The pedunculopontine nucleus and Parkinson’s disease · The pedunculopontine nucleus and Parkinson’s disease 1769 and physiology of the PPN are often incomplete, and are the role

Brain (2000), 123, 1767–1783

R E V I E W A R T I C L E

The pedunculopontine nucleus and Parkinson’sdiseasePeter A. Pahapill and Andres M. Lozano

Department of Surgery, University of Toronto, Division of Correspondence to: Dr A. M. Lozano, The Toronto WesternNeurosurgery, The Toronto Western Hospital, Toronto, Hospital, 399 Bathurst Street, McL 2-433, Toronto,Ontario, Canada Ontario, Canada M5T 2S8

E-mail: [email protected]

SummaryAkinesia and gait disturbances are particularly in- to the initiation of programmed movements while non-

bursting cholinergic PPNc neurones are related to thecapacitating for patients with Parkinson’s disease. Theanatomical and physiological substrates for these disturb- maintenance of steady-state locomotion. Furthermore,

since patients with Parkinson’s disease have significantances are poorly understood. The pedunculopontinenucleus (PPN) is thought to be involved in the initiation loss of PPN neurones and experimental lesions in the PPN

of normal monkeys result in akinesia, the degenerationand modulation of gait and other stereotyped movements,because electrical stimulation and the application of of PPN neurones or their dysfunction may be important

in the pathophysiology of locomotor and posturalneuroactive substances in the PPN can elicit locomotoractivity in experimental animals. Glutamatergic neurones disturbances of parkinsonism. The goal of this review is (i)

to highlight the anatomical connections and physiologicalof the PPNd (pars dissipatus) are thought to be importantregulators of the basal ganglia and spinal cord. The other attributes of the PPN, (ii) to discuss how the function of

these connections may be altered in the parkinsoniancomponent of the PPN, the cholinergic pars compacta(PPNc), is a principal component in a feedback loop from state, and (iii) to speculate how present and potential

future therapy directed to the PPN might improve akinesiathe spinal cord and limbic system back into the basalganglia and thalamus. Electrophysiological studies suggest and gait difficulties in parkinsonian patients.that ‘bursting’ glutamatergic PPNd neurones are related

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 parsreticulata; SP � superior cerebellar peduncle; STN � subthalamic nucleus

Introductionchanges in posture (Elble et al., 1994). Although a numberLocomotion in Parkinson’s diseaseof kinetic studies have focused on steady-state locomotion,Gait disturbances are major impediments for parkinsonianstudies on gait initiation in Parkinson’s disease are few. Itpatients (Murray et al., 1978; Morris et al., 1994, 1996).has been proposed that two types of difficulty can contributeAlthough slowness of movement (bradykinesia) may affectto gait akinesia in Parkinson’s disease: (i) slowed movementsall phases of gait, it is the failure of gait initiation (gaitand prolonged motor preparation times, leading to a delayakinesia) which can be a particularly incapacitating problem.in the execution of an otherwise preserved sequence ofGait initiation (the phase between motionless standing andsubmovements (i.e. a problem in motor planning in whichsteady-state locomotion) can be divided into a movementthe patient is unable to call up or run an already-formedpreparation period and a movement execution periodand preserved gait-initiation motor programme); and (ii) a(Breniere and Cuong, 1991). Gait initiation involves a highly

stereotyped pattern of limb and trunk submovements with problem in the ability to form the normal sequence of

© Oxford University Press 2000

1768 P. A. Pahapill and A. M. Lozano

submovements that compose the initiation of normal gait in parkinsonism are poorly understood, but recentobservations suggest that dysfunction of the pedunculopontine(i.e. a problem in motor programming in which there is a

loss of or an inability to form the appropriate set of nucleus (PPN) may be important.The upper brainstem contains neurones which controlsubmovements or subroutines that make up the actual gait-

initiation motor programme that otherwise should be available axial and proximal limb musculature for gait through theirprojections to the lower brainstem and spinal cord viato be called up during motor planning) (Marsden, 1987;

Rosin et al., 1997). bilateral, midline, descending pathways. These brainstemnuclei are, in turn, under the influence of descending inputsStudies of steady-state locomotion in Parkinson’s disease

have supported alterations in both motor programming and from basal ganglia nuclei [globus pallidus interna (GPi);subthalamic nucleus (STN); substantia nigra pars reticulatamotor planning (Knutstson, 1972; Stern et al., 1983; Forssberg

et al., 1984; Dietz, 1993). Studies on gait initiation have (SNr)]. Because the function of these basal ganglia structuresis markedly disrupted in parkinsonism, the brainstem motorsuggested that the problems with gait initiation in Parkinson’s

disease are due primarily to faulty motor planning that areas to which they project and which they control mayalso be dysfunctional. Hence, interventions which block theimpedes the calling up of otherwise relatively preserved gait-

initiation motor programmes (Rosin et al., 1997). Others abnormal activity of the basal ganglia in parkinsonism,including surgical lesions and high-frequency stimulation ofhave demonstrated that patients may also suffer from altered

sensory feedback processing that can effectively interfere with basal ganglia targets, are potential ways of restoring thenormal function of the brainstem centres which controlgait initiation (Rogers and Chan, 1988; Horak et al., 1992).

