Local and Relayed Effects of Deep Brain Stimulation of the Pedunculopontine Nucleus

Our discovery of low-threshold stimulation-induced locomotion in the pedunculopontine nucleus (PPN) led to the clinical use of deep brain stimulation (DBS) for the treatment of disorders such as Parkinson’s disease (PD) that manifest gait and postural disorders. Three additional major discoveries on the properties of PPN neurons have opened new areas of research for the treatment of motor and arousal disorders. The description of (a) electrical coupling, (b) intrinsic gamma oscillations, and (c) gene regulation in the PPN has identified a number of novel therapeutic targets and methods for the treatment of a number of neurological and psychiatric disorders. We first delve into the circuit, cellular, intracellular, and molecular organization of the PPN, and then consider the clinical results to date on PPN DBS. This comprehensive review will provide valuable information to explain the network effects of PPN DBS, point to new directions for treatment, and highlight a number of issues related to PPN DBS.

[1]  E. Garcia-Rill,et al.  Bottom-up gamma maintenance in various disorders , 2019, Neurobiology of Disease.

[2]  A. Parent,et al.  Deep Brain Stimulation of the Pedunculopontine Nucleus Area in Parkinson Disease: MRI-Based Anatomoclinical Correlations and Optimal Target , 2019, Neurosurgery.

[3]  E. Garcia-Rill,et al.  Class II histone deacetylases require P/Q-type Ca2+ channels and CaMKII to maintain gamma oscillations in the pedunculopontine nucleus , 2018, Scientific Reports.

[4]  S. Schmid,et al.  The Role of Cholinergic Midbrain Neurons in Startle and Prepulse Inhibition , 2018, The Journal of Neuroscience.

[5]  A. Engel,et al.  Adverse events in deep brain stimulation: A retrospective long-term analysis of neurological, psychiatric and other occurrences , 2017, PloS one.

[6]  E. Arrigoni,et al.  Neural Circuitry of Wakefulness and Sleep , 2017, Neuron.

[7]  Clement Hamani,et al.  Pedunculopontine Nucleus Region Deep Brain Stimulation in Parkinson Disease: Surgical Techniques, Side Effects, and Postoperative Imaging , 2016, Stereotactic and Functional Neurosurgery.

[8]  Anand I. Rughani,et al.  Pedunculopontine Nucleus Region Deep Brain Stimulation in Parkinson Disease: Surgical Anatomy and Terminology , 2016, Stereotactic and Functional Neurosurgery.

[9]  E. Garcia-Rill,et al.  Intracellular mechanisms modulating gamma band activity in the pedunculopontine nucleus (PPN) , 2016, Physiological reports.

[10]  Olivier David,et al.  The primate pedunculopontine nucleus region: towards a dual role in locomotion and waking state , 2016, Journal of Neural Transmission.

[11]  K. Eliceiri,et al.  Blue Light Modulates Murine Microglial Gene Expression in the Absence of Optogenetic Protein Expression , 2016, Scientific Reports.

[12]  P. Bougnoux,et al.  Lipid rafts, KCa/ClCa/Ca2+ channel complexes and EGFR signaling: Novel targets to reduce tumor development by lipids? , 2015, Biochimica et biophysica acta.

[13]  Hayriye Cagnan,et al.  Bilateral adaptive deep brain stimulation is effective in Parkinson's disease , 2015, Journal of Neurology, Neurosurgery & Psychiatry.

[14]  F. Bradke,et al.  Coordinating Neuronal Actin–Microtubule Dynamics , 2015, Current Biology.

[15]  E. Garcia-Rill,et al.  High-threshold Ca2+ channels behind gamma band activity in the pedunculopontine nucleus (PPN) , 2015, Physiological reports.

[16]  E. Garcia-Rill,et al.  Modulation of gamma oscillations in the pedunculopontine nucleus by neuronal calcium sensor protein-1: relevance to schizophrenia and bipolar disorder. , 2015, Journal of neurophysiology.

[17]  E. Garcia-Rill,et al.  The physiology of the pedunculopontine nucleus: implications for deep brain stimulation , 2015, Journal of Neural Transmission.

[18]  H. Kennedy,et al.  Visual Areas Exert Feedforward and Feedback Influences through Distinct Frequency Channels , 2014, Neuron.

