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01-10-2011 | Basic Neurosciences, Genetics and Immunology - Review Article

The pedunculopontine tegmental nucleus: implications for a role in modulating spinal cord motoneuron excitability

Authors: Eugenio Scarnati, Tiziana Florio, Annamaria Capozzo, Giuseppina Confalone, Paolo Mazzone

Published in: Journal of Neural Transmission | Issue 10/2011

Abstract

There is evidence that deep brain stimulation (DBS) of the pedunculopontine tegmental nucleus (PPTg) improves parkinsonian motor signs. The mechanisms that mediate these effects and the modifications that occur in the PPTg in Parkinson’s disease (PD) are not fully known and are the object of current debate. The aim of this paper was to critically review available data with respect to (1) the presence of PPTg neurons linked to reticulospinal projections, (2) the involvement of these neurons in modulating spinal reflexes, and (3) the participation of fibers close to or within the PPTg region in such modulation. The PPTg neurons are distributed in a large pontotegmental region, stimulation of which can evoke activity in hindlimb, shoulder and neck muscles, and potentiate motor responses evoked by stimulation of dorsal roots. This influence seems to be carried out by fast-conducting descending fibers, which likely run in the medial reticulospinal pathway. It is yet unclear which neurotransmitters are involved and on which elements of the gray matter of the spinal cord PPTg fibers synapse. The modulation of spinal cord activity which can be achieved by stimulating the PPTg region seems to be mediated not only by PPTg neurons, but also by tecto-reticular fibers which run in the pontotegmental area, and which likely are activated during PPTg-DBS. The importance of these fibers is discussed taking into account the degeneration of PPTg neurons in PD and the benefits in gait and postural control that PPTg-DBS exerts in PD. The potential usefulness of PPTg-DBS in other neurodegenerative disorders characterized by neuronal loss in the brainstem is also considered.

Alstermark B, Pinter MJ, Sasaki S (1992a) Descending pathways mediating disynaptic excitation of dorsal neck motoneurones in the cat: brain stem relay. Neurosci Res 15:42–57PubMedCrossRef

Alstermark B, Pinter MJ, Sasaki S (1992b) Tectal and tegmental excitation in dorsal neck motoneurones of the cat. J Physiol 454:517–532PubMed

Ammari R, Lopez C, Bioulac B, Garcia L, Hammond C (2010) Subthalamic nucleus evokes similar long lasting glutamatergic excitations in pallidal, entopeduncular and nigral neurons in the basal ganglia slice. Neuroscience 166:808–818PubMedCrossRef

Angel RW, Hofmann WW (1963) The H reflex in normal, spastic, and rigid subjects. Arch Neurol 8:591–596

Anglade P, Tsuji S, Agid Y, Hirsch EC (1995) Neuronal plasticity and Parkinson disease. Mol Chem Neuropathol 24:251–255PubMedCrossRef

Atsuta Y, Abraham P, Iwahara T, Garcia-Rill E, Skinner RD (1991) Control of locomotion in vitro: II. Chemical stimulation. Somatosens. Mot Res 8:55–63

Baldissera F, Lundberg A, Udo M (1972) Activity evoked from the mesencephalic tegmentum in descending pathways other than the rubrospinal tract. Exp Brain Res 15:133–150PubMed

Baldissera F, Di Loreto S, Florio T, Scarnati E (1994) Short-latency excitation of hindlimb motoneurons induced by electrical stimulation of the pontomesencephalic tegmentum in the rat. Neurosci Lett 169:13–16PubMedCrossRef

Bevan MD, Bolam JP (1995) Cholinergic, GABAergic, and glutamate-enriched inputs from the mesopontine tegmentum to the subthalamic nucleus in the rat. J Neurosci 15:7105–7120PubMed

Bohnen NI, Muller ML, Koeppe RA, Studenski SA, Kilbourn MA, Frey KA, Albin RL (2009) History of falls in Parkinson disease is associated with reduced cholinergic activity. Neurology 73:1670–1676PubMedCrossRef

