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Distinct Roles of the Human Subthalamic Nucleus and Dorsal Pallidum in Parkinson’s Disease Impulsivity

      Abstract

      Background

      Impulsivity and impulse control disorders are common in Parkinson’s disease and lead to increased morbidity and reduced quality of life. Impulsivity is thought to arise from aberrant reward processing and inhibitory control, but it is unclear why deep brain stimulation of either the subthalamic nucleus (STN) or globus pallidus internus (GPi) affects levels of impulsivity. Our aim was to assess the role of the STN and GPi in impulsivity using invasive local field potential (LFP) recordings from deep brain stimulation electrodes.

      Methods

      We measured LFPs during a simple rewarding Go/NoGo paradigm in 39 female and male human patients with Parkinson’s disease manifesting variable amounts of impulsivity who were undergoing unilateral deep brain stimulation of either the STN (18 nuclei) or GPi (28 nuclei). We identified reward-specific LFP event-related potentials and correlated them to impulsivity severity.

      Results

      LFPs in both structures modulated during reward-specific Go and NoGo stimulus evaluation, reward feedback, and loss feedback. Motor and limbic functions were anatomically separable in the GPi but not in the STN. Across participants, LFP reward processing responses in the STN and GPi uniquely depended on the severity of impulsivity.

      Conclusions

      This study establishes LFP correlates of impulsivity within the STN and GPi regions. We propose a model for basal ganglia reward processing that includes the bottom-up role of the GPi in reward salience and the top-down role of the STN in cognitive control.