[19]  E. Garcia-Rill,et al.  Gamma band activity in the RAS-intracellular mechanisms , 2014, Experimental Brain Research.

[20]  M. Morales,et al.  Discharge Profiles across the Sleep–Waking Cycle of Identified Cholinergic, GABAergic, and Glutamatergic Neurons in the Pontomesencephalic Tegmentum of the Rat , 2014, The Journal of Neuroscience.

[21]  P. Sah,et al.  Imagined gait modulates neuronal network dynamics in the human pedunculopontine nucleus , 2014, Nature Neuroscience.

[22]  A. Benabid,et al.  Pedunculopontine Nucleus Area Oscillations during Stance, Stepping and Freezing in Parkinson’s Disease , 2013, PloS one.

[23]  E. Garcia-Rill,et al.  Muscarinic Modulation of High Frequency Oscillations in Pedunculopontine Neurons , 2013, Front. Neurol..

[24]  E. Garcia-Rill,et al.  Spatiotemporal properties of high-speed calcium oscillations in the pedunculopontine nucleus. , 2013, Journal of applied physiology.

[25]  Alessandro Stefani,et al.  The Serendipity Case of the Pedunculopontine Nucleus Low-Frequency Brain Stimulation: Chasing a Gait Response, Finding Sleep, and Cognition Improvement , 2013, Front. Neurol..

[26]  E. Garcia-Rill,et al.  Visualization of fast calcium oscillations in the parafascicular nucleus , 2013, Pflügers Archiv - European Journal of Physiology.

[27]  Tipu Z. Aziz,et al.  A spatiotemporal analysis of gait freezing and the impact of pedunculopontine nucleus stimulation , 2012, Brain : a journal of neurology.

[28]  E. Garcia-Rill,et al.  Gamma band activity in the developing parafascicular nucleus. , 2012, Journal of neurophysiology.

[29]  E. Garcia-Rill,et al.  Gamma Band Activity in the Reticular Activating System , 2012, Front. Neur..

[30]  S. Datta,et al.  Calcium/Calmodulin Kinase II in the Pedunculopontine Tegmental Nucleus Modulates the Initiation and Maintenance of Wakefulness , 2011, The Journal of Neuroscience.

[31]  E. Garcia-Rill,et al.  Mechanism behind gamma band activity in the pedunculopontine nucleus , 2011, The European journal of neuroscience.

[32]  Lief E. Fenno,et al.  The development and application of optogenetics. , 2011, Annual review of neuroscience.

[33]  S. Datta,et al.  Protein Kinase A in the Pedunculopontine Tegmental Nucleus of Rat Contributes to Regulation of Rapid Eye Movement Sleep , 2010, The Journal of Neuroscience.

[34]  S. Lehéricy,et al.  Cholinergic mesencephalic neurons are involved in gait and postural disorders in Parkinson disease. , 2010, The Journal of clinical investigation.

[35]  E. Garcia-Rill,et al.  Gamma band unit activity and population responses in the pedunculopontine nucleus. , 2010, Journal of neurophysiology.

[36]  P. Brown,et al.  The impact of low-frequency stimulation of the pedunculopontine nucleus region on reaction time in parkinsonism , 2010, Journal of Neurology, Neurosurgery & Psychiatry.

[37]  A. Costa,et al.  Non-motor functions in parkinsonian patients implanted in the pedunculopontine nucleus: Focus on sleep and cognitive domains , 2010, Journal of the Neurological Sciences.

[38]  Paolo Mazzone,et al.  The Deep Brain Stimulation of the Pedunculopontine Tegmental Nucleus , 2009, Neuromodulation : journal of the International Neuromodulation Society.

[39]  Nicola J. Ray,et al.  Anatomy, physiology, and pathophysiology of the pedunculopontine nucleus , 2009, Movement disorders : official journal of the Movement Disorder Society.

[40]  M. Morales,et al.  Pedunculopontine and laterodorsal tegmental nuclei contain distinct populations of cholinergic, glutamatergic and GABAergic neurons in the rat , 2009, The European journal of neuroscience.

[41]  J. Bolam,et al.  Cholinergic brainstem neurons modulate cortical gamma activity during slow oscillations , 2008, The Journal of physiology.