In patients with advanced Parkinson’s disease, akinesia or locomotion. Recent attention to the brainstem areas involvedin the control of locomotion has focused on the PPN.‘freezing’, the failure of willed movement to occur, is often

only mildly improved by dopaminergic medication (Pullman Although considerable animal data are available, little isknown of the function of this nucleus in humans or to whatet al., 1988; Starkstein et al., 1989) or unilateral surgical

intervention (Lang et al., 1997; Lozano and Lang, 1998). extent observations in experimental animals are relevant tohumans. Furthermore, studies on the anatomical connectionsThe pathological substrates of gait and postural disturbances

The pedunculopontine nucleus and Parkinson’s disease 1769

and physiology of the PPN are often incomplete, and are the role of the PPN in locomotion. The involvement of thePPN in human locomotion is supported by the observationdifficult to interpret because of methodological limitations,

which often produce controversial and even contradictory of Masdeu and colleagues, who described the inability of apatient to stand and to generate stepping after a haemorrhageinterpretations. Despite these difficulties, which are some-

times serious, there is a large body of evidence supporting 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 extentof 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 � nucleusparalemniscalis; 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 � fasciculuslongitudinalis 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 � fibraepontocerebellares. (B) Inferior collicular level (caudal extent of PPN). 1 � nucleus intercollicularis; 2 � colliculus inferior, nucleuscentralis; 3 � colliculus inferior, zona lateralis; 4 � griseum centrale mesencephali; 5 � locus coeruleus; 6 � nucleus mesencephalicusnervi 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 mesencephalicusnervi trigemini; 18 � lemniscus lateralis; 19 � tractus tectopontinus; 20 � fasciculus anterolateralis; 21 � fasciculus longitudinalismedialis; 22 � tractus tegmentalis centralis; 23 � lemniscus medialis; 24 � pedunculus cerebellaris superior; 25 � decussatiopedunculorum 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), withpermission.


1994). Although they emphasized damage to the PPN as a tegmental region containing the PPN. However, because ofits neurochemical heterogeneity and close apposition toprobable cause, the damage appeared to extend beyond the

boundaries of the PPN. several other functionally distinct regions and fibre tracts, ithas been difficult to determine precisely which afferentsactually terminate in the PPN and, of these, which terminateAnatomy 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 widelythe PPN is bounded on its lateral side by fibres of the medial studied and established connections to the primate PPNlemniscus and on its medial side by fibres of the superior (Shink et al., 1997). Pallidal efferent pathways to the PPNcerebellar peduncle and its decussation (Olszewski and and midbrain tegmentum descend along the pallidotegmentalBaxter, 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 tegmentumof the posterolateral substantia nigra, while the retrorubral near the ventrolateral border of the red nucleus. Recentfield borders it dorsally. The most dorsal aspect of the anatomical studies on humans and other primates have shownPPN is bounded caudally by the pontine cuneiform and that the pallidal projections appear to terminate preferentiallysubcuneiform nuclei and ventrally by the pontine reticular on the non-cholinergic cells of the PPNd and largely avoidformation. 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 indorsolateral 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 PPNpeduncle and central tegmental tract. The pars compacta and or converge onto the same PPNd neurones. The pallidal anddissipatus 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 thatand Parent, 1994a). The number of cholinergic neurones

�80% of GPi neurones send axon collaterals to both thewithin the PPN in humans has been estimated at between ventrolateral nucleus of the thalamus and the PPN in monkeys10 000 and 15 000 (Garcia-Rill et al., 1995, 1996). (Harnois and Filion, 1982). Indeed, the axonal branch of GPiCholinergic PPNc neurones are clustered along the neurones projecting to the PPN in non-human primates is ofdorsolateral border of the superior cerebellar peduncle (SP) larger diameter than the thalamic branch (A. Parent, personalat trochlear nucleus levels, whereas those in the PPNd are communication). This suggests that the PPN may be thescattered along the SP from midmesencephalic to midpontine principal target of pallidal outflow. This collateralization haslevels. 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 beenneuronal 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. Thewithin 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 inputsnucleus, ~40% of monkey PPN cells express cholinergic and

to the rat PPN (Groenewegen et al., 1993). However, veryglutamatergic 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 spinalboundary of the non-human PPN include a dopaminergic

cord to the area of the PPN have been shown in the ratpopulation (Rye et al., 1987), a noradrenergic group and a

(Grunwerg et al., 1992) and cat (Hylden et al., 1985), butsmall group of GABAergic interneurones (Jones, 1991).

not in primates. These studies have suggested that cholinergicDespite numerous studies, however, there has been no

PPN neurones act as a relay station for spinal cord sensoryconsensus regarding the average number of PPNc or PPNd

afferents to the thalamus. The neurotransmitter systemneurones or the breakdown of cell types in the PPNd found

involved in this spinal input is unknown. The major putativein humans or other species.

inputs to the PPN from the basal ganglia and related structuresthe primate are summarized in Fig. 2.

A number of other putative afferents to the PPN in ratsInputs to the PPNand cats (but not primates) have been proposed (but notAnatomical and electrophysiological studies on non-humans

have identified many putative afferents to the mesopontine firmly established because of non-specific uptake of tracers


Fig. 2 The major proposed inputs to the primate PPN from thebasal ganglia and related structures (see text for details):glutamatergic input from the STN; GABAergic input from theGPi; GABAergic input from the SNr; glutamatergic input fromthe cerebral cortex; and sensory inputs from the spinal cord.The STN, GPi and SNr inputs are predominantly to the

Fig. 3 The major proposed projections from the primate PPNglutamatergic neurones of the PPNd. Spinal inputs areto the basal ganglia and related structures (see text for details):primarily to the cholinergic neurones of PPNc. Glu �projections to the STN, Gpi, SNc, cerebral cortex, caudate/glutamate; Ach � acetylcholine.putamen, thalamus, spinal cord and brainstem. Projections tothe spinal cord are primarily from PPNd glutamatergicneurones. Projections to the thalamus and brainstem are

from surrounding midbrain structures) to arise from areas primarily from cholinergic PPN neurones. Abbreviations as inFig. 2.within the limbic system (amygdala, hypothalamus, zona

incerta) and the ascending reticular activating system (raphenuclei, locus coeruleus, laterodorsal tegmental nucleus,

and Parent, 1994b); the percentage has not been establishedcontralateral PPN), as well as from premotor and

for each individual basal ganglia target.supplementary motor cortical areas (Monakow et al.,1979; Edley and Graybiel, 1983), the subtantia nigra parscompacta (SNc) and the caudate, putamen, superior colliculus, Ascending projectionsbasal forebrain and deep cerebellar nuclei. This work and

Ascending PPN outputs project via the dorsal and ventralthe methods used have been reviewed recently (Reese et al.,

tegmental bundles, the dorsal tegmental pathway carrying1995; Winn et al., 1997). The significance of these projections

the major cholinergic projection (Garcia-Rill, 1991). Theis not understood.