      Keywords

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      References

        • Corvol J.C.
        • Artaud F.
        • Cormier-Dequaire F.
        • Rascol O.
        • Durif F.
        • Derkinderen P.
        • et al.
        Longitudinal analysis of impulse control disorders in Parkinson disease.
        Neurology. 2018; 91: e189-e201
        • Eisinger R.S.
        • Ramirez-Zamora A.
        • Carbunaru S.
        • Ptak B.
        • Peng-Chen Z.
        • Okun M.S.
        • Gunduz A.
        Medications, deep brain stimulation, and other factors influencing impulse control disorders in Parkinson’s disease.
        Front Neurol. 2019; 10: 86
        • Dalley J.W.
        • Robbins T.W.
        Fractionating impulsivity: Neuropsychiatric implications.
        Nat Rev Neurosci. 2017; 18: 158-171
        • Evenden J.L.
        Varieties of impulsivity.
        Psychopharmacology (Berl). 1999; 146: 348-361
        • Ramirez-Zamora A.
        • Ostrem J.L.
        Globus pallidus interna or subthalamic nucleus deep brain stimulation for Parkinson disease: A review.
        JAMA Neurol. 2018; 75: 367-372
        • Tinkhauser G.
        • Pogosyan A.
        • Little S.
        • Beudel M.
        • Herz D.M.
        • Tan H.
        • Brown P.
        The modulatory effect of adaptive deep brain stimulation on beta bursts in Parkinson’s disease.
        Brain. 2017; 140: 1053-1067
        • de Hemptinne C.
        • Swann N.C.
        • Ostrem J.L.
        • Ryapolova-Webb E.S.
        • San Luciano M.
        • Galifianakis N.B.
        • Starr P.A.
        Therapeutic deep brain stimulation reduces cortical phase-amplitude coupling in Parkinson’s disease.
        Nat Neurosci. 2015; 18: 779-786
        • Rektor I.
        • Bočková M.
        • Chrastina J.
        • Rektorová I.
        • Baláž M.
        The modulatory role of subthalamic nucleus in cognitive functions - A viewpoint.
        Clin Neurophysiol. 2015; 126: 653-658
        • Volkmann J.
        • Daniels C.
        • Witt K.
        Neuropsychiatric effects of subthalamic neurostimulation in Parkinson disease.
        Nat Rev Neurol. 2010; 6: 487-498
        • Hack N.
        • Akbar U.
        • Thompson-Avila A.
        • Fayad S.M.
        • Hastings E.M.
        • Moro E.
        • et al.
        Impulsive and compulsive behaviors in Parkinson Study Group (PSG) centers performing deep brain stimulation surgery.
        J Parkinsons Dis. 2014; 4: 591-598
        • Moum S.J.
        • Price C.C.
        • Limotai N.
        • Oyama G.
        • Ward H.
        • Jacobson C.
        • et al.
        Effects of STN and GPi deep brain stimulation on impulse control disorders and dopamine dysregulation syndrome.
        PLoS One. 2012; 7e29768
        • Krause M.
        • Fogel W.
        • Heck A.
        • Hacke W.
        • Bonsanto M.
        • Trenkwalder C.
        • Tronnier V.
        Deep brain stimulation for the treatment of Parkinson’s disease: Subthalamic nucleus versus globus pallidus internus.
        J Neurol Neurosurg Psychiatry. 2001; 70: 464-470
        • Roane D.M.
        • Yu M.
        • Feinberg T.E.
        • Rogers J.D.
        Hypersexuality after pallidal surgery in Parkinson disease.
        Neuropsychiatry Neuropsychol Behav Neurol. 2002; 15: 247-251
        • Cagnan H.
        • Denison T.
        • McIntyre C.
        • Brown P.
        Emerging technologies for improved deep brain stimulation.
        Nat Biotechnol. 2019; 37: 1024-1033
        • Justin Rossi P.
        • Peden C.
        • Castellanos O.
        • Foote K.D.
        • Gunduz A.
        • Okun M.S.
        The human subthalamic nucleus and globus pallidus internus differentially encode reward during action control.
        Hum Brain Mapp. 2017; 38: 1952-1964
        • Howell N.A.
        • Prescott I.A.
        • Lozano A.M.
        • Hodaie M.
        • Voon V.
        • Hutchison W.D.
        Preliminary evidence for human globus pallidus pars interna neurons signaling reward and sensory stimuli.
        Neuroscience. 2016; 328: 30-39
        • Cavanagh J.F.
        • Wiecki T.V.
        • Cohen M.X.
        • Figueroa C.M.
        • Samanta J.
        • Sherman S.J.
        • Frank M.J.
        Subthalamic nucleus stimulation reverses mediofrontal influence over decision threshold.
        Nat Neurosci. 2011; 14: 1462-1467
        • Brittain J.S.
        • Watkins K.E.
        • Joundi R.A.
        • Ray N.J.
        • Holland P.
        • Green A.L.
        • et al.
        A role for the subthalamic nucleus in response inhibition during conflict.
        J Neurosci. 2012; 32: 13396-13401
        • Baker P.M.
        • Jhou T.
        • Li B.
        • Matsumoto M.