[42]  M. Hariz,et al.  Stereotactic localization of the human pedunculopontine nucleus: atlas-based coordinates and validation of a magnetic resonance imaging protocol for direct localization. , 2008, Brain : a journal of neurology.

[43]  E. Garcia-Rill,et al.  The developmental decrease in REM sleep: the role of transmitters and electrical coupling. , 2008, Sleep.

[44]  Clement Hamani,et al.  Pedunculopontine nucleus microelectrode recordings in movement disorder patients , 2008, Experimental Brain Research.

[45]  P. Mazzone,et al.  Stereotactic surgery of nucleus tegmenti pedunculopontini , 2008, British journal of neurosurgery.

[46]  Meijun Ye,et al.  Electrical coupling: novel mechanism for sleep-wake control. , 2007, Sleep.

[47]  R. Llinás,et al.  Modafinil enhances thalamocortical activity by increasing neuronal electrotonic coupling , 2007, Proceedings of the National Academy of Sciences.

[48]  P. Stanzione,et al.  Bilateral deep brain stimulation of the pedunculopontine and subthalamic nuclei in severe Parkinson's disease. , 2007, Brain : a journal of neurology.

[49]  R. E. Brown,et al.  Electrophysiological characterization of neurons in the dorsolateral pontine rapid-eye-movement sleep induction zone of the rat: Intrinsic membrane properties and responses to carbachol and orexins , 2006, Neuroscience.

[50]  S. Gill,et al.  Bilateral deep brain stimulation of the pedunculopontine nucleus for Parkinson's disease , 2005, Neuroreport.

[51]  P. Stanzione,et al.  Implantation of human pedunculopontine nucleus: a safe and clinically relevant target in Parkinson's disease , 2005, Neuroreport.

[52]  E. Garcia-Rill,et al.  Induction of long-lasting depolarization in medioventral medulla neurons by cholinergic input from the pedunculopontine nucleus. , 2005, Journal of applied physiology.

[53]  J. Martens,et al.  Functional role of lipid raft microdomains in cyclic nucleotide-gated channel activation. , 2004, Molecular pharmacology.

[54]  S. Datta,et al.  Single cell activity patterns of pedunculopontine tegmentum neurons across the sleep‐wake cycle in the freely moving rats , 2002, Journal of neuroscience research.

[55]  S. Datta.  Evidence that REM sleep is controlled by the activation of brain stem pedunculopontine tegmental kainate receptor. , 2002, Journal of neurophysiology.

[56]  S. Datta,et al.  Excitation of the pedunculopontine tegmental NMDA receptors induces wakefulness and cortical activation in the rat , 2001, Journal of neuroscience research.

[57]  E. Garcia-Rill,et al.  Pedunculopontine stimulation induces prolonged activation of pontine reticular neurons , 2001, Neuroscience.

[58]  S. Datta,et al.  Microinjection of glutamate into the pedunculopontine tegmentum induces REM sleep and wakefulness in the rat. , 2001, American journal of physiology. Regulatory, integrative and comparative physiology.

[59]  K. Shen,et al.  Dynamic control of CaMKII translocation and localization in hippocampal neurons by NMDA receptor stimulation. , 1999, Science.

[60]  Tobias Meyer,et al.  CaMKIIβ Functions As an F-Actin Targeting Module that Localizes CaMKIIα/β Heterooligomers to Dendritic Spines , 1998, Neuron.

[61]  J. Bullier,et al.  Axons, but not cell bodies, are activated by electrical stimulation in cortical gray matter I. Evidence from chronaxie measurements , 1998, Experimental Brain Research.

[62]  S. Datta,et al.  Excitation of the brain stem pedunculopontine tegmentum cholinergic cells induces wakefulness and REM sleep. , 1997, Journal of neurophysiology.

[63]  E. Garcia-Rill,et al.  The pedunculopontine nucleus—Auditory input, arousal and pathophysiology , 1995, Progress in Neurobiology.

[64]  E. Jodo,et al.  Firing of ‘possibly’ cholinergic neurons in the rat laterodorsal tegmental nucleus during sleep and wakefulness , 1992, Brain Research.

[65]  D. Paré,et al.  Fast oscillations (20-40 Hz) in thalamocortical systems and their potentiation by mesopontine cholinergic nuclei in the cat. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[66]  M. Jouvet,et al.  Inhibition of carbachol microinjections of presumptive cholinergic PGO-on neurons in freely moving cats , 1990, Brain Research.

