Brain (2000), 123, 1767–1783

REVIEW ARTICLE
The pedunculopontine nucleus and Parkinson’s
disease
Peter A. Pahapill and Andres M. Lozano

Department of Surgery, University of Toronto, Division of Correspondence to: Dr A. M. Lozano, The Toronto Western
Neurosurgery, The Toronto Western Hospital, Toronto, Hospital, 399 Bathurst Street, McL 2-433, Toronto,
Ontario, Canada Ontario, Canada M5T 2S8
E-mail: lozano@playfair.utoronto.ca

Summary
Akinesia and gait disturbances are particularly in-
capacitating for patients with Parkinson’s disease. The
anatomical and physiological substrates for these disturb-
ances are poorly understood. The pedunculopontine
nucleus (PPN) is thought to be involved in the initiation
and modulation of gait and other stereotyped movements,
because electrical stimulation and the application of
neuroactive substances in the PPN can elicit locomotor
activity in experimental animals. Glutamatergic neurones
of the PPNd (pars dissipatus) are thought to be important
regulators of the basal ganglia and spinal cord. The other
component of the PPN, the cholinergic pars compacta
(PPNc), is a principal component in a feedback loop from
the spinal cord and limbic system back into the basal
ganglia and thalamus. Electrophysiological studies suggest
that ‘bursting’ glutamatergic PPNd neurones are related
to the initiation of programmed movements while non-
bursting cholinergic PPNc neurones are related to the
maintenance of steady-state locomotion. Furthermore,
since patients with Parkinson’s disease have significant
loss of PPN neurones and experimental lesions in the PPN
of normal monkeys result in akinesia, the degeneration
of PPN neurones or their dysfunction may be important
in the pathophysiology of locomotor and postural
disturbances of parkinsonism. The goal of this review is (i)
to highlight the anatomical connections and physiological
attributes of the PPN, (ii) to discuss how the function of
these connections may be altered in the parkinsonian
state, and (iii) to speculate how present and potential
future therapy directed to the PPN might improve akinesia
and gait difficulties in parkinsonian patients.

Keywords: Parkinson’s disease; pedunculopontine nucleus; akinesia; gait; posture

Abbreviations: GABA ⫽ γ-aminobutyric acid; GPi ⫽ globus pallidus interna; IPSP ⫽ inhibitory postsynaptic potential;
NMDA ⫽ N-methyl-D-aspartate; PPN ⫽ pedunculopontine nucleus; PPNc ⫽ pedunculopontine nucleus, pars compacta;
PPNd ⫽ pedunculopontine nucleus, pars dissipatus; SNc ⫽ substantia nigra pars compacta; SNr ⫽ substantia nigra pars
reticulata; SP ⫽ superior cerebellar peduncle; STN ⫽ subthalamic nucleus

Introduction
Locomotion in Parkinson’s disease
Gait disturbances are major impediments for parkinsonian
patients (Murray et al., 1978; Morris et al., 1994, 1996).
Although slowness of movement (bradykinesia) may affect
all phases of gait, it is the failure of gait initiation (gait
akinesia) which can be a particularly incapacitating problem.
Gait initiation (the phase between motionless standing and
steady-state locomotion) can be divided into a movement
preparation period and a movement execution period
(Brenière and Cuong, 1991). Gait initiation involves a highly
stereotyped pattern of limb and trunk submovements with
© Oxford University Press 2000
changes in posture (Elble et al., 1994). Although a number
of kinetic studies have focused on steady-state locomotion,
studies on gait initiation in Parkinson’s disease are few. It
has been proposed that two types of difficulty can contribute
to gait akinesia in Parkinson’s disease: (i) slowed movements
and prolonged motor preparation times, leading to a delay
in the execution of an otherwise preserved sequence of
submovements (i.e. a problem in motor planning in which
the patient is unable to call up or run an already-formed
and preserved gait-initiation motor programme); and (ii) a
problem in the ability to form the normal sequence of
1768 P. A. Pahapill and A. M. Lozano
submovements that compose the initiation of normal gait
(i.e. a problem in motor programming in which there is a
loss of or an inability to form the appropriate set of
submovements or subroutines that make up the actual gait-
initiation motor programme that otherwise should be available
to be called up during motor planning) (Marsden, 1987;
Rosin et al., 1997).
Studies of steady-state locomotion in Parkinson’s disease
have supported alterations in both motor programming and
motor planning (Knutstson, 1972; Stern et al., 1983; Forssberg
et al., 1984; Dietz, 1993). Studies on gait initiation have
suggested that the problems with gait initiation in Parkinson’s
disease are due primarily to faulty motor planning that
impedes the calling up of otherwise relatively preserved gait-
initiation motor programmes (Rosin et al., 1997). Others
have demonstrated that patients may also suffer from altered
sensory feedback processing that can effectively interfere with
gait initiation (Rogers and Chan, 1988; Horak et al., 1992).
In patients with advanced Parkinson’s disease, akinesia or
‘freezing’, the failure of willed movement to occur, is often
only mildly improved by dopaminergic medication (Pullman
et al., 1988; Starkstein et al., 1989) or unilateral surgical
intervention (Lang et al., 1997; Lozano and Lang, 1998).
The pathological substrates of gait and postural disturbances
in parkinsonism are poorly understood, but recent
observations suggest that dysfunction of the pedunculopontine
nucleus (PPN) may be important.
The upper brainstem contains neurones which control
axial and proximal limb musculature for gait through their
projections to the lower brainstem and spinal cord via
bilateral, midline, descending pathways. These brainstem
nuclei are, in turn, under the influence of descending inputs
from basal ganglia nuclei [globus pallidus interna (GPi);
subthalamic nucleus (STN); substantia nigra pars reticulata
(SNr)]. Because the function of these basal ganglia structures
is markedly disrupted in parkinsonism, the brainstem motor
areas to which they project and which they control may
also be dysfunctional. Hence, interventions which block the
abnormal activity of the basal ganglia in parkinsonism,
including surgical lesions and high-frequency stimulation of
basal ganglia targets, are potential ways of restoring the
normal function of the brainstem centres which control
locomotion. Recent attention to the brainstem areas involved
in the control of locomotion has focused on the PPN.
Although considerable animal data are available, little is
known of the function of this nucleus in humans or to what
extent observations in experimental animals are relevant to
humans. Furthermore, studies on the anatomical connections
 The pedunculopontine nucleus and Parkinson’s disease 1769

and physiology of the PPN are often incomplete, and are
difficult to interpret because of methodological limitations,
which often produce controversial and even contradictory
interpretations. Despite these difficulties, which are some-
times serious, there is a large body of evidence supporting
the role of the PPN in locomotion. The involvement of the
PPN in human locomotion is supported by the observation
of Masdeu and colleagues, who described the inability of a
patient to stand and to generate stepping after a haemorrhage
into the tegmentum of the posterior midbrain (Masdeu et al.,

Fig. 1 Axial sections through the brainstem showing cellular architecture (left) and tracts (right) at (A) intercollicular level (rostral extent
of PPN) and (B) inferior collicular level (caudal extent of PPN). The PPNd is labelled 8 in A and the PPNc is labelled 9 in B.