        • Mizumori S.J.Y.
        • Stephenson-Jones M.
        • Vicentic A.
        The lateral habenula circuitry: Reward processing and cognitive control.
        J Neurosci. 2016; 36: 11482-11488
        • Hong S.
        • Hikosaka O.
        Diverse sources of reward value signals in the basal ganglia nuclei transmitted to the lateral habenula in the monkey.
        Front Hum Neurosci. 2013; 7: 778
        • Fiore V.G.
        • Nolte T.
        • Rigoli F.
        • Smittenaar P.
        • Gu X.
        • Dolan R.J.
        Value encoding in the globus pallidus: fMRI reveals an interaction effect between reward and dopamine drive.
        Neuroimage. 2018; 173: 249-257
        • Rossi P.J.
        • Shute J.B.
        • Opri E.
        • Molina R.
        • Peden C.
        • Castellanos O.
        • et al.
        Impulsivity in Parkinson’s disease is associated with altered subthalamic but not globus pallidus internus activity.
        J Neurol Neurosurg Psychiatry. 2017; 88: 968-970
        • Weintraub D.
        • Mamikonyan E.
        • Papay K.
        • Shea J.A.
        • Xie S.X.
        • Siderowf A.
        Questionnaire for impulsive-compulsive disorders in Parkinson’s Disease-Rating Scale.
        Mov Disord. 2012; 27: 242-247
        • Evans A.H.
        • Okai D.
        • Weintraub D.
        • Lim S.Y.
        • O’Sullivan S.S.
        • Voon V.
        • et al.
        Scales to assess impulsive and compulsive behaviors in Parkinson’s disease: Critique and recommendations.
        Mov Disord. 2019; 34: 791-798
        • Alcantara J.D.
        • Eisinger R.S.
        • Opri E.
        • Kelberman M.
        • Cagle J.N.
        • Gomez J.
        • et al.
        Florida research open-source synchronization tool (FROST) for electrophysiology experiments.
        J Neurosci Methods. 2020; 341: 108800
        • Van Wouwe N.C.
        • Claassen D.O.
        • Neimat J.S.
        • Kanoff K.E.
        • Wylie S.A.
        Dopamine selectively modulates the outcome of learning unnatural action-valence associations.
        J Cogn Neurosci. 2017; 29: 816-826
        • Georgiev D.
        • Dirnberger G.
        • Wilkinson L.
        • Limousin P.
        • Jahanshahi M.
        In Parkinson’s disease on a probabilistic Go/NoGo task deep brain stimulation of the subthalamic nucleus only interferes with withholding of the most prepotent responses.
        Exp Brain Res. 2016; 234: 1133-1143
        • Eisinger R.S.
        • Scott B.M.
        • Le A.
        • Ponce E.M.T.
        • Lanese J.
        • Hundley C.
        • et al.
        Pavlovian bias in Parkinson’s disease: An objective marker of impulsivity that modulates with deep brain stimulation.
        Sci Rep. 2020; 10: 13448
        • Eisinger R.S.
        • Urdaneta M.E.
        • Foote K.D.
        • Okun M.S.
        • Gunduz A.
        Non-motor characterization of the basal ganglia: Evidence from human and non-human primate electrophysiology.
        Front Neurosci. 2018; 12: 385
        • Baláz M.
        • Rektor I.
        • Pulkrábek J.
        Participation of the subthalamic nucleus in executive functions: An intracerebral recording study.
        Mov Disord. 2008; 23: 553-557
        • Rektor I.
        • Baláz M.
        • Bocková M.
        Cognitive activities in the subthalamic nucleus. Invasive studies.
        Parkinsonism Relat Disord. 2009; 15: S83-S86
        • Huebl J.
        • Schoenecker T.
        • Siegert S.
        • Brücke C.
        • Schneider G.H.
        • Kupsch A.
        • et al.
        Modulation of subthalamic alpha activity to emotional stimuli correlates with depressive symptoms in Parkinson’s disease.
        Mov Disord. 2011; 26: 477-483
        • Hershberger W.A.
        An approach through the looking-glass.
        Anim Learn Behav. 1986; 14: 443-451
        • Herreras O.
        Local field potentials: Myths and misunderstandings.
        Front Neural Circuits. 2016; 10: 101
        • Dalley J.W.
        • Everitt B.J.
        • Robbins T.W.
        Impulsivity, compulsivity, and top-down cognitive control.
        Neuron. 2011; 69: 680-694
        • Mirabito G.
        • Taiwo Z.
        • Bezdek M.
        • Light S.N.
        Fronto-striatal activity predicts anhedonia and positive empathy subtypes.
        Brain Imaging Behav. 2019; 13: 1554-1565
        • Robbins T.W.
        • Gillan C.M.
        • Smith D.G.
        • de Wit S.
        • Ersche K.D.
        Neurocognitive endophenotypes of impulsivity and compulsivity: Towards dimensional psychiatry.
        Trends Cogn Sci. 2012; 16: 81-91
        • Zink C.F.
        • Pagnoni G.
        • Chappelow J.
        • Martin-Skurski M.
        • Berns G.S.