[67]  G Oakson,et al.  Different cellular types in mesopontine cholinergic nuclei related to ponto-geniculo-occipital waves , 1990, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[68]  C. Saper,et al.  Pedunculopontine tegmental nucleus of the rat: Cytoarchitecture, cytochemistry, and some extrapyramidal connections of the mesopontine tegmentum , 1987, The Journal of comparative neurology.

[69]  E. Garcia-Rill,et al.  Connections of the mesencephalic locomotor region (MLR) I. Substantia nigra afferents , 1983, Brain Research Bulletin.

[70]  E. Garcia-Rill,et al.  Connections of the mesencephalic locomotor region (MLR) II. Afferents and efferents , 1983, Brain Research Bulletin.

[71]  E. Garcia-Rill,et al.  Pallidal projections to the mesencephalic locomotor region (MLR) in the cat. , 1981, The American journal of anatomy.

[72]  W Irnich,et al.  The Chronaxie Time and Its Practical Importance , 1980, Pacing and clinical electrophysiology : PACE.

[73]  M. Carpenter,et al.  Projections of the globus pallidus and adjacent structures: An autoradiographic study in the monkey , 1976, The Journal of comparative neurology.

[74]  M. Steriade,et al.  Correlations between alterations of the cortical transaminase activity and EEG patterns of sleep and wakefulness induced by brain-stem transections. , 1969, Brain research.

[75]  C. Shute,et al.  The ascending cholinergic reticular system: neocortical, olfactory and subcortical projections. , 1967, Brain : a journal of neurology.

[76]  E. Garcia-Rill,et al.  The 10 Hz Frequency: A Fulcrum For Transitional Brain States. , 2016, Translational brain rhythmicity.

[77]  E. Garcia-Rill,et al.  Bottom-up Gamma: the Pedunculopontine Nucleus and Reticular Activating System. , 2016, Translational brain rhythmicity.

[78]  E. Garcia-Rill,et al.  Modulation of Gamma Oscillations in the Pedunculopontine Nucleus (ppn) by Neuronal Calcium Sensor Protein-1 (ncs-1): Relevance to Schizophrenia and Bipolar Disorder 3 4 , 2014 .

[79]  Clement Hamani,et al.  Unilateral pedunculopontine stimulation improves falls in Parkinson's disease. , 2010, Brain : a journal of neurology.

[80]  B Piallat,et al.  Effects of pedunculopontine nucleus area stimulation on gait disorders in Parkinson's disease. , 2010, Brain : a journal of neurology.

[81]  K. Shen,et al.  CaMKIIbeta functions as an F-actin targeting module that localizes CaMKIIalpha/beta heterooligomers to dendritic spines. , 1998, Neuron.

[82]  G. Moruzzi,et al.  The sleep-waking cycle. , 1972, Ergebnisse der Physiologie, biologischen Chemie und experimentellen Pharmakologie.

[83]  W. Nauta,et al.  Projections of the lentiform nucleus in the monkey. , 1966, Brain research.

[84]  M. L. Shik,et al.  [Control of walking and running by means of electric stimulation of the midbrain]. , 1966, Biofizika.

[85]  Shik Ml,et al.  Control of walking and running by means of electric stimulation of the midbrain , 1966 .

[86]  K. Fuxe,et al.  EVIDENCE FOR THE EXISTENCE OF MONOAMINE-CONTAINING NEURONS IN THE CENTRAL NERVOUS SYSTEM. I. DEMONSTRATION OF MONOAMINES IN THE CELL BODIES OF BRAIN STEM NEURONS. , 1964, Acta physiologica Scandinavica. Supplementum.

[87]  G. Moruzzi,et al.  Brain stem reticular formation and activation of the EEG. , 1949, Electroencephalography and clinical neurophysiology.

[88]  D B Lindsley,et al.  Effect upon the EEG of acute injury to the brain stem activating system. , 1949, Electroencephalography and clinical neurophysiology.

[89]  Henry Orr,et al.  Contribution to the embryology of the lizard; With especial reference to the central nervous system and some organs of the head; together with observations on the origin of the vertebrates , 1887 .