(A) Intercollicular level (rostral extent of PPN). 1 ⫽ nucleus intercollicularis; 2 ⫽ griseum centrale mesencephali; 3 ⫽ nucleus
paralemniscalis; 4 ⫽ nucleus centralis colliculi inferioris; 5 ⫽ nucleus mesencephalicus nervi trigemini; 6 ⫽ nucleus nervi trochlearis;
7 ⫽ nucleus cuneiformis; 8 ⫽ nucleus tegmentalis pedunculopontinus, pars dissipata (PPNd); 9 ⫽ substantia nigra, pars compacta; 10 ⫽
nucleus interpeduncularis; 11 ⫽ nucleus pontis; 12 ⫽ commissura colliculi inferioris; 13 ⫽ brachium colliculi inferioris; 14 ⫽ fasciculus
longitudinalis dorsalis; 15 ⫽ tractus mesencephalicus nervi trigemini; 16 ⫽ fasciculus anterolateralis; 17 ⫽ tractus tectospinalis; 18 ⫽
tractus trigeminothalamicus dorsalis; 19 ⫽ nervus trochlearis; 20 ⫽ fasciculus longitudinalis medialis; 21 ⫽ tractus tegmentalis centralis;
22 ⫽ lemniscus medialis; 23 ⫽ pedunculus cerebellaris superior; 24 ⫽ decussatio pedunculorum cerebellarium superiorum; 25 ⫽
pedunculus mamillaris; 26 ⫽ tractus parietotemporopontinus; 27 ⫽ tractus pyramidalis; 28 ⫽ tractus frontopontinus; 29 ⫽ fibrae
pontocerebellares. (B) Inferior collicular level (caudal extent of PPN). 1 ⫽ nucleus intercollicularis; 2 ⫽ colliculus inferior, nucleus
centralis; 3 ⫽ colliculus inferior, zona lateralis; 4 ⫽ griseum centrale mesencephali; 5 ⫽ locus coeruleus; 6 ⫽ nucleus mesencephalicus
nervi trigemini; 7 ⫽ nucleus cuneiformis; 8 ⫽ corpus parabigeminum; 9 ⫽ nucleus tegmentalis pedunculopontinus, pars compacta
(PPNc); 10 ⫽ nucleus centralis superior; 11 ⫽ substantia nigra, pars compacta; 12 ⫽ nucleus interpeduncularis; 13 ⫽ nuclei pontis;
14 ⫽ commissura colliculi inferioris; 15 ⫽ fasciculus longitudinalis dorsalis; 16 ⫽ nervus trochlearis; 17 ⫽ tractus mesencephalicus
nervi trigemini; 18 ⫽ lemniscus lateralis; 19 ⫽ tractus tectopontinus; 20 ⫽ fasciculus anterolateralis; 21 ⫽ fasciculus longitudinalis
medialis; 22 ⫽ tractus tegmentalis centralis; 23 ⫽ lemniscus medialis; 24 ⫽ pedunculus cerebellaris superior; 25 ⫽ decussatio
pedunculorum cerebellarium superiorum; 26 ⫽ fibrae corticotegmentales; 27 ⫽ pedunculus mamillaris; 28 ⫽ fibrae pontocerebellares;
29 ⫽ tractus parietotemporopontinus; 30 ⫽ tractus pyramidalis; 31 ⫽ tractus frontopontinus. From Nieuwenhuys et al. (1998), with
permission.
1770 P. A. Pahapill and A. M. Lozano

1994). Although they emphasized damage to the PPN as a tegmental region containing the PPN. However, because of
probable cause, the damage appeared to extend beyond the its neurochemical heterogeneity and close apposition to
boundaries of the PPN. several other functionally distinct regions and fibre tracts, it
has been difficult to determine precisely which afferents
actually terminate in the PPN and, of these, which terminate
Anatomy of the PPN on cholinergic versus non-cholinergic PPN neurones. Very
The PPN consists of a neurochemically and morphologically
little is known about the inputs and outputs of the human PPN.
heterogeneous population of neurones. In the human brain,
Afferents from the GPi and the SNr are the most widely
the PPN is bounded on its lateral side by fibres of the medial
studied and established connections to the primate PPN
lemniscus and on its medial side by fibres of the superior
(Shink et al., 1997). Pallidal efferent pathways to the PPN
cerebellar peduncle and its decussation (Olszewski and
and midbrain tegmentum descend along the pallidotegmental
Baxter, 1982; Geula et al., 1993) (Fig. 1). Rostrally, the
tract, which runs dorsomedially from the globus pallidus,
anterior aspect of the PPN contacts the dorsomedial aspect
past the subthalamic nucleus and into the midbrain tegmentum
of the posterolateral substantia nigra, while the retrorubral
near the ventrolateral border of the red nucleus. Recent
field borders it dorsally. The most dorsal aspect of the
anatomical studies on humans and other primates have shown
PPN is bounded caudally by the pontine cuneiform and
that the pallidal projections appear to terminate preferentially
subcuneiform nuclei and ventrally by the pontine reticular
on the non-cholinergic cells of the PPNd and largely avoid
formation. The most caudal pole of the PPN is adjacent to
the cholinergic neurones of the PPNc and PPNd (Rye et al.,
neurones of the locus coeruleus.
1995b; Shink et al., 1997). Projections from the SNr also
Two subdivisions of the PPN have been recognized on the
appear to terminate mainly but not exclusively on the non-
basis of cell density. The pars compacta of the PPN (PPNc)
cholinergic cells of the PPNd in rats (Kang and Kitai, 1990;
is located within the caudal half of the nucleus in its
Spann and Grofova, 1991). This has not been shown in
dorsolateral aspect. Cells of the subnucleus pars dissipatus
primates. It is also not known to what extent GPi and SNr
(PPNd) are distributed sparsely within the superior cerebellar
inputs are segregated to separate territories within the PPN
peduncle and central tegmental tract. The pars compacta and
or converge onto the same PPNd neurones. The pallidal and
dissipatus have been described in humans, monkeys and
SNr projections to the PPN are GABAergic (Noda and Oka,
subprimates (Mesulam et al., 1983; Geula et al., 1993; Lavoie
1986; Granata and Kitai, 1991). Studies have shown that
and Parent, 1994a). The number of cholinergic neurones
⬎80% of GPi neurones send axon collaterals to both the
within the PPN in humans has been estimated at between
ventrolateral nucleus of the thalamus and the PPN in monkeys
10 000 and 15 000 (Garcia-Rill et al., 1995, 1996).
(Harnois and Filion, 1982). Indeed, the axonal branch of GPi
Cholinergic PPNc neurones are clustered along the
neurones projecting to the PPN in non-human primates is of
dorsolateral border of the superior cerebellar peduncle (SP)
larger diameter than the thalamic branch (A. Parent, personal
at trochlear nucleus levels, whereas those in the PPNd are
communication). This suggests that the PPN may be the
scattered along the SP from midmesencephalic to midpontine
principal target of pallidal outflow. This collateralization has
levels. In the human brainstem, the cholinergic neuronal
not been shown for SNr inputs to the PPN.
population of the PPN (Ch5) constitutes ⬎90% of the
Glutamatergic inputs to PPN from the STN have been
neuronal population of the PPNc, and 25–75% in the PPNd
described in rats (Hammond et al., 1983; Jackson and
(Mesulam et al., 1989).