Braak H, Del Tredici K (2008) Cortico-basal ganglia-cortical circuitry in Parkinson’s disease reconsidered. Exp Neurol 212:226–229PubMedCrossRef

Breit S, Bouali-Benazzouz R, Benabid AL, Benazzouz A (2001) Unilateral lesion of the nigrostriatal pathway induces an increase of neuronal activity of the pedunculopontine nucleus, which is reversed by the lesion of the subthalamic nucleus in the rat. Eur J Neurosci 14:1833–1842PubMedCrossRef

Carlson JD, Pearlstein RD, Buchholz J, Iacono RP, Maeda G (1999) Regional metabolic changes in the pedunculopontine nucleus of unilateral 6-hydroxydopamine Parkinson’s model rats. Brain Res 828:12–19PubMedCrossRef

Chung KA, Lobb BM, Nutt JG, Horak FB (2010) Effects of a central cholinesterase inhibitor on reducing falls in Parkinson disease. Neurology 75:1263–1269PubMedCrossRef

Delwaide PJ, Pepin JL, De Pasqua V, de Noordhout AM (2000) Projections from basal ganglia to tegmentum: a subcortical route for explaining the pathophysiology of Parkinson’s disease signs? J Neurol 247(Suppl 2):II75–II81

Ebert U, Koch M (1992) Glutamate receptors mediate acoustic input to the reticular brain stem. Neuroreport 3:429–432PubMedCrossRef

Ebert U, Ostwald J (1991) The mesencephalic locomotor region is activated during the auditory startle response of the unrestrained rat. Brain Res 565:209–217PubMedCrossRef

Edwards SB (1975) Autoradiographic studies of the projections of the midbrain reticular formation: descending projections of nucleus cuneiformis. J Comp Neurol 161:341–358PubMedCrossRef

Ferraye MU, Debu B, Fraix V, Goetz L, Ardouin C, Yelnik J, Henry-Lagrange C, Seigneuret E, Piallat B, Krack P, Le Bas JF, Benabid AL, Chabardes S, Pollak P (2010) Effects of pedunculopontine nucleus area stimulation on gait disorders in Parkinson’s disease. Brain 133:205–214PubMedCrossRef

Florio T, Scarnati E, Confalone G, Minchella D, Galati S, Stanzione P, Stefani A, Mazzone P (2007) High-frequency stimulation of the subthalamic nucleus modulates the activity of pedunculopontine neurons through direct activation of excitatory fibres as well as through indirect activation of inhibitory pallidal fibres in the rat. Eur J Neurosci 25:1174–1186PubMedCrossRef

Futami T, Takakusaki K, Kitai ST (1995) Glutamatergic and cholinergic inputs from the pedunculopontine tegmental nucleus to dopamine neurons in the substantia nigra pars compacta. Neurosci Res 21:331–342PubMedCrossRef

Galati S, Scarnati E, Mazzone P, Stanzione P, Stefani A (2008) Deep brain stimulation promotes excitation and inhibition in subthalamic nucleus in Parkinson’s disease. Neuroreport 19:661–666PubMedCrossRef

Garcia-Rill E, Skinner RD, Fitzgerald JA (1985) Chemical activation of the mesencephalic locomotor region. Brain Res 330:43–54PubMedCrossRef

Garcia-Rill E, Houser CR, Skinner RD, Smith W, Woodward DJ (1987) Locomotion-inducing sites in the vicinity of the pedunculopontine nucleus. Brain Res Bull 18:731–738PubMedCrossRef

Garcia-Rill E, Kinjo N, Atsuta Y, Ishikawa Y, Webber M, Skinner RD (1990) Posterior midbrain-induced locomotion. Brain Res Bull 24:499–508PubMedCrossRef

Garcia-Rill E, Skinner RD, Miyazato H, Homma Y (2001) Pedunculopontine stimulation induces prolonged activation of pontine reticular neurons. Neuroscience 104:455–465PubMedCrossRef

