons reach the bladder via the
pelvic nerve. In cats the parasympathetic preganglionic
motoneurons are located in the S
1
S
3
segments [28],
and in humans in S
2
S
4
[25].
The striated EUS forms part of the pelvic oor
musculature, and is innervated by the pudendal nerve.
In the cat its motoneurons are located in the ventrolat-
eral part of the so-called nucleus of Onuf in the ventral
horn at the level S
1
S
2
of the spinal cord [36]. The
dorsomedial part of Onufs nucleus is occupied by
motoneurons innervating the external anal sphincter
(EAS). The same situation exists in the dog, monkey
and human, where the motoneurons of the anal and
urethral sphincters are also located in Onufs nucleus
([24,32,35,40]; Fig. 1). However, in the rat the motoneu-
rons of the anal and urethral sphincters are located in
two separate nuclei, the dorsolateral and the dorsome-
dial nucleus, respectively, at the levels L
5
L
6
[21,27,37].
Remarkably, the motoneurons of the EAS in the do-
mestic pig [9] and the Mongolian gerbil [41] are not
located in the ventral horn, but in the intermediate zone
just dorsolateral to the central canal (Fig. 1).
2.2. Brainstem-spinal cord pathways co-ordinate
bladder and sphincter motoneurons
In young kittens De Groat et al. [10] demonstrated
that the sacral cord in itself is capable of producing a
micturition reex, but it needs to be elicited by the
mother licking the perineum of the kittens. This behav-
ior stops after approximately 4 weeks post partum,
after which the supraspinal centers play an essential
role.
From the work of Barrington [2] it is known that a
crucial structure of the micturition reex is located in
dorsolateral pontine tegmentum, because bilateral le-
sions in this area in the cat results in urinary retention.
In the cat two different pontine projection systems have
been identied ([17,18]; Fig. 2). A group of neurons in
the medial part of the dorsolateral pons projects to the
parasympathetic bladder motoneurons in the sacral in-
termediolateral cell column. Neurons in the lateral part
of the dorsolateral pons specically project to the nu-
cleus of Onuf. The medial cell group was called M-re-
gion (M=medial), and the lateral cell group L-region
(L=lateral). The M-region is also called the pontine
micturition center or PMC or Barringtons nucleus.
Ultrastructurally, Blok and Holstege [6] have demon-
strated that the projection from the PMC to the blad-
der parasympathetic motoneurons in the sacral cord is
monosynaptic and excitatory.
B.F.M. Blok, G. Holstege / Beha6ioural Brain Research 92 (1998) 119125 121
Fig. 2. A schematic overview of the spinal and supraspinal structures involved in the efferent control of micturition. The solid lines represent
excitatory projections; the dashed line from sacral inhibitory interneurons to the nucleus of Onuf represents an inhibitory pathway. Pathways are
indicated on one side only. Abbreviations: BC, brachium conjunctivum; CA, anterior commissure; IC, inferior colliculus; OC, optic chiasm; PON,
pontine nuclei; SC, superior colliculus; S2, second sacral segment.
In accordance with these ndings, electric and chemi-
cal stimulation in the PMC in the cat produces a steep
rise in the intravesical pressure [17,26], it also produces
an immediate and sharp decrease in the urethral pres-
sure and pelvic oor electromyogram. This decrease
cannot be caused by a direct PMC projection to the
nucleus of Onuf, because such a projection does not
exist [17,18], and the PMC does not project to the
L-region (Blok and Holstege, unpublished observa-
tions). In this respect, the PMC projection to interneu-
rons in the sacral intermediomedial cell column [17,26]
might play a crucial role. Retrograde tracing studies
with the pseudorabies virus have shown that this area
contains interneurons projecting to the nucleus of Onuf
[30] and electrical stimulation in the intermediomedial
cell column results in an inhibition of the EUS via
GABAergic interneurons in the IMM (Blok and Hol-
stege, unpublished observations).