Crossman, 1983; Kita and Kitai, 1987; Granata and Kitai,
The second prominent neuronal population contained
1989; Steininger et al., 1992), but not in primates. The
within the traditional boundary of the PPNd is glutamatergic
different subpopulations of rat PPN neurones that serve as
(Lavoie and Parent, 1994a; Rye et al., 1995b, 1996). Lavoie
targets for the STN inputs have not been established.
and Parent found that, at the brainstem level of the trochlear
Similarly, the nucleus accumbens provides significant inputs
nucleus, ~40% of monkey PPN cells express cholinergic and
to the rat PPN (Groenewegen et al., 1993). However, very
glutamatergic immunoreactivity (Lavoie and Parent, 1994a).
little is known about the nature of this connection in primates.
Additional neuronal types contained within the traditional
Inputs from the cervical and lumbar segments of the spinal
boundary of the non-human PPN include a dopaminergic
cord to the area of the PPN have been shown in the rat
population (Rye et al., 1987), a noradrenergic group and a
(Grunwerg et al., 1992) and cat (Hylden et al., 1985), but
small group of GABAergic interneurones (Jones, 1991).
not in primates. These studies have suggested that cholinergic
Despite numerous studies, however, there has been no
PPN neurones act as a relay station for spinal cord sensory
consensus regarding the average number of PPNc or PPNd
afferents to the thalamus. The neurotransmitter system
neurones or the breakdown of cell types in the PPNd found
involved in this spinal input is unknown. The major putative
in humans or other species.
inputs to the PPN from the basal ganglia and related structures
the primate are summarized in Fig. 2.
Inputs to the PPN A number of other putative afferents to the PPN in rats
Anatomical and electrophysiological studies on non-humans and cats (but not primates) have been proposed (but not
have identified many putative afferents to the mesopontine firmly established because of non-specific uptake of tracers
 The pedunculopontine nucleus and Parkinson’s disease
Fig. 2 The major proposed inputs to the primate PPN from the
basal ganglia and related structures (see text for details):
glutamatergic input from the STN; GABAergic input from the
GPi; GABAergic input from the SNr; glutamatergic input from
the cerebral cortex; and sensory inputs from the spinal cord.
The STN, GPi and SNr inputs are predominantly to the
glutamatergic neurones of the PPNd. Spinal inputs are
primarily to the cholinergic neurones of PPNc. Glu ⫽
glutamate; Ach ⫽ acetylcholine.
from surrounding midbrain structures) to arise from areas
within the limbic system (amygdala, hypothalamus, zona
incerta) and the ascending reticular activating system (raphe
nuclei, locus coeruleus, laterodorsal tegmental nucleus,
contralateral PPN), as well as from premotor and
supplementary motor cortical areas (Monakow et al.,
1979; Edley and Graybiel, 1983), the subtantia nigra pars
compacta (SNc) and the caudate, putamen, superior colliculus,
basal forebrain and deep cerebellar nuclei. This work and
the methods used have been reviewed recently (Reese et al.,
1995; Winn et al., 1997). The significance of these projections
is not understood.
Outputs from the PPN
Most information regarding PPN outputs comes from non-
primate studies. The outputs of the PPN (Fig. 3) can be
divided into descending and ascending components, with
cholinergic and non-cholinergic neurones contributing to
both. Although some PPN neurones have specific ascending
projections and others specific descending projections, some
collateralize and project in both directions (Rye et al., 1987;
Spann and Grofova, 1991). The ascending projections of
the PPN are much more prominent than the descending
projections, although there is no consensus about their relative
proportions or which subpopulations of PPN neurones
(cholinergic versus non-cholinergic or PPNc versus PPNd)
contribute to the various output pathways. Furthermore, it
has been estimated that ~40% of monkey PPN neurones
project contralaterally to their basal ganglia targets (Lavoie
1771
Fig. 3 The major proposed projections from the primate PPN
to the basal ganglia and related structures (see text for details):
projections to the STN, Gpi, SNc, cerebral cortex, caudate/
putamen, thalamus, spinal cord and brainstem. Projections to
the spinal cord are primarily from PPNd glutamatergic
neurones. Projections to the thalamus and brainstem are
primarily from cholinergic PPN neurones. Abbreviations as in
Fig. 2.
and Parent, 1994b); the percentage has not been established
for each individual basal ganglia target.
Ascending projections
Ascending PPN outputs project via the dorsal and ventral
tegmental bundles, the dorsal tegmental pathway carrying
the major cholinergic projection (Garcia-Rill, 1991). The
majority of ascending cholinergic PPN neurones are thought
to project to all thalamic nuclei in the rat (Hallanger et al.,
1987; Rye et al., 1987), cat (Steriade et al., 1988) and
monkey (Lavoie and Parent, 1994b), but especially to the
associative and non-specific midline thalamic nuclei. In the
rat it has been estimated that 60% of cholinergic PPN
neurones project to the thalamus and that 90% of PPN inputs
to the thalamus are cholinergic (Sofroniew et al., 1985).
Similar quantitative data are not available for primates.
Ascending projections also provide dense innervation to
the non-thalamic basal ganglia structures via the ventral
tegmental bundle (Lavoie and Parent, 1994a, b, c). Neurones
located in the core of the PPN (presumably PPNc neurones,
although this is not clearly stated by Lavoie and Parent) are
those that provide the most dense innervation of the basal
ganglia. Labelling with anterograde tracers has shown that
the SNc and the STN are by far the most densely innervated
structures of the basal ganglia. PPN efferents reach their
target sites in the basal ganglia by ascending along the
1772 P. A. Pahapill and A. M. Lozano
lenticular fasciculus and ansa lenticularis, which are
the major output projection paths of the GPi.
Substantia nigra (SN). The PPN sends cholinergic
projections to the dopamine-containing neurones of the SNc
with a minor cholinergic contingent to the SNr in the rat
(Woolf and Butcher, 1986; Scarnati et al., 1988). Recently,
it has been shown that PPN cholinergic and glutamatergic
neurones form synaptic contacts with dopaminergic neurones
in the SNc in non-human primates and rats (Charara et al.,
1996; Takakusaki et al., 1996). There are also studies which
suggest that single PPN terminals in contact with SNc
dopaminergic neurones may contain both glutamate and
acetylcholine (Lavoie and Parent, 1994c; Charara et al.,
1996). In the anaesthetized rat, electrical stimulation of PPN
neurones leads to excitation of SNc neurones via a short-
latency, direct, excitatory PPN–substantia nigra pathway and
a less marked and rather sparse activation via a short
polysynaptic pathway (Scarnati et al., 1984, 1986, 1987),
probably involving non-cholinergic PPN neurones (Scarnati
et al., 1986; Di Loreto et al., 1992). The proportion of PPN
neurones projecting to the substantia nigra is ~40% in the
rat and only 25% in the monkey (Gould et al., 1989; Lavoie
and Parent, 1994c). The relative proportions of PPN outflow
to the SNc versus the SNr and the subpopulations of
PPN neurones giving rise to this projection have not been
determined. The PPN may also be a source of GABAergic
afferents to the SNc in primates (Charara et al., 1996).