majority of ascending cholinergic PPN neurones are thoughtto project to all thalamic nuclei in the rat (Hallanger et al.,1987; Rye et al., 1987), cat (Steriade et al., 1988) andmonkey (Lavoie and Parent, 1994b), but especially to theOutputs from the PPN

Most information regarding PPN outputs comes from non- associative and non-specific midline thalamic nuclei. In therat it has been estimated that 60% of cholinergic PPNprimate studies. The outputs of the PPN (Fig. 3) can be

divided into descending and ascending components, with neurones project to the thalamus and that 90% of PPN inputsto the thalamus are cholinergic (Sofroniew et al., 1985).cholinergic and non-cholinergic neurones contributing to

both. Although some PPN neurones have specific ascending Similar quantitative data are not available for primates.Ascending projections also provide dense innervation toprojections and others specific descending projections, some

collateralize and project in both directions (Rye et al., 1987; the non-thalamic basal ganglia structures via the ventraltegmental bundle (Lavoie and Parent, 1994a, b, c). NeuronesSpann and Grofova, 1991). The ascending projections of

the PPN are much more prominent than the descending located in the core of the PPN (presumably PPNc neurones,although this is not clearly stated by Lavoie and Parent) areprojections, although there is no consensus about their relative

proportions or which subpopulations of PPN neurones those that provide the most dense innervation of the basalganglia. Labelling with anterograde tracers has shown that(cholinergic versus non-cholinergic or PPNc versus PPNd)

contribute to the various output pathways. Furthermore, it the SNc and the STN are by far the most densely innervatedstructures of the basal ganglia. PPN efferents reach theirhas been estimated that ~40% of monkey PPN neurones

project contralaterally to their basal ganglia targets (Lavoie target sites in the basal ganglia by ascending along the


lenticular fasciculus and ansa lenticularis, which are not been shown. Although excitatory responses after PPNstimulation were found in cat pallidal neurones (Gonya-the major output projection paths of the GPi.Magee and Anderson, 1983), it was not clear whichpopulations of PPN neurones were stimulated or whichSubstantia nigra (SN). The PPN sends cholinergic

projections to the dopamine-containing neurones of the SNc populations of pallidal neurones were activated.with a minor cholinergic contingent to the SNr in the rat

Striatum. A pedunculostriatal projection has been shown(Woolf and Butcher, 1986; Scarnati et al., 1988). Recently,in the monkey (Lavoie and Parent, 1994b). These PPN fibresit has been shown that PPN cholinergic and glutamatergicare poorly arborized in most of the caudate nucleus andneurones form synaptic contacts with dopaminergic neuronesputamen. The chemical nature of this projection is unknown.in the SNc in non-human primates and rats (Charara et al.,

1996; Takakusaki et al., 1996). There are also studies which Other ascending targets. Other ascending targets thoughtsuggest that single PPN terminals in contact with SNc

to exist in non-primate species include the superior colliculusdopaminergic neurones may contain both glutamate and

and a number of limbic structures (basal forebrain,acetylcholine (Lavoie and Parent, 1994c; Charara et al.,

hypothalamus, zona incerta, amygdala). These ascending1996). In the anaesthetized rat, electrical stimulation of PPN

connections have been reviewed recently (Inglis and Winn,neurones leads to excitation of SNc neurones via a short-

1995; Reese et al., 1995; Winn et al., 1997).latency, direct, excitatory PPN–substantia nigra pathway anda less marked and rather sparse activation via a shortpolysynaptic pathway (Scarnati et al., 1984, 1986, 1987), Descending projectionsprobably involving non-cholinergic PPN neurones (Scarnati Although studied predominantly in non-primates, descendinget al., 1986; Di Loreto et al., 1992). The proportion of PPN targets include several midbrain, pontine and medullary areasneurones projecting to the substantia nigra is ~40% in the including several nuclei of the reticular formation, the deeprat and only 25% in the monkey (Gould et al., 1989; Lavoie cerebellar nuclei and the spinal cord (reviewed by Inglis andand Parent, 1994c). The relative proportions of PPN outflow Winn, 1995; Reese et al., 1995). These descending projectionsto the SNc versus the SNr and the subpopulations of are thought to collateralize extensively to caudal structuresPPN neurones giving rise to this projection have not been (Rye et al., 1988) as well as to the thalamus (Semba et al.,determined. The PPN may also be a source of GABAergic 1990). The relative contributions of cholinergic and non-afferents to the SNc in primates (Charara et al., 1996). cholinergic neurones to the innervation of the medulla and

spinal cord have been assessed only in the rat (GoldsmithSubthalamic nucleus (STN). The existence of a bilateral and van der Kooy, 1988; Rye et al., 1988; Skinner et al.,projection from the PPN to the STN has been documented 1990) and cat (Edley and Graybiel, 1983). Most of thein a number of species, including the rat (Woolf and Butcher, descending cholinergic PPN neurones travel a shorter distance1986), cat (Edley and Graybiel, 1983) and monkey (Lavoie to the medullary reticular formation, which in turn providesand Parent, 1994b). These studies fall short of assessing bilateral outputs to the spinal cord. The direct projectionthe anatomical (PPNd versus PPNc) and neurochemical from the PPN to the cervical and thoracic cord is thought to(cholinergic versus non-cholinergic) nature of this pathway, be mainly non-cholinergic, although a small number ofalthough in the rat these have shown to be both cholinergic cholinergic PPN neurones may project as far as the spinal(Woolf and Butcher, 1986) or non-cholinergic (Lee et al., cord (Rye et al., 1988). Some of these descending projections1988) and excitatory (Hammond et al., 1983). Other studies are thought to terminate unilaterally in intermediate laminaein the rat suggest that PPN efferents to the STN and adjacent of the cervical and thoracic cord and bilaterally in the centralzona incerta are collaterals of PPN efferents to the pallidal grey of the cervical cord, rather than directly on motorcomplex (Hammond et al., 1983; Hallanger and Wainer, neurones (Goldsmith and van der Kooy, 1988; Rye et al.,1988). 1988). The major outputs from the PPN to the basal ganglia