Bilateral lesions in the PMC result in total urinary
retention leading to depressed detrusor activity and
increased bladder capacity [14,17]. Unilateral chemical
lesions of the PMC attenuate the bladder response [26].
Stimulation in the L-region results in strong excitation
of the pelvic oor musculature and an increase in the
urethral pressure [17]. Bilateral lesions in the L-region
give rise to an inability to store urine; bladder capacity
is reduced and urine is expelled prematurely by exces-
sive detrusor activity accompanied by urethral relax-
ation. Outside the episodes of detrusor activity, the
urethral pressure is not depressed below normal values
B.F.M. Blok, G. Holstege / Beha6ioural Brain Research 92 (1998) 119125 122
Fig. 3. Horizontal sections showing brain areas where activity showed a signicant positive correlation with micturition. Functional PET results
are displayed at threshold of Z=2.58 (PB0.005), superimposed for anatomical reference, upon a T1-weighted magnetic resonance imaging scan
normalized into stereotactic space. Section numbers refer to the coordinates relative to the intercommissural plane. (a) M-region or pontine
micturition center; (b) periaqueductal grey; (c) hypothalamus; (d) inferior frontal gyrus; and (e) anterior cingulate gyrus. L, left side; and R, right
side of the brain.
Fig. 4. Horizontal sections showing brain areas where activity showed a signicant positive correlation with the condition during which the
volunteers were trying to micturate, but did not succeed. (a) L-region or pontine storage center; and (b) inferior frontal gyrus. L, left side; R, right
side of the brain.
[26]. These observations suggest that during the lling
phase the L-region has a continuous excitatory effect
on the nucleus of Onuf resulting in inhibition of ure-
thral relaxation coupled with detrusor contraction. Re-
cently, a positron emission tomography (PET) study
has provided evidence that there also exists a PMC and
a L-region in humans [7]. A group of ten right handed
male volunteers were able to micturate during scanning.
In this group an increase in regional blood ow during
micturition was found in the dorsomedial part of the
pons close to the fourth ventricle (Fig. 3). The location
of this area in humans is similar to that of the PMC
described in the cat. In the same PET study there was
a second group of seven right handed volunteers, who
were not able to micturate during scanning. In this
group there was no activation in the dorsomedial, but
in the ventrolateral pons, as predicted on the basis of
the location of the L-region in cats (Fig. 4). Apparently,
B.F.M. Blok, G. Holstege / Beha6ioural Brain Research 92 (1998) 119125 123
the volunteers in this not successful micturition group,
probably because of emotional reasons, contracted
their urethral sphincter and withheld their urine, al-
though they had a full bladder and tried to urinate.
3. Afferent systems
3.1. Peripheral afferent ner6es
Most afferent bers from the bladder enter the
sacral cord via the pelvic nerve. The peripheral bers
of the dorsal root ganglia neurons of the pelvic nerve
contact the bladder wall mechanoreceptors. The prox-
imal bers enter Lissauers tract and terminate mainly
in Rexeds [34] laminae I, V, VII and X of the lum-
bosacral spinal cord at segments L
4
S
2
[29] in the cat.
The majority of these afferents are thin myelinated
and unmyelinated axons, and their conduction veloc-
ities are in the Al- and C-ber range, respectively
[19]. Most Al-bers originate from slowly adapting
mechanoreceptors in the bladder wall, because excita-
tion of these bers results in activation of the micturi-
tion reex. In all likelihood, the Al-bers are the
peripheral afferent bers for this reex [11,26], be-
cause the unmyelinated C-bers in the pelvic nerve do
not respond to distension and contraction of the uri-
nary bladder [20].
3.2. Spinal cord-brainstem pathways in6ol6ed in the
micturition reex
Obviously, bladder lling information from sensory
neurons in the sacral cord must nally reach the
PMC in order to empty the bladder at an appropriate
time. However, Blok et al. [8] have demonstrated that
the lumbosacral cord does not project strongly to
PMC neurons. This raises the question, what other
area relays bladder lling information to the PMC.