Subthalamic nucleus (STN). The existence of a bilateral
projection from the PPN to the STN has been documented
in a number of species, including the rat (Woolf and Butcher,
1986), cat (Edley and Graybiel, 1983) and monkey (Lavoie
and Parent, 1994b). These studies fall short of assessing
the anatomical (PPNd versus PPNc) and neurochemical
(cholinergic versus non-cholinergic) nature of this pathway,
although in the rat these have shown to be both cholinergic
(Woolf and Butcher, 1986) or non-cholinergic (Lee et al.,
1988) and excitatory (Hammond et al., 1983). Other studies
in the rat suggest that PPN efferents to the STN and adjacent
zona incerta are collaterals of PPN efferents to the pallidal
complex (Hammond et al., 1983; Hallanger and Wainer,
1988).
Globus pallidus (GP). In the monkey, the PPN
innervation of the pallidal complex is less dense than that of
the STN and substantia nigra. Pedunculopallidal fibres travel
back along both the ansa lenticularis and lenticular fasciculus
and arborize more profusely in the monkey GPi than the
globus pallidus externa (Lavoie and Parent, 1994b), as has
been shown in the rat and cat. The neurotransmitter used by
pedunculopallidal neurones has not yet been identified with
certainty. In the human brain, the GP receives cholinergic
innervation, the majority of which is thought to originate
from brainstem cholinergic nuclei (Mesulam et al., 1983),
but specific cholinergic innervation from PPN neurones has
not been shown. Although excitatory responses after PPN
stimulation were found in cat pallidal neurones (Gonya-
Magee and Anderson, 1983), it was not clear which
populations of PPN neurones were stimulated or which
populations of pallidal neurones were activated.
Striatum. A pedunculostriatal projection has been shown
in the monkey (Lavoie and Parent, 1994b). These PPN fibres
are poorly arborized in most of the caudate nucleus and
putamen. The chemical nature of this projection is unknown.
Other ascending targets. Other ascending targets thought
to exist in non-primate species include the superior colliculus
and a number of limbic structures (basal forebrain,
hypothalamus, zona incerta, amygdala). These ascending
connections have been reviewed recently (Inglis and Winn,
1995; Reese et al., 1995; Winn et al., 1997).
Descending projections
Although studied predominantly in non-primates, descending
targets include several midbrain, pontine and medullary areas
including several nuclei of the reticular formation, the deep
cerebellar nuclei and the spinal cord (reviewed by Inglis and
Winn, 1995; Reese et al., 1995). These descending projections
are thought to collateralize extensively to caudal structures
(Rye et al., 1988) as well as to the thalamus (Semba et al.,
1990). The relative contributions of cholinergic and non-
cholinergic neurones to the innervation of the medulla and
spinal cord have been assessed only in the rat (Goldsmith
and van der Kooy, 1988; Rye et al., 1988; Skinner et al.,
1990) and cat (Edley and Graybiel, 1983). Most of the
descending cholinergic PPN neurones travel a shorter distance
to the medullary reticular formation, which in turn provides
bilateral outputs to the spinal cord. The direct projection
from the PPN to the cervical and thoracic cord is thought to
be mainly non-cholinergic, although a small number of
cholinergic PPN neurones may project as far as the spinal
cord (Rye et al., 1988). Some of these descending projections
are thought to terminate unilaterally in intermediate laminae
of the cervical and thoracic cord and bilaterally in the central
grey of the cervical cord, rather than directly on motor
neurones (Goldsmith and van der Kooy, 1988; Rye et al.,
1988). The major outputs from the PPN to the basal ganglia
and related structures in the primate are summarized in Figs
2 and 3. In general, the ascending and descending projections
of the PPN in the primate are similar to those in the cat and
the rodent. However, again it should be pointed out that
minimal data are available for humans.
Electrophysiological properties of PPN
neurones
Types of PPN neurones
Intracellular recordings
Three types of PPN neurones have been identified on the basis
of their electrophysiological membrane properties obtained by
 The pedunculopontine nucleus and Parkinson’s disease
intracellular recordings (Kang and Kitai, 1990; Takakusaki
et al., 1996, 1997; Takakusaki and Kitai, 1997). Type I
neurones are characterized by bursts of fast action potentials.
The bursting (phasic) pattern of action potentials can be
elicited by depolarizing current or by the offset of
hyperpolarizing current, indicating that this type of neurone
can shift into a bursting mode in response to either an
excitatory or an inhibitory input. Morphologically, type I
neurones are small to medium spindle-shaped or triangular
cells with three to five primary dendrites. Type I neurones
are dispersed throughout the extent of the PPN and are
probably glutamatergic (Takakusaki et al., 1996).
As stated above, GABAergic pallidal and nigral efferents
to the PPN project preferentially to non-cholinergic PPNd
neurones (Kang and Kitai, 1990; Spann and Grofova, 1991;
Rye et al., 1995b; Shink et al., 1997). Several investigators
have shown that electrical stimulation of the SNr evokes
predominantly monosynaptic inhibitory postsynaptic
potentials (IPSPs) and decreases the firing rate in PPN
neurones in the anaesthetized rat (Granata and Kitai, 1991)
and cat (Noda and Oka, 1984) and in rat brain slices (Kang
and Kitai, 1990; Takakusaki et al., 1996). After a period of
suppressed activity, PPN neurones can rebound with increased
spike discharges (Kang and Kitai, 1990). Histochemical
staining has shown that IPSPs can be recorded from both non-
cholinergic and cholinergic PPN neurones by SNr stimulation
(Kang and Kitai, 1990).
Type II neurones do not have burst-firing. Instead they fire
single action potentials with large afterhyperpolarizations in
response to injections of depolarizing current. This
characteristic is suited to a relatively slow tonic repetitive
firing pattern. Type II neurones are located in the rostral and
middle sections of the PPN and in general are medium to
large, fusiform or polygonal cells possessing five to seven
primary dendrites. About 50% of type II neurones are
cholinergic. Thus, there seem to be two electrophysiologically
distinct populations of PPN neurones: ‘bursting’ (type I;
likely glutamatergic) and ‘non-bursting’ (type II; 50%
cholinergic). A third type of PPN neurone has characteristics
of both type I and type II PPN neurones. A second group of
investigators has also described three major classes of PPN
neurones following intracellular recordings from thalamic-
projecting, rhodamine-labelled PPN neurones in the guinea-
pig slice preparation (Leonard and Llinás, 1988). These were
similar to the three types described above in the rat.
Extracellular recordings
Extracellular spike discharges from PPN neurones have been
observed in the anaesthetized rat (Hammond et al., 1983;
Scarnati et al., 1987; Granata and Kitai, 1991; Ogura et al.,
1997) and cat (Noda and Oka, 1984). In these animals, one
group of cells had broad spikes with low and regular
spontaneous firing rates (0.5–8 spikes/s). A second set of
cells exhibited narrow spikes with higher discharge rates,
ranging from 10 to 20 spikes/s (Scarnati et al., 1987).