Goldsmith M, van der Kooy D (1988) Separate non-cholinergic descending projections and cholinergic ascending projections from the nucleus tegmenti pedunculopontinus. Brain Res 445:386–391PubMedCrossRef

Gomez-Gallego M, Fernandez-Villalba E, Fernandez-Barreiro A, Herrero MT (2007) Changes in the neuronal activity in the pedunculopontine nucleus in chronic MPTP-treated primates: an in situ hybridization study of cytochrome oxidase subunit I, choline acetyl transferase and substance P mRNA expression. J Neural Transm 114:319–326PubMedCrossRef

Grantyn A, Grantyn R (1982) Axonal patterns and sites of termination of cat superior colliculus neurons projecting in the tecto-bulbo-spinal tract. Exp Brain Res 46:243–256PubMedCrossRef

Grillner S, Lund S (1968) The origin of a descending pathway with monosynaptic action on flexor motoneurones. Acta Physiol Scand 74:274–284PubMedCrossRef

Grofova I, Keane S (1991) Descending brainstem projections of the pedunculopontine tegmental nucleus in the rat. Anat Embryol (Berl) 184:275–290CrossRef

Hawkes CH, Del Tredici K, Braak H (2010) A timeline for Parkinson’s disease. Parkinsonism Relat Disord 16:79–84PubMedCrossRef

Hiraoka K, Matuo Y, Iwata A, Onishi T, Abe K (2006) The effects of external cues on ankle control during gait initiation in Parkinson’s disease. Parkinsonism Relat Disord 12:97–102PubMedCrossRef

Hirsch EC, Graybiel AM, Duyckaerts C, Javoy-Agid F (1987) Neuronal loss in the pedunculopontine tegmental nucleus in Parkinson disease and in progressive supranuclear palsy. Proc Natl Acad Sci USA 84:5976–5980PubMedCrossRef

Hoffmann P (1922) Untersuchungen uber die eigenreflexe (sehnenreflexe) menschlicher muskeln. Julius Springer, Berlin

Holstege JC, Kuypers HG (1982) Brain stem projections to spinal motoneuronal cell groups in rat studied by means of electron microscopy autoradiography. Prog Brain Res 57:177–183PubMedCrossRef

Homma Y, Skinner RD, Garcia-Rill E (2002) Effects of pedunculopontine nucleus (PPN) stimulation on caudal pontine reticular formation (PnC) neurons in vitro. J Neurophysiol 87:3033–3047PubMed

Huerta MF, Harting JK (1982) Projections of the superior colliculus to the supraspinal nucleus and the cervical spinal cord gray of the cat. Brain Res 242:326–331PubMedCrossRef

Iwamoto Y (1990) Disynaptic tectal and pyramidal excitation of hindlimb motoneurons mediated by pontine reticulospinal neurons in the cat. Exp Brain Res 79:175–186PubMedCrossRef

Jellinger K (1988) The pedunculopontine nucleus in Parkinson’s disease, progressive supranuclear palsy and Alzheimer’s disease. J Neurol Neurosurg Psychiatry 51:540–543PubMedCrossRef

Jenkinson N, Nandi D, Oram R, Stein JF, Aziz TZ (2006) Pedunculopontine nucleus electric stimulation alleviates akinesia independently of dopaminergic mechanisms. Neuroreport 17:639–641PubMedCrossRef

Kang Y, Kitai ST (1990) Electrophysiological properties of pedunculopontine neurons and their postsynaptic responses following stimulation of substantia nigra reticulata. Brain Res 535:79–95PubMedCrossRef

Kelland MD, Asdourian D (1989) Pedunculopontine tegmental nucleus-induced inhibition of muscle activity in the rat. Behav Brain Res 34:213–234PubMedCrossRef

Kobayashi Y, Okada K (2009) Reward processing of the basal ganglia:reward function of pedunculopontine tegmental nucleus. Brain Nerve 61:397–404PubMed