The micturition reex is not abolished by precollicular
decerebration [39], which means that lumbosacral pro-
jections to forebrain areas, as thalamus and hypotha-
lamus, are not essential for this reex. However, the
very strong projections from the lumbosacral cord to
the lateral and dorsal parts of the mesencephalic peri-
aqueductal grey (PAG) probably play a much more
important role ([8]; Fig. 5). The lateral PAG is the
only caudal brainstem structure known to project spe-
cically to the PMC ([4]; Fig. 5). Moreover, stimula-
tion of afferent bladder nerves in the rat evokes short
latency potentials (1393 ms) in the most caudal
PAG, while much longer latency potentials (4297
ms) are found in the PMC [31]. In the cat electrical
stimulation of the PAG has been shown to evoke
complete micturition ([38]; Blok, personal observa-
tion), facilitate bladder reexes, and reduce bladder
capacity [22]. The PAG has also been implicated in
the control of micturition in humans, because in the
previously discussed PET study the regional cerebral
blood ow (rCBF) in the PAG was signicantly in-
creased during micturition ([7]; Fig. 3).
4. Forebrain involvement in the control of micturition
Although, the forebrain is not essential for the ba-
sic micturition reex (see previous paragraph), clinical
observations suggest that it determines the beginning
of micturition [3]. In the cat, stimulation of forebrain
structures, such as the anterior cingulate gyrus, pre-
optic area of the hypothalamus, amygdala, bed nu-
cleus of the strict terminalis and septal nuclei, elicits
bladder contractions [12,13]. Although most of these
regions send bers to the brainstem [16], only the
pre-optic area projects to the PMC [15]. Our PET
study suggests that this might also be true in humans,
because the hypothalamus, including the pre-optic
area, showed an increased rCBF during micturition
([7]; Fig. 3). The direct projection of the pre-optic
area to the PMC is the tool needed by the emotional
motor system to control the PMC and thus to deter-
mine the beginning of micturition. The emotional mo-
tor system uses this tool for giving a safe signal to
the PMC to start micturition, but also to use micturi-
tion for sexual behavior and territorial marking.
5. Cortex
The human PET scan results of Blok et al. [7] point
to two cortical areas involved in micturition. The
right dorsolateral prefrontal cortex is active when mic-
turition takes place (Fig. 3), but also when micturition
is allowed but does not take place (Fig. 4). The rCBF
in the right anterior cingulate gyrus was signicantly
decreased during the voluntary withholding of urine.
Possibly, activation of the prefrontal cortex and the
anterior cingulate gyrus are not specically involved
in micturition, but in general mechanisms, such as
attention and response selection [33]. Forebrain le-
sions including the anterior cingulate gyrus are known
to cause urge incontinence [1], which might be due to
an attention decit that interferes with the patients
ability to recognize a lled bladder.
A striking observation of the PET study on mictu-
rition of Blok et al. [7] was that the control areas
were found predominantly on the right side of the
brain and the brainstem (cortex and pons), which cor-
responds with studies reporting that urge incontinence
is correlated with lesions in the right hemisphere [23].
B.F.M. Blok, G. Holstege / Beha6ioural Brain Research 92 (1998) 119125 124
Fig. 5. A schematic overview of the spinal and supraspinal structures involved in the afferent information concerning bladder lling. Pathways
are indicated on one side only. For abbreviations see Fig. 2.
6. Conclusions
The organization of the central nervous system con-
trol of the basic micturition reex is probably the
same in humans and cats. Several levels of the central
nervous system (CNS) are involved in the control of
micturition. Sensory information concerning bladder
lling is relayed, via the pelvic nerve and dorsal root
ganglion cells, to the sacral cord, where second order
sensory neurons are located. These neurons convey
the information to the caudal PAG where it is pro-
cessed and ltered. When the amount of urine in the
bladder makes voiding desirable, PAG neurons acti-
vate the premotor interneurons in the M-region,
which, via long descending bers to the bladder mo-
toneurons in the sacral cord, let micturition take
place. The direct projection from the pre-optic area to
the M-region may determine the beginning of micturi-
tion.
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