1773
Preliminary experiments have suggested that ~75% of PPN
neurones in rats have a regular pattern of activity (possibly
corresponding to cholinergic neurones) and 25% a ‘bursting’
pattern (possibly corresponding to non-cholinergic neurones;
Ogura et al., 1997). In awake cats, 25% of cells had broad
spikes (2 ms duration) with a mean resting firing rate of
12 Hz, while 75% of cells had narrow spikes (0.7 ms duration)
with a mean discharge rate of 24 Hz (Dormont et al., 1998).
The cells with broad spikes and low discharge rates are
thought to be cholinergic (Takakusaki et al., 1997) and
probably correspond to the type II neurones described above.
The other set of cells, with higher discharge rates, correspond
to the non-cholinergic type I neurones. Similar extracellular
recordings have been reported in awake monkeys (Matsumura
et al., 1997). Recordings from the human PPN have not
been reported.
The descending PPN projection to the spinal cord has been
suggested to be a source of muscle tone control (Rye et al.,
1988) and a pattern generator for locomotion (see below).
Thus, PPN neurones may act as a pace-setter for firing (be
it bursting or non-bursting) of their target neurones (Kang
and Kitai, 1990). As described above, the PPN contains
populations of neurones with intrinsic membrane properties
that allow tonic or non-burst firing (type II, cholinergic) and
those that allow phasic or burst firing (type I, non-cholinergic;
Takakusaki et al., 1996). Thus, the membrane properties of
the type II cholinergic neurones could allow tonic pace-
setting (as in regulating the velocity of steady-state
locomotion), whereas those of the non-cholinergic type I
neurones could be involved in phasic pace-setting (i.e. as in
gait initiation). However, there is no direct evidence to
support this. Since projections from the GPi and SNr seem
to preferentially target the non-cholinergic PPN neurones and
since this population of PPN neurones provides the prominent
descending PPN outputs to the spinal cord (Rye et al.,
1988), one could further speculate that pallidal and nigral
connections to the type I (bursting, non-cholinergic) PPN
neurones may be an important means by which the basal
ganglia regulate the initiation of gait.
Membrane receptors and pharmacology of
PPN neurones
Numerous neurotransmitters have been proposed to influence
PPN neurones directly (Table 1). Data have been generated
both in vitro and in vivo. In vitro studies have used
experimental rat and guinea-pig slice preparations with bath
applications or local microinjections of neuroactive agents.
These studies provide strong evidence for the direct influence
of a number of neuroactive agents on PPN neuronal activity.
In vivo studies have observed animal behaviour in awake or
anaesthetized rats or cats during intracerebral microinjections
of various neuroactive agents. These studies provide
behavioural information that may be of physiological
significance, but the actual microinjection sites are
1774 P. A. Pahapill and A. M. Lozano

Table 1 PPN pharmacology, electrophysiology and behaviour

Drug Preparation Effect Behaviour

Acetylcholine
Carbachol (AGO) GPS, MI ↓ firing, hyperpolarization secondary to
↑ I(k)1,2
Atropine (ANT) Blocks carbachol effects1
Carbachol (AGO) Awake rat, MI Inhibition of scopolamine effect7 ↓ locomotion3–6
Atropine/scopolamine (ANT) ↑ striatal dopamine metabolism7 ↓ locomotion3,5,6
GABA
Muscimol (AGO) Awake monkey8, rat4,5,9, MI ↓ motor performance4,5,8,9
Bicuculline (ANT) RS, BA SN elicited IPSPs in PPN are blocked10
Awake rat, MI ↑ locomotion4,5,9
Picrotoxin (ANT) Neuroleptic-induced rat ↑ locomotion11
catalepsy model
Glutamate
NMDA, AMPA (AGO) GPS, BA ↑ firing with depolarization12
AP-5, DNQX, CNQX (ANT) Blocks glutamate effects12
NMDA/kainate (AGO) Anaesthetized rat, MI ↑ firing of PPN13 and SN14
Awake rat, MI ↑ striatal dopamine turnover15,16 ↑ locomotion4,5,16
Histamine GPS, BA ↑ firing17
Mepyramine (H1-ANT) Blocks histamine effect17
Cimetidine (H2-ANT) No effect17
Noradrenaline RS, BA ↓ firing, hyperpolarization 2o to ↑ I(k)18
Opiates
µ-AGO GPS, BA ↓ firing, hyperpolarization 2o to ↑ I(k)2
Naloxone (ANT) Blocks opiate effect2
κ-AGO, δ-AGO No effect2
Serotonin RS/GPS, BA/MI ↓ firing, hyperpolarization 2o to ↑ I(k)1
Spiperone (5HT1-ANT, also Blocks serotonin effect1
has dopamine D2 receptor
blocking properties)
Substance P Awake rat, MI ↑ locomotion5
Glycine No effects on
Strychnine (ANT) locomotion4

AGO ⫽ agonist; ANT ⫽ antagonist; GPS ⫽ guinea-pig brain slice; RS ⫽ rat brain slice; BA ⫽ bath application; MI ⫽ microinjection;
I(k) ⫽ potassium current; SN ⫽ substantia nigra; EPSP ⫽ excitatory postsynaptic potential; ↑ ⫽ increase(s); ↓ ⫽ decreases.
Superscript numbers refer to references: 1Leonard and Llinás, 1994; 2Serafin et al., 1990; 3Mathur et al., 1997; 4Milner and Mogenson,
1988; 5Garcia-Rill et al., 1990; 6Brudzynski et al., 1988; 7Chapman et al., 1997; 8Condé et al., 1998; 9Childs and Gale, 1984; 10Kang
and Kitai, 1990; 11Miwa et al., 1996; 12Sanchez and Leonard, 1994; 13Hammond et al., 1983; 14Clarke et al., 1987; 15Hernández-López
et al., 1992; 16Niijima and Yoshida, 1988; 17Khateb et al., 1990; 18Williams and Reiner, 1993.

anatomically localized by gross stereotaxic techniques and
are only later documented by histochemical staining. This is
an important consideration, since microinjections that are
only 1–2 mm apart can give completely opposite behavioural
effects (Garcia-Rill et al., 1990). No studies have combined
microinjection and electrophysiological techniques in intact
animals to obtain better functional targeting of the actual
sites of microinjections with electrophysiology techniques
while assessing behavioural responses. It should be noted
that there have been many other reports of microinjections
into the general region of the mesencephalic locomotor area
or the lateral dorsal tegmental area. We will summarize only
those thought to be specific to the PPN.
Glutamate/NMDA
In the guinea-pig brain slice, bath applications or
microinjections of glutamate or N-methyl-D-aspartate
(NMDA) caused dose-dependent depolarization and increased
firing of cholinergic PPN neurones lasting up to several
minutes (Sanchez and Leonard, 1994). These effects were
blocked by the appropriate antagonists (Table 1). In
behavioural studies, microinjections of glutamate agonists in
the area of the rat PPN generally increased locomotion
(Milner and Mogenson, 1988; Niijima and Yoshida, 1988).