and related structures in the primate are summarized in Figs2 and 3. In general, the ascending and descending projectionsGlobus pallidus (GP). In the monkey, the PPNof the PPN in the primate are similar to those in the cat andinnervation of the pallidal complex is less dense than that ofthe rodent. However, again it should be pointed out thatthe STN and substantia nigra. Pedunculopallidal fibres travelminimal data are available for humans.back along both the ansa lenticularis and lenticular fasciculus

and arborize more profusely in the monkey GPi than theglobus pallidus externa (Lavoie and Parent, 1994b), as has Electrophysiological properties of PPNbeen shown in the rat and cat. The neurotransmitter used by

neuronespedunculopallidal neurones has not yet been identified withTypes of PPN neuronescertainty. In the human brain, the GP receives cholinergic

innervation, the majority of which is thought to originate Intracellular recordingsfrom brainstem cholinergic nuclei (Mesulam et al., 1983), Three types of PPN neurones have been identified on the basis

of their electrophysiological membrane properties obtained bybut specific cholinergic innervation from PPN neurones has


intracellular recordings (Kang and Kitai, 1990; Takakusaki Preliminary experiments have suggested that ~75% of PPNneurones in rats have a regular pattern of activity (possiblyet al., 1996, 1997; Takakusaki and Kitai, 1997). Type I

neurones are characterized by bursts of fast action potentials. corresponding to cholinergic neurones) and 25% a ‘bursting’pattern (possibly corresponding to non-cholinergic neurones;The bursting (phasic) pattern of action potentials can be

elicited by depolarizing current or by the offset of Ogura et al., 1997). In awake cats, 25% of cells had broadspikes (2 ms duration) with a mean resting firing rate ofhyperpolarizing current, indicating that this type of neurone

can shift into a bursting mode in response to either an 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).excitatory or an inhibitory input. Morphologically, type I

neurones are small to medium spindle-shaped or triangular The cells with broad spikes and low discharge rates arethought to be cholinergic (Takakusaki et al., 1997) andcells with three to five primary dendrites. Type I neurones

are dispersed throughout the extent of the PPN and are probably correspond to the type II neurones described above.The other set of cells, with higher discharge rates, correspondprobably glutamatergic (Takakusaki et al., 1996).

As stated above, GABAergic pallidal and nigral efferents to the non-cholinergic type I neurones. Similar extracellularrecordings have been reported in awake monkeys (Matsumurato the PPN project preferentially to non-cholinergic PPNd

neurones (Kang and Kitai, 1990; Spann and Grofova, 1991; et al., 1997). Recordings from the human PPN have notbeen reported.Rye et al., 1995b; Shink et al., 1997). Several investigators

have shown that electrical stimulation of the SNr evokes The descending PPN projection to the spinal cord has beensuggested to be a source of muscle tone control (Rye et al.,predominantly monosynaptic inhibitory postsynaptic

potentials (IPSPs) and decreases the firing rate in PPN 1988) and a pattern generator for locomotion (see below).Thus, PPN neurones may act as a pace-setter for firing (beneurones in the anaesthetized rat (Granata and Kitai, 1991)

and cat (Noda and Oka, 1984) and in rat brain slices (Kang it bursting or non-bursting) of their target neurones (Kangand Kitai, 1990). As described above, the PPN containsand Kitai, 1990; Takakusaki et al., 1996). After a period of

suppressed activity, PPN neurones can rebound with increased populations of neurones with intrinsic membrane propertiesthat allow tonic or non-burst firing (type II, cholinergic) andspike discharges (Kang and Kitai, 1990). Histochemical

staining has shown that IPSPs can be recorded from both non- those that allow phasic or burst firing (type I, non-cholinergic;Takakusaki et al., 1996). Thus, the membrane properties ofcholinergic and cholinergic PPN neurones by SNr stimulation

(Kang and Kitai, 1990). the type II cholinergic neurones could allow tonic pace-setting (as in regulating the velocity of steady-stateType II neurones do not have burst-firing. Instead they fire

single action potentials with large afterhyperpolarizations in locomotion), whereas those of the non-cholinergic type Ineurones could be involved in phasic pace-setting (i.e. as inresponse to injections of depolarizing current. This

characteristic is suited to a relatively slow tonic repetitive gait initiation). However, there is no direct evidence tosupport this. Since projections from the GPi and SNr seemfiring pattern. Type II neurones are located in the rostral and

middle sections of the PPN and in general are medium to to preferentially target the non-cholinergic PPN neurones andsince this population of PPN neurones provides the prominentlarge, fusiform or polygonal cells possessing five to seven

primary dendrites. About 50% of type II neurones are descending PPN outputs to the spinal cord (Rye et al.,1988), one could further speculate that pallidal and nigralcholinergic. Thus, there seem to be two electrophysiologically

distinct populations of PPN neurones: ‘bursting’ (type I; connections to the type I (bursting, non-cholinergic) PPNneurones may be an important means by which the basallikely glutamatergic) and ‘non-bursting’ (type II; 50%

cholinergic). A third type of PPN neurone has characteristics ganglia regulate the initiation of gait.of both type I and type II PPN neurones. A second group ofinvestigators has also described three major classes of PPNneurones following intracellular recordings from thalamic-

Membrane receptors and pharmacology ofprojecting, rhodamine-labelled PPN neurones in the guinea-pig slice preparation (Leonard and Llinas, 1988). These were PPN neurones

Numerous neurotransmitters have been proposed to influencesimilar to the three types described above in the rat.PPN neurones directly (Table 1). Data have been generatedboth in vitro and in vivo. In vitro studies have usedexperimental rat and guinea-pig slice preparations with bathExtracellular recordings

Extracellular spike discharges from PPN neurones have been applications or local microinjections of neuroactive agents.These studies provide strong evidence for the direct influenceobserved in the anaesthetized rat (Hammond et al., 1983;

Scarnati et al., 1987; Granata and Kitai, 1991; Ogura et al., of a number of neuroactive agents on PPN neuronal activity.In vivo studies have observed animal behaviour in awake or1997) and cat (Noda and Oka, 1984). In these animals, one

group of cells had broad spikes with low and regular anaesthetized rats or cats during intracerebral microinjectionsof various neuroactive agents. These studies providespontaneous firing rates (0.5–8 spikes/s). A second set of

cells exhibited narrow spikes with higher discharge rates, behavioural information that may be of physiologicalsignificance, but the actual microinjection sites areranging from 10 to 20 spikes/s (Scarnati et al., 1987).