Kushnir M, Klein C, Rabey JM (2000) H reflex behavior in Parkinson’s disease patients. Effect of stimulus duration. Parkinsonism Relat Disord 6:243–246PubMedCrossRef

Lavoie B, Parent A (1994) Pedunculopontine nucleus in the squirrel monkey: cholinergic and glutamatergic projections to the substantia nigra. J Comp Neurol 344:232–241PubMedCrossRef

Manaye KF, Zweig R, Wu D, Hersh LB, De Lacalle S, Saper CB, German DC (1999) Quantification of cholinergic and select non-cholinergic mesopontine neuronal populations in the human brain. Neuroscience 89:759–770PubMedCrossRef

Mazzone P, Insola A, Sposato S, Scarnati E (2009) The deep brain stimulation of the pedunculopontine tegmental nucleus. Neuromodulation 12:191–204CrossRef

Mena-Segovia J, Sims HM, Magill PJ, Bolam JP (2008) Cholinergic brainstem neurons modulate cortical gamma activity during slow oscillations. J Physiol 586:2947–2960PubMedCrossRef

Mesulam MM, Mufson EJ, Wainer BH, Levey AI (1983) Central cholinergic pathways in the rat: an overview based on an alternative nomenclature (Ch1-Ch6). Neuroscience 10:1185–1201PubMedCrossRef

Meunier S, Pol S, Houeto JL, Vidailhet M (2000) Abnormal reciprocal inhibition between antagonist muscles in Parkinson’s disease. Brain 123(Pt 5):1017–1026PubMedCrossRef

Mitchell IJ, Clarke CE, Boyce S, Robertson RG, Peggs D, Sambrook MA, Crossman AR (1989) Neural mechanisms underlying parkinsonian symptoms based upon regional uptake of 2-deoxyglucose in monkeys exposed to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Neuroscience 32:213–226PubMedCrossRef

Miyazato H, Skinner RD, Reese NB, Mukawa J, Garcia-Rill E (1996) Midlatency auditory evoked potentials and the startle response in the rat. Neuroscience 75:289–300PubMedCrossRef

Moro E, Hamani C, Poon YY, Al Khairallah T, Dostrovsky JO, Hutchison WD, Lozano AM (2010) Unilateral pedunculopontine stimulation improves falls in Parkinson’s disease. Brain 133:215–224PubMedCrossRef

Newmann DB (1985) Distinguishing rat brainstem reticulospinal nuclei and their morphology. II. Pontine and mesencephalic nuclei. J Hirnforsch 26:385–418

Okada K, Kobayashi Y (2009) Characterization of oculomotor and visual activities in the primate pedunculopontine tegmental nucleus during visually guided saccade tasks. Eur J Neurosci 30:2211–2223PubMedCrossRef

Okada K, Toyama K, Inoue Y, Isa T, Kobayashi Y (2009) Different pedunculopontine tegmental neurons signal predicted and actual task rewards. J Neurosci 29:4858–4870PubMedCrossRef

Olszewski J, Baxter D (1982) Cytoarchitecture of the Human Brain Stem. Karger, Basel

Orieux G, Francois C, Feger J, Yelnik J, Vila M, Ruberg M, Agid Y, Hirsch EC (2000) Metabolic activity of excitatory parafascicular and pedunculopontine inputs to the subthalamic nucleus in a rat model of Parkinson’s disease. Neuroscience 97:79–88PubMedCrossRef

Palombo E, Porrino LJ, Bankiewicz KS, Crane AM, Sokoloff L, Kopin IJ (1990) Local cerebral glucose utilization in monkeys with hemiparkinsonism induced by intracarotid infusion of the neurotoxin MPTP. J Neurosci 10:860–869PubMed

Paxinos G, Huang XF (1995) Atlas of the human brainstem. Academic Press, San Diego

Paxinos G, Watson C (1986) The rat brain in stereotaxic coordinates, 2nd edn. Academic Press, Sydney