In an in vivo study using anaesthetized precollicular-
transected rats, the PPN injection site was further defined
functionally by locomotion induced by electrical stimulation
(Garcia-Rill et al., 1990). In these experiments, additional
injections of NMDA could drive stepping from a walk to a
trot to a gallop. These effects were blocked in a dose-
dependent manner by specific NMDA antagonists. Since they
occurred in rats with a transection at the upper brainstem,
the effects were independent of brain structures rostral to the
cut. These studies suggest that the application of glutamate
agonists excites cholinergic PPN neurones and leads to
increased locomotion. However, there have been no reports
showing increased locomotion coincident with increased PPN
 The pedunculopontine nucleus and Parkinson’s disease
activity during injections of glutamate agonist. One group
showed increased activity of presumed PPN neurones with
local microinjections of glutamate in the anaesthetized rat
(Hammond et al., 1983). However, very high concentrations
of glutamate (1 mol/l) were required and no behavioural
observations were made. It has been shown that
microinjections of glutamate agonists into the area of the
PPN increases the firing rate of presumed dopaminergic
neurones of SNc via a cholinergic pathway (Clarke et al.,
1987) and elicits the turning behaviour associated with an
increase in dopamine turnover in the neostriatum (Niijima
and Yoshida, 1988; Hernandez-Lopez et al., 1992).
Acetylcholine
In the guinea-pig brain slice, microinjections of carbachol
(an acetylcholine agonist) caused dose-dependent hyper-
polarization and decreased firing of cholinergic PPN neurones
(Serafin et al., 1990; Leonard and Llinás, 1994). These effects
were blocked with atropine (a muscarinic antagonist). In a
number of behavioural studies, investigators showed that
microinjections of carbachol into the rat PPN area decreased
locomotion with a similar time-course of effect (a delay of
a few minutes and a duration of 10–30 min) (Brudzynski
et al., 1988; Milner and Mogenson, 1988; Garcia-Rill et al.,
1990; Mathur et al., 1997). These effects could also be
blocked by antimuscarinics (atropine or scopolamine) but
not by anti-nicotinics. These studies suggest that the
application of cholinergic agonists inhibits cholinergic PPN
neuronal activity and leads to decreased locomotion. There
have been no reports of decreased locomotion coincident
with decreased PPN neuronal activity during injections of
acetylcholine agonists. Cholinergic input onto PPN neurones
appears to originate in the contralateral PPN and ipsilateral
laterodorsal tegmentum in the rat (Fibiger and Semba, 1988).
GABA
Bath applications of bicuculline (a GABA antagonist) in rat
brain slices blocked the IPSPs in cholinergic PPN neurones
that were evoked by electrical stimulation of the SNr (Kang
and Kitai, 1990). Microinjections of bicuculline or picrotoxin
(GABA antagonists) into the PPN area increased locomotion
in a dose-dependent manner and with similar time-courses
of effect, whereas muscimol (a GABA agonist) inhibited
locomotion in intact rats (Childs and Gale, 1984; Milner and
Mogenson, 1988; Garcia-Rill et al., 1990). These effects
were unaltered in rats with the brainstem hemitransected just
rostral to the PPN (Childs and Gale, 1984). In addition, in
the neuroleptic-induced catalepsy rat model of parkinsonism,
microinjections of picrotoxin (a GABA antagonist) into the
PPN area increased locomotion with a similar time-course
(Miwa et al., 1996). Furthermore, in freely moving cats in
which the PPN was physiologically identified with single-
unit recordings, muscimol caused a similar arrest of motor
performance (Condé et al., 1998). Unfortunately, any
1775
Table 2 Summary of effects of major neurotransmitter
systems on cholinergic PPN neuronal activity and
locomotion
Neurotransmitter system Cholinergic PPN Locomotion
neuronal activity
Glutamate ↑ ↑
Acetylcholine ↓ ↓
GABA ↓ ↓
Both cholinergic and GABAergic systems seem to inhibit
cholinergic PPN neuronal activity and diminish animal
locomotion, whereas the glutamatergic system seems to increase
cholinergic neuronal activity in the PPN and to increase animal
locomotion.
concomitant effects on PPN neuronal activity were not
reported.
Others agents
A number of other neuroactive agents (including serotonin,
noradrenaline, histamine and opiates (Table 1), are thought
to influence the firing of PPN neurones. All of these, except
histamine, may be inhibitory. Even less is known, however,
concerning the relative importances of these other agents,
their distribution and origin, and the specific cell types of
the PPN with which they are in synaptic contact (i.e.
cholinergic versus non-cholinergic or bursting versus non-
bursting). Immunohistochemical and electron microscope
studies in rats have shown that serotonergic afferents onto
cholinergic PPN neurones apparently arise in the raphe nuclei
(Honda and Semba, 1994). Possible excitatory histaminergic
afferents from the posterior hypothalamus to the PPN (Khateb
et al., 1990) have been implicated in an H1 receptor-mediated
arousing action of histamine. Other possible neurotransmitter
inputs to the PPN include glycine and galanin. Glycine-
immunoreactive fibres and terminals have been observed
apposed to cholinergic neurones in the cat PPN (Fort et al.,
1993). The peptide neurotransmitter galanin has been
localized in axonal fibres and terminals in the region of
substance-P-containing neurones of the human PPN (Gai
et al., 1993). Microinjection of substance P into the rat PPN
area increases locomotion (Garcia-Rill et al., 1990). The
physiological significance of these connections remains
unknown.
In summary, the studies suggest that GABA and
acetylcholine decrease cholinergic PPN activity and diminish
locomotion, while glutamate increases cholinergic PPN
activity and increases locomotion (Table 2). No studies have
shown simultaneous effects on PPN neuronal activity or
behavioural effects. The glutamate and GABA effects were
similar in transected animals, suggesting that the expression
of PPN outputs is not dependent upon ongoing influences
from the basal ganglia. Interactions of these different
neurotransmitter systems at the level of the PPN have also
been shown. In studies on rats, carbachol and GABA have
1776 P. A. Pahapill and A. M. Lozano
been shown to block NMDA-induced locomotion (Garcia-
Rill et al., 1990).
In general, there has been little reproduction of experiments
from different laboratories. If attempted, they suffer from
great differences in the methods and drug concentrations
used. This has resulted in great variability of results, especially
in the time-course of effects. Work has concentrated mainly
on the cholinergic PPN neurones (as identified by
electrophysiological properties in slices or postinjection
histochemistry in behavioural studies), with little emphasis
on the non-cholinergic population of PPN neurones. In
addition, studies have been limited to non-primate species,
and there has been only one study in a rodent model of
Parkinson’s disease (Miwa et al., 1996).
Although the in vitro experiments summarized above
suggest that the various types of receptors are present and
function in PPN neurones, they do not give conclusive proof.
Receptor-localization studies have established the presence
of NMDA-sensitive receptors in the area of the PPN (Stone
and Burton, 1988), but have not confirmed their actual
existence on PPN neurones. Muscarinic cholinergic (M2, M3
and M4) receptors were reported to be located on monkey
and human cholinergic PPN and laterodorsal tegmentum
neurones (Rye et al., 1995a), the M2 receptor possessing
characteristics consistent with an inhibitory autoreceptor,
although the physiological role of these receptors is unknown.
It has been proposed that the psychotropic actions of
antimuscarinics occur via M2 autoreceptors on cholinergic
PPN cells, whereas their antiparkinsonian effects occur via
M1 receptors in the forebrain (Yeomans, 1995). Glycine
receptors have also been demonstrated in the area of the
human PPN (Probst et al., 1986).