Table 1 PPN pharmacology, electrophysiology and behaviour

Drug Preparation Effect Behaviour

AcetylcholineCarbachol (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

GABAMuscimol (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 modelGlutamate

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

Opiatesµ-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 receptorblocking properties)

Substance P Awake rat, MI ↑ locomotion5

Glycine No effects onStrychnine (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 Llinas, 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; 8Conde et al., 1998; 9Childs and Gale, 1984; 10Kangand Kitai, 1990; 11Miwa et al., 1996; 12Sanchez and Leonard, 1994; 13Hammond et al., 1983; 14Clarke et al., 1987; 15Hernandez-Lopezet al., 1992; 16Niijima and Yoshida, 1988; 17Khateb et al., 1990; 18Williams and Reiner, 1993.

anatomically localized by gross stereotaxic techniques and firing of cholinergic PPN neurones lasting up to severalminutes (Sanchez and Leonard, 1994). These effects wereare only later documented by histochemical staining. This is

an important consideration, since microinjections that are blocked by the appropriate antagonists (Table 1). Inbehavioural studies, microinjections of glutamate agonists inonly 1–2 mm apart can give completely opposite behavioural

effects (Garcia-Rill et al., 1990). No studies have combined the area of the rat PPN generally increased locomotion(Milner and Mogenson, 1988; Niijima and Yoshida, 1988).microinjection and electrophysiological techniques in intact

animals to obtain better functional targeting of the actual In an in vivo study using anaesthetized precollicular-transected rats, the PPN injection site was further definedsites of microinjections with electrophysiology techniques

while assessing behavioural responses. It should be noted functionally by locomotion induced by electrical stimulation(Garcia-Rill et al., 1990). In these experiments, additionalthat there have been many other reports of microinjections

into the general region of the mesencephalic locomotor area injections of NMDA could drive stepping from a walk to atrot to a gallop. These effects were blocked in a dose-or the lateral dorsal tegmental area. We will summarize only

those thought to be specific to the PPN. dependent manner by specific NMDA antagonists. Since theyoccurred in rats with a transection at the upper brainstem,the effects were independent of brain structures rostral to thecut. These studies suggest that the application of glutamateGlutamate/NMDA

In the guinea-pig brain slice, bath applications or agonists excites cholinergic PPN neurones and leads toincreased locomotion. However, there have been no reportsmicroinjections of glutamate or N-methyl-D-aspartate

(NMDA) caused dose-dependent depolarization and increased showing increased locomotion coincident with increased PPN


Table 2 Summary of effects of major neurotransmitteractivity during injections of glutamate agonist. One groupsystems on cholinergic PPN neuronal activity andshowed increased activity of presumed PPN neurones withlocomotionlocal microinjections of glutamate in the anaesthetized rat

(Hammond et al., 1983). However, very high concentrations Neurotransmitter system Cholinergic PPN Locomotionof glutamate (1 mol/l) were required and no behavioural neuronal activityobservations were made. It has been shown that

Glutamate ↑ ↑microinjections of glutamate agonists into the area of theAcetylcholine ↓ ↓PPN increases the firing rate of presumed dopaminergic GABA ↓ ↓

neurones of SNc via a cholinergic pathway (Clarke et al.,1987) and elicits the turning behaviour associated with an Both cholinergic and GABAergic systems seem to inhibit

cholinergic PPN neuronal activity and diminish animalincrease in dopamine turnover in the neostriatum (Niijimalocomotion, whereas the glutamatergic system seems to increaseand Yoshida, 1988; Hernandez-Lopez et al., 1992).cholinergic neuronal activity in the PPN and to increase animallocomotion.

AcetylcholineIn the guinea-pig brain slice, microinjections of carbachol concomitant effects on PPN neuronal activity were not

reported.(an acetylcholine agonist) caused dose-dependent hyper-polarization and decreased firing of cholinergic PPN neurones(Serafin et al., 1990; Leonard and Llinas, 1994). These effectswere blocked with atropine (a muscarinic antagonist). In a Others agents

A number of other neuroactive agents (including serotonin,number of behavioural studies, investigators showed thatmicroinjections of carbachol into the rat PPN area decreased noradrenaline, histamine and opiates (Table 1), are thought

to influence the firing of PPN neurones. All of these, exceptlocomotion with a similar time-course of effect (a delay ofa few minutes and a duration of 10–30 min) (Brudzynski histamine, may be inhibitory. Even less is known, however,

concerning the relative importances of these other agents,et al., 1988; Milner and Mogenson, 1988; Garcia-Rill et al.,1990; Mathur et al., 1997). These effects could also be their distribution and origin, and the specific cell types of

the PPN with which they are in synaptic contact (i.e.blocked by antimuscarinics (atropine or scopolamine) butnot by anti-nicotinics. These studies suggest that the cholinergic versus non-cholinergic or bursting versus non-

bursting). Immunohistochemical and electron microscopeapplication of cholinergic agonists inhibits cholinergic PPNneuronal activity and leads to decreased locomotion. There studies in rats have shown that serotonergic afferents onto

cholinergic PPN neurones apparently arise in the raphe nucleihave been no reports of decreased locomotion coincidentwith decreased PPN neuronal activity during injections of (Honda and Semba, 1994). Possible excitatory histaminergic

afferents from the posterior hypothalamus to the PPN (Khatebacetylcholine agonists. Cholinergic input onto PPN neuronesappears to originate in the contralateral PPN and ipsilateral et al., 1990) have been implicated in an H1 receptor-mediated

arousing action of histamine. Other possible neurotransmitterlaterodorsal tegmentum in the rat (Fibiger and Semba, 1988).inputs to the PPN include glycine and galanin. Glycine-immunoreactive fibres and terminals have been observedapposed to cholinergic neurones in the cat PPN (Fort et al.,GABA