Peterson BW, Pitts NG, Fukushima K (1979) Reticulospinal connections with limb and axial motoneurons. Exp Brain Res 36:1–20PubMedCrossRef

Pierantozzi M, Palmieri MG, Galati S, Stanzione P, Peppe A, Tropepi D, Brusa L, Pisani A, Moschella V, Marciani MG, Mazzone P, Stefani A (2008) Pedunculopontine nucleus deep brain stimulation changes spinal cord excitability in Parkinson’s disease patients. J Neural Transm 115:731–735PubMedCrossRef

Plenz D, Kital ST (1999) A basal ganglia pacemaker formed by the subthalamic nucleus and external globus pallidus. Nature 400:677–682PubMedCrossRef

Ransmayr G, Faucheux B, Nowakowski C, Kubis N, Federspiel S, Kaufmann W, Henin D, Hauw JJ, Agid Y, Hirsch EC (2000) Age-related changes of neuronal counts in the human pedunculopontine nucleus. Neurosci Lett 288:195–198PubMedCrossRef

Redgrave P, Dean P, Mitchell IJ, Odekunle A, Clark A (1988) The projection from superior colliculus to cuneiform area in the rat. I. Anatomical studies. Exp Brain Res 72:611–625PubMedCrossRef

Rinne JO, Ma SY, Lee MS, Collan Y, Roytta M (2008) Loss of cholinergic neurons in the pedunculopontine nucleus in Parkinson’s disease is related to disability of the patients. Parkinsonism Relat Disord 14:553–557PubMedCrossRef

Robbins A, Schwartz-Giblin S, Pfaff DW (1990) Ascending and descending projections to medullary reticular formation sites which activate deep lumbar back muscles in the rat. Exp Brain Res 80:463–474PubMedCrossRef

Rye DB, Saper CB, Lee HJ, Wainer BH (1987) Pedunculopontine tegmental nucleus of the rat: cytoarchitecture, cytochemistry, and some extrapyramidal connections of the mesopontine tegmentum. J Comp Neurol 259:483–528PubMedCrossRef

Rye DB, Lee HJ, Saper CB, Wainer BH (1988) Medullary and spinal efferents of the pedunculopontine tegmental nucleus and adjacent mesopontine tegmentum in the rat. J Comp Neurol 269:315–341PubMedCrossRef

Satoh K (1979) The origin of reticulospinal fibers in the rat: a HRP study. J Hirnforsch 20:313–332PubMed

Scarnati E, Campana E, Pacitti C (1984) Pedunculopontine-evoked excitation of substantia nigra neurons in the rat. Brain Res 304:351–361PubMedCrossRef

Schieppati M (1987) The Hofmann reflex: a mean of assessing spinal reflex excitability and its descending control in man. Prog Neurobiol 28:345–376PubMedCrossRef

Shammah-Lagnado SJ, Negrao N, Silva BA, Ricardo JA (1987) Afferent connections of the nuclei reticularis pontis oralis and caudalis: a horseradish peroxidase study in the rat. Neuroscience 20:961–989PubMedCrossRef

Shimamoto SA, Larson PS, Ostrem JL, Glass GA, Turner RS, Starr PA (2010) Physiological identification of the human pedunculopontine nucleus. J Neurol Neurosurg Psychiatry 81:80–86PubMedCrossRef

Simon C, Kezunovic N, Ye M, Hyde JR, Hayar A, Williams DK, Garcia-Rill E (2010) Gamma band unit activity and population responses in the pedunculopontine nucleus (PPN). J Neurophysiol 104:463–474PubMedCrossRef

Simonetta MM, Meunier S, Vidailhet M, Pol S, Galitzky M, Rascol O (2002) Transmission of group II heteronymous pathways is enhanced in rigid lower limb of de novo patients with Parkinson’s disease. Brain 125:2125–2133CrossRef

Skinner RD, Kinjo N, Henderson V, Garcia-Rill E (1990a) Locomotor projections from the pedunculopontine nucleus to the spinal cord. Neuroreport 1:183–186PubMedCrossRef