The role of the PPN in locomotion
The mesencephalic locomotor region
The PPN is believed to be part of the so-called mesencephalic
locomotor region. This is a functionally defined area of the
brainstem within which it is possible to elicit controlled
locomotion (locomotion in which increasingly higher levels
of electrical stimulation drive the frequency of stepping from
a walk to a trot to a gallop) on a treadmill in decerebrate
animals including the cat (Garcia-Rill and Skinner, 1987a, b),
rat (Garcia-Rill, 1990) and possibly the monkey (Eidelberg
et al., 1981).
Although the optimal sites for the induction of locomotion
appear to be within the cholinergic neurone mass of the
PPNc (Garcia-Rill et al., 1987), there are several brainstem
regions, including prominent sensory nuclei, which can be
stimulated to initiate locomotion (for a recent review, see
Reese et al., 1995). Each of these areas possesses direct
outputs to the spinal cord (the site of putative locomotor
pattern generators) and none of these areas can be considered
to be specific to locomotion.
Neural networks have been used to model brain function
during locomotion in all classes of vertebrates (Grillner,
1985). Thus, the same mesopontine and diencephalic centres
initiate locomotion in lampreys and primates, through the
activation of lower brainstem reticulospinal neurones. These,
in turn, activate spinal networks of neurones which generate
the motor pattern, be it swimming or walking. Sensory
feedback is an integral part of the control system and helps
to adapt the motor pattern to external events. This sensory
input is important for the initiation of movements and
for providing ongoing feedback for the maintenance of
movement. Details of the cellular and molecular function
of this network are now being revealed in simple model
systems in vertebrates such as the lamprey (Di Prisco
et al., 1997).
The responsiveness of PPN neurones to somatosensory
stimuli (Grunwerg et al., 1992; Reese et al., 1995), coupled
with the cholinergic PPN projections to the thalamus (as
described above) and the proposed inputs to the PPN from
lamina I of the cat spinal cord (Hylden et al., 1985), suggests
that the PPN may also take part in the modulation of sensory
information to thalamic nuclei. The potential role of the PPN
as a relay station, providing feedback information important
for the modulation of posture and gait initiation, is facilitated
by its prominent cholinergic ascending projections to the
thalamus and its connections with deep cerebellar nuclei.
PPN neuronal activity during locomotion
Three separate populations of neurones displaying rhythmic
activity in relation to locomotion can be recorded
extracellularly in the area of the PPN in the decerebrate cat
(Garcia-Rill and Skinner, 1988). One group of neurones
displays a tonic firing pattern during locomotion which
decreases in frequency or stops entirely with the cessation
of the locomotor episode. These neurones have been termed
‘on’ cells. A second group of neurones, called ‘off’ cells, also
display a tonic firing pattern, but their frequency decreases as
the locomotion frequency increases and their firing rate
increases before the cessation of locomotion. These two
groups of neurones are located primarily within the PPN and
may represent different subtypes of the previously defined
cholinergic type II neurones (‘non-bursting’ neurones). The
third group of neurones display a bursting pattern of firing
during locomotion (termed ‘bursters’). These are located in
more widespread areas and may represent the non-cholinergic
type I neurones. The ‘on/off’ cells might modulate the
duration of the stepping episode, while the bursters may be
involved in modulating the frequency (and possible initiation)
of stepping (Garcia-Rill and Skinner, 1991). Although their
precise role remains to be defined, one can speculate that
bursting, glutamatergic PPNd neurones, which are primarily
innervated by GABAergic GPi (and possibly SNr) neurones
and provide the main PPN outputs to the spinal cord, may
be important for the initiation of programmed movements.
In contrast, the non-bursting, possibly cholinergic PPNc
neurones, which relay feedback sensory information from
 The pedunculopontine nucleus and Parkinson’s disease
the spinal cord and provide the main inputs back into the
thalamus and SNc, may be more important for the main-
tenance of gait.
Recently, the activity of PPN neurones was recorded in
awake cats (Dormont et al., 1998) and monkeys (Matsumura
et al., 1997) conditioned to perform lever-movement tasks.
In cats, the broad-spiked, low-frequency discharging neurones
(thought to be cholinergic) displayed increased activity,
especially during the programmed movements. In contrast,
the narrow-spiked, high-frequency discharging neurones
(thought to be non-cholinergic) displayed early activation
before the programmed movements (Dormont et al., 1998).
In monkeys, changes in PPN neuronal activity preceded the
onset of movement and occurred for both contralateral and
ipsilateral limb movements (Matsumura et al., 1997).
Regulation of gait and locomotion in the PPN
Continuous mid-frequency (20–60 Hz) stimulation in the cat
PPN is required to elicit locomotion. Hundreds of stimuli
delivered for several seconds must be applied before the first
step is induced (Garcia-Rill and Skinner, 1991). This effect
has been interpreted as one of ‘recruitment’ of locomotion, in
which spinal pattern-generators are activated by reticulospinal
systems triggered by stimulation of brainstem centres (Garcia-
Rill and Skinner, 1987b). Similarly, electrical stimulation of
the PPN in the rat (Kelland and Asdourian, 1989) and cat
(Lai and Siegel, 1990) has been reported either to reduce or
to stimulate muscle tone, depending on the rate of stimulation.
These results can be quite variable across laboratories because
of differences in stimulation protocols (Garcia-Rill et al.,
1990). In contrast, high-frequency (⬎100 Hz) stimulation of
the cat PPN consistently induces suppression of muscle tone
(Lai and Siegel, 1990). It has been speculated that certain
stimulation parameters are necessary to shift PPN neurones
to a voltage ‘window’ conducive to increased locomotion
(Garcia-Rill et al., 1990). Mid-range frequencies may be
best, while higher frequencies appear to set the system into
a condition reminiscent of depolarization block.
The function of the PPN has also been inferred from
lesion and inhibitory neurotransmitter application studies.
Excitotoxic lesions (with kainic acid injections) of the monkey
PPN (as identified with extracellular recordings) produced
contralateral hemiparkinsonism characterized by flexed
posture and hypokinesia (Kojima et al., 1997). Radio-
frequency lesions in the PPN in rhesus monkeys reduced
motor activity significantly, as reflected by a generalized
bradykinesia that resembled Parkinson’s disease (Aziz et al.,
1998). Bilateral lesions were required to achieve long-
lasting effects. As outlined above, reversible pharmacological
inactivation of the monkey PPN with unilateral intracerebral
microinjections of lidocaine or a GABA agonist resulted in
delayed arrest of performance of a conditioned motor task
without motor impairment, suggesting an alteration in the
selection process of the appropriate motor programme (Condé
et al., 1998). Electrical stimulation at 50–60 Hz near the
1777
PPN (Kölliker-Fuse nucleus) in a patient with chronic pain
produced increased tone in the contralateral limb muscles
(Young et al., 1992). There have been no other reports of
lesioning or stimulation of PPN areas in humans.