Bath applications of bicuculline (a GABA antagonist) in rat 1993). The peptide neurotransmitter galanin has beenlocalized in axonal fibres and terminals in the region ofbrain slices blocked the IPSPs in cholinergic PPN neurones

that were evoked by electrical stimulation of the SNr (Kang substance-P-containing neurones of the human PPN (Gaiet al., 1993). Microinjection of substance P into the rat PPNand Kitai, 1990). Microinjections of bicuculline or picrotoxin

(GABA antagonists) into the PPN area increased locomotion area increases locomotion (Garcia-Rill et al., 1990). Thephysiological significance of these connections remainsin a dose-dependent manner and with similar time-courses

of effect, whereas muscimol (a GABA agonist) inhibited unknown.In summary, the studies suggest that GABA andlocomotion in intact rats (Childs and Gale, 1984; Milner and

Mogenson, 1988; Garcia-Rill et al., 1990). These effects acetylcholine decrease cholinergic PPN activity and diminishlocomotion, while glutamate increases cholinergic PPNwere unaltered in rats with the brainstem hemitransected just

rostral to the PPN (Childs and Gale, 1984). In addition, in activity and increases locomotion (Table 2). No studies haveshown simultaneous effects on PPN neuronal activity orthe neuroleptic-induced catalepsy rat model of parkinsonism,

microinjections of picrotoxin (a GABA antagonist) into the behavioural effects. The glutamate and GABA effects weresimilar in transected animals, suggesting that the expressionPPN area increased locomotion with a similar time-course

(Miwa et al., 1996). Furthermore, in freely moving cats in of PPN outputs is not dependent upon ongoing influencesfrom the basal ganglia. Interactions of these differentwhich the PPN was physiologically identified with single-

unit recordings, muscimol caused a similar arrest of motor neurotransmitter systems at the level of the PPN have alsobeen shown. In studies on rats, carbachol and GABA haveperformance (Conde et al., 1998). Unfortunately, any


been shown to block NMDA-induced locomotion (Garcia- during locomotion in all classes of vertebrates (Grillner,1985). Thus, the same mesopontine and diencephalic centresRill et al., 1990).

In general, there has been little reproduction of experiments initiate locomotion in lampreys and primates, through theactivation of lower brainstem reticulospinal neurones. These,from different laboratories. If attempted, they suffer from

great differences in the methods and drug concentrations in turn, activate spinal networks of neurones which generatethe motor pattern, be it swimming or walking. Sensoryused. This has resulted in great variability of results, especially

in the time-course of effects. Work has concentrated mainly feedback is an integral part of the control system and helpsto adapt the motor pattern to external events. This sensoryon the cholinergic PPN neurones (as identified by

electrophysiological properties in slices or postinjection input is important for the initiation of movements andfor providing ongoing feedback for the maintenance ofhistochemistry in behavioural studies), with little emphasis

on the non-cholinergic population of PPN neurones. In movement. Details of the cellular and molecular functionof this network are now being revealed in simple modeladdition, studies have been limited to non-primate species,

and there has been only one study in a rodent model of systems in vertebrates such as the lamprey (Di Priscoet al., 1997).Parkinson’s disease (Miwa et al., 1996).

Although the in vitro experiments summarized above The responsiveness of PPN neurones to somatosensorystimuli (Grunwerg et al., 1992; Reese et al., 1995), coupledsuggest that the various types of receptors are present and

function in PPN neurones, they do not give conclusive proof. with the cholinergic PPN projections to the thalamus (asdescribed above) and the proposed inputs to the PPN fromReceptor-localization studies have established the presence

of NMDA-sensitive receptors in the area of the PPN (Stone lamina I of the cat spinal cord (Hylden et al., 1985), suggeststhat the PPN may also take part in the modulation of sensoryand Burton, 1988), but have not confirmed their actual

existence on PPN neurones. Muscarinic cholinergic (M2, M3 information to thalamic nuclei. The potential role of the PPNas a relay station, providing feedback information importantand M4) receptors were reported to be located on monkey

and human cholinergic PPN and laterodorsal tegmentum for the modulation of posture and gait initiation, is facilitatedby its prominent cholinergic ascending projections to theneurones (Rye et al., 1995a), the M2 receptor possessing

characteristics consistent with an inhibitory autoreceptor, thalamus and its connections with deep cerebellar nuclei.although the physiological role of these receptors is unknown.It has been proposed that the psychotropic actions ofantimuscarinics occur via M2 autoreceptors on cholinergic PPN neuronal activity during locomotion

Three separate populations of neurones displaying rhythmicPPN cells, whereas their antiparkinsonian effects occur viaM1 receptors in the forebrain (Yeomans, 1995). Glycine activity in relation to locomotion can be recorded

extracellularly in the area of the PPN in the decerebrate catreceptors have also been demonstrated in the area of thehuman PPN (Probst et al., 1986). (Garcia-Rill and Skinner, 1988). One group of neurones

displays a tonic firing pattern during locomotion whichdecreases in frequency or stops entirely with the cessationof the locomotor episode. These neurones have been termed

The role of the PPN in locomotion ‘on’ cells. A second group of neurones, called ‘off’ cells, alsodisplay a tonic firing pattern, but their frequency decreases asThe mesencephalic locomotor region