Skinner RD, Kinjo N, Ishikawa Y, Biedermann JA, Garcia-Rill E (1990b) Locomotor projections from the pedunculopontine nucleus to the medioventral medulla. Neuroreport 1:207–210PubMedCrossRef

Spann BM, Grofova I (1989) Origin of ascending and spinal pathways from the nucleus tegmenti pedunculopontinus in the rat. J Comp Neurol 283:13–27PubMedCrossRef

Struppler A (1974) Elektromyographie der zentralen innervationsstorungen. In: Hops HC, Struppler A (eds) Reflexuntersuchungen. Thieme, Stuttgart, pp 166–200

Takakusaki K, Shiroyama T, Yamamoto T, Kitai ST (1996) Cholinergic and noncholinergic tegmental pedunculopontine projection neurons in rats revealed by intracellular labeling. J Comp Neurol 371:345–361PubMedCrossRef

Takakusaki K, Shiroyama T, Kitai ST (1997) Two types of cholinergic neurons in the rat tegmental pedunculopontine nucleus: electrophysiological and morphological characterization. Neuroscience 79:1089–1109PubMedCrossRef

Takakusaki K, Habaguchi T, Ohtinata-Sugimoto J, Saitoh K, Sakamoto T (2003) Basal ganglia efferents to the brainstem centers controlling postural muscle tone and locomotion: a new concept for understanding motor disorders in basal ganglia dysfunction. Neuroscience 119:293–308PubMedCrossRef

Takakusaki K, Habaguchi T, Saitoh K, Kohyama J (2004) Changes in the excitability of hindlimb motoneurons during muscular atonia induced by stimulating the pedunculopontine tegmental nucleus in cats. Neuroscience 124:467–480PubMedCrossRef

Valls-Sole J (2000) Neurophysiological characterization of parkinsonian syndromes. Neurophysiol Clin 30:352–367PubMedCrossRef

Vincent SR, Satoh K, Armstrong DM, Fibiger HC (1983) NADPH-diaphorase: a selective histochemical marker for the cholinergic neurons of the pontine reticular formation. Neurosci Lett 43:31–36PubMedCrossRef

Wang HL, Morales M (2009) Pedunculopontine and laterodorsal tegmental nuclei contain distinct populations of cholinergic, glutamatergic and GABAergic neurons in the rat. Eur J Neurosci 29:340–358PubMedCrossRef

Weinberger M, Hamani C, Hutchison WD, Moro E, Lozano AM, Dostrovsky JO (2008) Pedunculopontine nucleus microelectrode recordings in movement disorder patients. Exp Brain Res 188:165–174PubMedCrossRef

Wichmann T, DeLong MR (1998) Models of basal ganglia function and pathophysiology of movement disorders. Neurosurg Clin N Am 9:223–236PubMed

Woolf NJ, Butcher LL (1989) Cholinergic systems in the rat brain: IV. Descending projections of the pontomesencephalic tegmentum. Brain Res Bull 23:519–540PubMedCrossRef

Zweig RM, Jankel WR, Hedreen JC, Mayeux R, Price DL (1989) The pedunculopontine nucleus in Parkinson’s disease. Ann Neurol 26:41–46PubMedCrossRef

Title: The pedunculopontine tegmental nucleus: implications for a role in modulating spinal cord motoneuron excitability
Authors: Eugenio Scarnati
Tiziana Florio
Annamaria Capozzo
Giuseppina Confalone
Paolo Mazzone
Publication date: 01-10-2011
Publisher: Springer Vienna
Published in: Journal of Neural Transmission / Issue 10/2011
Print ISSN: 0300-9564
Electronic ISSN: 1435-1463
DOI: https://doi.org/10.1007/s00702-010-0532-2

At a glance: The STEP trials

Springer Medicine

The pedunculopontine tegmental nucleus: implications for a role in modulating spinal cord motoneuron excitability

Abstract

At a glance: The STEP trials

Springer Medicine

Abstract

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