PPN, reward and motivation
The cholinergic PPN neurones may also provide a form of
non-specific facilitation for behaviours linked to the likelihood
of reward, so they may represent an interface between
limbic motivation systems and the brainstem motor apparatus
(Steckler et al., 1994). Cholinergic agonist stimulation of the
rat SNc (whose main cholinergic inputs may be provided by
PPNc neurones) increases the performance and initiation of
behaviours which the rat has pre-existing tendencies to
perform (Winn, 1991). Inhibition of cholinergic PPN neurones
with microinjections of carbachol can reduce the motor
performance elicited by amphetamine injected into the
nucleus accumbens (Brudzynski et al., 1988). In cats,
reinforcement-related activity in broad-spiked neurones
(thought to be cholinergic, as outlined above) is speculated
to be associated with the PPN cholinergic projection to the
SNc (Dormont et al., 1998). In contrast to Parkinson’s disease,
in human schizophrenic states, the number of cholinergic PPN
neurones is increased (Garcia-Rill et al., 1995; Yeomans,
1995). Since non-cholinergic neurones of the PPNd receive
inputs from the basal ganglia and possibly the limbic
structures (as described above), it has been proposed that
the PPN, as a whole, also acts as an interface between
the selection of motor outputs by the basal ganglia and the
incentive-motivational directives from the striatal–pallidal
complex to provide motivationally influenced activation of
motor pattern generators in the pons, medulla and spinal cord
(Inglis and Winn, 1995). Such incentive-motivational or
affective factors may influence motor function, as occurs, for
example, in kinesia paradoxica. PPN activation could improve
motor planning, enabling an increased motivational ability to
call up already preserved motor programmes for stereotyped
movements such as locomotion and reaching.
The PPN and Parkinson’s disease
PPN neuropathology
It has been proposed that abnormalities of gait and posture,
in addition to rigidity and bradykinesia, may, in part, reflect
the loss of neurones or the suppression of neuronal activity
in the PPN. Analysis of the limited clinical data that are
available suggests a relationship between the loss of
cholinergic neurones in the PPNc and the severity of
Parkinson’s disease symptoms (Zweig et al., 1989). Thus,
the progression of Parkinson’s disease, and possibly the
change in response to levodopa (especially the refractory
akinesia) that can occur as the disease progresses in certain
patients, may reflect increasing involvement of non-
1778 P. A. Pahapill and A. M. Lozano
dopaminergic neuronal systems, such as the PPNc cholinergic
and PPNd glutamatergic neuronal systems.
Neuropathological studies on humans have reported that
~50% of the large cholinergic neurones of the lateral part of
the PPNc degenerate in Parkinson’s disease (Hirsch et al.,
1987; Jellinger, 1988; Zweig et al., 1989; Gai et al., 1991).
The extent of non-cholinergic neuronal loss in the PPN has
not been determined. The observation that the magnitude of
the neuronal loss within the PPNc is similar to the neuronal
loss within the SNc raises the possibility that PPN neurones
may be susceptible to the same pathogenetic mechanisms as
nigral dopaminergic neurones. The PPN may also, at least in
theory, have a role in SNc degeneration through an excitotoxic
effect of glutamatergic synaptic contacts from the PPN onto
dopaminergic SNc neurones (Lavoie and Parent, 1994c). This
raises the intriguing possibility, for which there is so far no
evidence, that reducing the glutaminergic drive from the PPN
to the dopaminergic cells of the substantia nigra may have
neuroprotective effects and influence the rate of progression
of Parkinson’s disease.
PPN and the parkinsonian basal ganglia circuit
model
In parkinsonism, the inhibitory GABAergic projections from
the GPi (and possibly the SNr) to the thalamus and PPN are
overactive. Regional uptake studies of 2-deoxyglucose in
MPTP-treated parkinsonian monkeys show increased synaptic
activity in the PPN (Mitchell et al., 1989). It is not known,
however, what effect this increased synaptic activity has on
the net output of PPN neurones. Recent experiments
using extracellular single-unit recordings from anaesthet-
ized, 6-hydroxydopamine-lesioned rats have demonstrated
decreased firing rates of PPN neurones in the parkinsonian
state (Ogura et al., 1997), consistent with increased inhibition
from basal ganglia outputs. An interesting hypothesis is that
the increased GABAergic inhibition of PPN/locomotor region
neurones from overactive descending pallidal (and possibly
nigral) efferents in the parkinsonian state may underlie the
problems of initiating programmed movements, the akinesia
and the gait difficulties seen in parkinsonism. The pallidal–
nigral projections appear to terminate preferentially on the
non-cholinergic, glutamatergic neurones of the PPNd and
largely avoid neurones of the PPNc (Shink et al., 1997),
and these glutamatergic PPNd neurones provide descending
projections to the spinal cord. Furthermore, reducing PPN
activity, as occurs with destructive lesions, leads to a
parkinsonian-like state (Kojima et al., 1997; Aziz et al.,
1998). Medical or surgical intervention that reduces the
overactive inhibitory outflow from the basal ganglia to PPN
would be expected to release the activity of this nucleus and
facilitate a return towards normal function.
Potential surgery and the PPN in parkinsonism
There is already good evidence from animal and clinical
studies that surgical interventions which are designed to
reduce the inhibitory basal ganglia output to the thalamus
and PPN are associated with striking improvements in all
major features of parkinsonism. Lesions of the STN in normal
monkeys decrease the neuronal activity of inhibitory GPi
projections to the thalamus and PPN (Mitchell et al., 1989).
STN lesions and chronic electrical stimulation in parkinsonian
monkeys and patients with Parkinson’s disease reduce all the
major motor disturbances of Parkinson’s disease, including
akinesia, rigidity and tremor (Bergman et al., 1990; Aziz
et al., 1991, 1992; Benazzouz et al., 1993; Benabid et al.,
1994; Limousin et al., 1995, 1998; Pollak et al., 1996; Gill
and Heywood, 1997; Kumar et al., 1998a, b). Direct lesioning
or stimulation of the GPi in human and non-human primates
also improves parkinsonism (Gross et al., 1997, 1999; Lang
et al., 1997; Galvez-Jimenez et al., 1998; Krack et al., 1998;
Volkmann et al., 1998; Lieberman et al., 1999). These
observations are consistent with the hypothesis that the
overactive inhibitory influence from the basal ganglia to the
PPN is important in the pathogenesis of motor dysfunction
in parkinsonism and that removing this disruptive influence
on PPN improves motor function.
Would surgical procedures of the PPN be of therapeutic
value? The experimental data show that both electrical
stimulation and the delivery of neuroactive substances in
their PPN have striking effects on motor function. It may be
possible to place a chronic deep brain stimulation electrode
or a microinfusion cannula for the delivery of neuroactive
substances directly into the PPN to change its activity and
modulate its output to its targets. The direct infusion of
neuroactive substances into the PPN, as has been described
recently in the globus pallidus and thalamus of patients (Penn
et al., 1998; Pahapill et al., 1999), opens a number of new
possibilities. Experiments in parkinsonian animals are needed
to address some of these issues.
Acknowledgements
We wish to thank Dr T. Z. Aziz, and Professor J. O.
Dostrovsky for their helpful comments. This work was
supported by grants from the Parkinson’s Foundation of
Canada and the Medical Research Council of Canada grant
to A.M.L. and a Medical Research Council of Canada
Fellowship to P.A.P.
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Received December 3, 1999. Revised March 6, 2000.
Accepted March 10, 2000