The PPN is believed to be part of the so-called mesencephalic the locomotion frequency increases and their firing rateincreases before the cessation of locomotion. These twolocomotor region. This is a functionally defined area of the

brainstem within which it is possible to elicit controlled groups of neurones are located primarily within the PPN andmay represent different subtypes of the previously definedlocomotion (locomotion in which increasingly higher levels

of electrical stimulation drive the frequency of stepping from cholinergic type II neurones (‘non-bursting’ neurones). Thethird group of neurones display a bursting pattern of firinga walk to a trot to a gallop) on a treadmill in decerebrate

animals including the cat (Garcia-Rill and Skinner, 1987a, b), during locomotion (termed ‘bursters’). These are located inmore widespread areas and may represent the non-cholinergicrat (Garcia-Rill, 1990) and possibly the monkey (Eidelberg

et al., 1981). type I neurones. The ‘on/off’ cells might modulate theduration of the stepping episode, while the bursters may beAlthough the optimal sites for the induction of locomotion

appear to be within the cholinergic neurone mass of the involved in modulating the frequency (and possible initiation)of stepping (Garcia-Rill and Skinner, 1991). Although theirPPNc (Garcia-Rill et al., 1987), there are several brainstem

regions, including prominent sensory nuclei, which can be precise role remains to be defined, one can speculate thatbursting, glutamatergic PPNd neurones, which are primarilystimulated to initiate locomotion (for a recent review, see

Reese et al., 1995). Each of these areas possesses direct innervated by GABAergic GPi (and possibly SNr) neuronesand provide the main PPN outputs to the spinal cord, mayoutputs to the spinal cord (the site of putative locomotor

pattern generators) and none of these areas can be considered be important for the initiation of programmed movements.In contrast, the non-bursting, possibly cholinergic PPNcto be specific to locomotion.

Neural networks have been used to model brain function neurones, which relay feedback sensory information from


the spinal cord and provide the main inputs back into the PPN (Kolliker-Fuse nucleus) in a patient with chronic painproduced increased tone in the contralateral limb musclesthalamus and SNc, may be more important for the main-

tenance of gait. (Young et al., 1992). There have been no other reports oflesioning or stimulation of PPN areas in humans.Recently, the activity of PPN neurones was recorded in

awake cats (Dormont et al., 1998) and monkeys (Matsumuraet al., 1997) conditioned to perform lever-movement tasks.In cats, the broad-spiked, low-frequency discharging neurones

PPN, reward and motivation(thought to be cholinergic) displayed increased activity,The cholinergic PPN neurones may also provide a form ofespecially during the programmed movements. In contrast,non-specific facilitation for behaviours linked to the likelihoodthe narrow-spiked, high-frequency discharging neuronesof reward, so they may represent an interface between(thought to be non-cholinergic) displayed early activationlimbic motivation systems and the brainstem motor apparatusbefore the programmed movements (Dormont et al., 1998).(Steckler et al., 1994). Cholinergic agonist stimulation of theIn monkeys, changes in PPN neuronal activity preceded therat SNc (whose main cholinergic inputs may be provided byonset of movement and occurred for both contralateral andPPNc neurones) increases the performance and initiation ofipsilateral limb movements (Matsumura et al., 1997).behaviours which the rat has pre-existing tendencies toperform (Winn, 1991). Inhibition of cholinergic PPN neuroneswith microinjections of carbachol can reduce the motorRegulation of gait and locomotion in the PPNperformance elicited by amphetamine injected into theContinuous mid-frequency (20–60 Hz) stimulation in the catnucleus accumbens (Brudzynski et al., 1988). In cats,PPN is required to elicit locomotion. Hundreds of stimulireinforcement-related activity in broad-spiked neuronesdelivered for several seconds must be applied before the first(thought to be cholinergic, as outlined above) is speculatedstep is induced (Garcia-Rill and Skinner, 1991). This effectto be associated with the PPN cholinergic projection to thehas been interpreted as one of ‘recruitment’ of locomotion, inSNc (Dormont et al., 1998). In contrast to Parkinson’s disease,which spinal pattern-generators are activated by reticulospinalin human schizophrenic states, the number of cholinergic PPNsystems triggered by stimulation of brainstem centres (Garcia-neurones is increased (Garcia-Rill et al., 1995; Yeomans,Rill and Skinner, 1987b). Similarly, electrical stimulation of1995). Since non-cholinergic neurones of the PPNd receivethe PPN in the rat (Kelland and Asdourian, 1989) and catinputs from the basal ganglia and possibly the limbic(Lai and Siegel, 1990) has been reported either to reduce orstructures (as described above), it has been proposed thatto stimulate muscle tone, depending on the rate of stimulation.the PPN, as a whole, also acts as an interface betweenThese results can be quite variable across laboratories becausethe selection of motor outputs by the basal ganglia and theof differences in stimulation protocols (Garcia-Rill et al.,incentive-motivational directives from the striatal–pallidal1990). In contrast, high-frequency (�100 Hz) stimulation ofcomplex to provide motivationally influenced activation ofthe cat PPN consistently induces suppression of muscle tonemotor pattern generators in the pons, medulla and spinal cord(Lai and Siegel, 1990). It has been speculated that certain(Inglis and Winn, 1995). Such incentive-motivational orstimulation parameters are necessary to shift PPN neuronesaffective factors may influence motor function, as occurs, forto a voltage ‘window’ conducive to increased locomotionexample, in kinesia paradoxica. PPN activation could improve(Garcia-Rill et al., 1990). Mid-range frequencies may bemotor planning, enabling an increased motivational ability tobest, while higher frequencies appear to set the system intocall up already preserved motor programmes for stereotypeda condition reminiscent of depolarization block.movements such as locomotion and reaching.The function of the PPN has also been inferred from

lesion and inhibitory neurotransmitter application studies.Excitotoxic lesions (with kainic acid injections) of the monkeyPPN (as identified with extracellular recordings) produced

The PPN and Parkinson’s diseasecontralateral hemiparkinsonism characterized by flexedposture and hypokinesia (Kojima et al., 1997). Radio- PPN neuropathology

It has been proposed that abnormalities of gait and posture,frequency lesions in the PPN in rhesus monkeys reducedmotor activity significantly, as reflected by a generalized in addition to rigidity and bradykinesia, may, in part, reflect

the loss of neurones or the suppression of neuronal activitybradykinesia that resembled Parkinson’s disease (Aziz et al.,1998). Bilateral lesions were required to achieve long- in the PPN. Analysis of the limited clinical data that are

available suggests a relationship between the loss oflasting effects. As outlined above, reversible pharmacologicalinactivation of the monkey PPN with unilateral intracerebral cholinergic neurones in the PPNc and the severity of

Parkinson’s disease symptoms (Zweig et al., 1989). Thus,microinjections of lidocaine or a GABA agonist resulted indelayed arrest of performance of a conditioned motor task the progression of Parkinson’s disease, and possibly the

change in response to levodopa (especially the refractorywithout motor impairment, suggesting an alteration in theselection process of the appropriate motor programme (Conde akinesia) that can occur as the disease progresses in certain

patients, may reflect increasing involvement of non-et al., 1998). Electrical stimulation at 50–60 Hz near the


dopaminergic neuronal systems, such as the PPNc cholinergic reduce the inhibitory basal ganglia output to the thalamusand PPNd glutamatergic neuronal systems. and PPN are associated with striking improvements in all

Neuropathological studies on humans have reported that major features of parkinsonism. Lesions of the STN in normal~50% of the large cholinergic neurones of the lateral part of monkeys decrease the neuronal activity of inhibitory GPithe PPNc degenerate in Parkinson’s disease (Hirsch et al., projections to the thalamus and PPN (Mitchell et al., 1989).1987; Jellinger, 1988; Zweig et al., 1989; Gai et al., 1991). STN lesions and chronic electrical stimulation in parkinsonianThe extent of non-cholinergic neuronal loss in the PPN has monkeys and patients with Parkinson’s disease reduce all thenot been determined. The observation that the magnitude of major motor disturbances of Parkinson’s disease, includingthe neuronal loss within the PPNc is similar to the neuronal akinesia, rigidity and tremor (Bergman et al., 1990; Azizloss within the SNc raises the possibility that PPN neurones et al., 1991, 1992; Benazzouz et al., 1993; Benabid et al.,may be susceptible to the same pathogenetic mechanisms as 1994; Limousin et al., 1995, 1998; Pollak et al., 1996; Gillnigral dopaminergic neurones. The PPN may also, at least in and Heywood, 1997; Kumar et al., 1998a, b). Direct lesioningtheory, have a role in SNc degeneration through an excitotoxic or stimulation of the GPi in human and non-human primateseffect of glutamatergic synaptic contacts from the PPN onto also improves parkinsonism (Gross et al., 1997, 1999; Langdopaminergic SNc neurones (Lavoie and Parent, 1994c). This et al., 1997; Galvez-Jimenez et al., 1998; Krack et al., 1998;raises the intriguing possibility, for which there is so far no Volkmann et al., 1998; Lieberman et al., 1999). Theseevidence, that reducing the glutaminergic drive from the PPN observations are consistent with the hypothesis that theto the dopaminergic cells of the substantia nigra may have overactive inhibitory influence from the basal ganglia to theneuroprotective effects and influence the rate of progression PPN is important in the pathogenesis of motor dysfunctionof Parkinson’s disease. in parkinsonism and that removing this disruptive influence

on PPN improves motor function.Would surgical procedures of the PPN be of therapeuticPPN and the parkinsonian basal ganglia circuit

value? The experimental data show that both electricalmodel stimulation and the delivery of neuroactive substances inIn parkinsonism, the inhibitory GABAergic projections from their PPN have striking effects on motor function. It may bethe GPi (and possibly the SNr) to the thalamus and PPN are possible to place a chronic deep brain stimulation electrodeoveractive. Regional uptake studies of 2-deoxyglucose in or a microinfusion cannula for the delivery of neuroactiveMPTP-treated parkinsonian monkeys show increased synaptic substances directly into the PPN to change its activity andactivity in the PPN (Mitchell et al., 1989). It is not known, modulate its output to its targets. The direct infusion ofhowever, what effect this increased synaptic activity has on

neuroactive substances into the PPN, as has been describedthe net output of PPN neurones. Recent experiments

recently in the globus pallidus and thalamus of patients (Pennusing extracellular single-unit recordings from anaesthet-

et al., 1998; Pahapill et al., 1999), opens a number of newized, 6-hydroxydopamine-lesioned rats have demonstrated

possibilities. Experiments in parkinsonian animals are neededdecreased firing rates of PPN neurones in the parkinsonian

to address some of these issues.state (Ogura et al., 1997), consistent with increased inhibitionfrom basal ganglia outputs. An interesting hypothesis is thatthe increased GABAergic inhibition of PPN/locomotor regionneurones from overactive descending pallidal (and possibly Acknowledgementsnigral) efferents in the parkinsonian state may underlie the We wish to thank Dr T. Z. Aziz, and Professor J. O.problems of initiating programmed movements, the akinesia Dostrovsky for their helpful comments. This work wasand the gait difficulties seen in parkinsonism. The pallidal– supported by grants from the Parkinson’s Foundation ofnigral projections appear to terminate preferentially on the

Canada and the Medical Research Council of Canada grantnon-cholinergic, glutamatergic neurones of the PPNd and

to A.M.L. and a Medical Research Council of Canadalargely avoid neurones of the PPNc (Shink et al., 1997),

Fellowship to P.A.P.and these glutamatergic PPNd neurones provide descendingprojections to the spinal cord. Furthermore, reducing PPNactivity, as occurs with destructive lesions, leads to aparkinsonian-like state (Kojima et al., 1997; Aziz et al., References1998). Medical or surgical intervention that reduces the Aziz TZ, Peggs D, Sambrook MA, Crossman AR.overactive inhibitory outflow from the basal ganglia to PPN Lesion of the subthalamic nucleus for the alleviation of 1-methyl-would be expected to release the activity of this nucleus and 4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced parkinsonism infacilitate a return towards normal function. the primate. Mov Disord 1991; 6: 288–92.

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The pedunculopontine nucleus and Parkinson’s disease · The pedunculopontine nucleus and Parkinson’s disease 1769 and physiology of the PPN are often incomplete, and are the role