        Human striatal activation reflects degree of stimulus saliency.
        Neuroimage. 2006; 29: 977-983
        • Cooper J.C.
        • Knutson B.
        Valence and salience contribute to nucleus accumbens activation.
        Neuroimage. 2008; 39: 538-547
        • Dayan P.
        • Niv Y.
        • Seymour B.
        • Daw N.D.
        The misbehavior of value and the discipline of the will.
        Neural Netw. 2006; 19: 1153-1160
        • Hill W.F.
        • Mackintosh N.J.
        Conditioning and associative learning.
        Am J Psychol. 1984; 97 (Available at: https://www.jstor.org/stable/1422540?seq=1. Accessed April 23, 2021): 472
        • Cilia R.
        • van Eimeren T.
        Impulse control disorders in Parkinson’s disease: Seeking a roadmap toward a better understanding.
        Brain Struct Funct. 2011; 216: 289-299
        • Péron J.
        • Frühholz S.
        • Vérin M.
        • Grandjean D.
        Subthalamic nucleus: A key structure for emotional component synchronization in humans.
        Neurosci Biobehav Rev. 2013; 37: 358-373
        • Zénon A.
        • Duclos Y.
        • Carron R.
        • Witjas T.
        • Baunez C.
        • Régis J.
        • et al.
        The human subthalamic nucleus encodes the subjective value of reward and the cost of effort during decision-making.
        Brain. 2016; 139: 1830-1843
        • Fumagalli M.
        • Rosa M.
        • Giannicola G.
        • Marceglia S.
        • Lucchiari C.
        • Servello D.
        • et al.
        Subthalamic involvement in monetary reward and its dysfunction in parkinsonian gamblers.
        J Neurol Neurosurg Psychiatry. 2015; 86: 355-358
        • Pasquereau B.
        • Turner R.S.
        A selective role for ventromedial subthalamic nucleus in inhibitory control.
        Elife. 2017; 6e31627
        • Benis D.
        • David O.
        • Lachaux J.P.
        • Seigneuret E.
        • Krack P.
        • Fraix V.
        • et al.
        Subthalamic nucleus activity dissociates proactive and reactive inhibition in patients with Parkinson’s disease.
        Neuroimage. 2014; 91: 273-281
        • Hong S.
        • Amemori S.
        • Chung E.
        • Gibson D.J.
        • Amemori K.I.
        • Graybiel A.M.
        Predominant striatal input to the lateral habenula in macaques comes from striosomes.
        Curr Biol. 2019; 29: 51-61.e5
        • Stephenson-Jones M.
        Pallidal circuits for aversive motivation and learning.
        Curr Opin Behav Sci. 2019; 26: 82-89
        • Münte T.F.
        • Marco-Pallares J.
        • Bolat S.
        • Heldmann M.
        • Lütjens G.
        • Nager W.
        • et al.
        The human globus pallidus internus is sensitive to rewards - Evidence from intracerebral recordings.
        Brain Stimul. 2017; 10: 657-663
        • Rodriguez-Oroz M.C.
        • López-Azcárate J.
        • Garcia-Garcia D.
        • Alegre M.
        • Toledo J.
        • Valencia M.
        • et al.
        Involvement of the subthalamic nucleus in impulse control disorders associated with Parkinson’s disease.
        Brain. 2011; 134: 36-49
        • Espinosa-Parrilla J.F.
        • Baunez C.
        • Apicella P.
        Modulation of neuronal activity by reward identity in the monkey subthalamic nucleus.
        Eur J Neurosci. 2015; 42: 1705-1717
        • Weafer J.
        • Crane N.A.
        • Gorka S.M.
        • Phan K.L.
        • de Wit H.
        Neural correlates of inhibition and reward are negatively associated.
        Neuroimage. 2019; 196: 188-194
        • Mosley P.E.
        • Paliwal S.
        • Robinson K.
        • Coyne T.
        • Silburn P.
        • Tittgemeyer M.
        • et al.
        The structural connectivity of discrete networks underlies impulsivity and gambling in Parkinson’s disease.
        Brain. 2019; 142: 3917-3935
        • He Y.
        • Li Y.
        • Pu Z.
        • Chen M.
        • Gao Y.
        • Chen L.
        • et al.
        Striatopallidal pathway distinctly modulates goal-directed valuation and acquisition of instrumental behavior via striatopallidal output projections.
        Cereb Cortex. 2020; 30: 1366-1381
        • Rektor I.
        • Bareš M.
        • Brázdil M.
        • Kaňovský P.
        • Rektorová I.
        • Sochurková D.
        • et al.
        Cognitive- and movement-related potentials recorded in the human basal ganglia.
        Mov Disord. 2005; 20: 562-568
        • Sieger T.
        • Serranová T.
        • Růžička F.
        • Vostatek P.
        • Wild J.
        • Šťastná D.
        • et al.
        Distinct populations of neurons respond to emotional valence and arousal in the human subthalamic nucleus.
        Proc Natl Acad Sci U S A. 2015; 112: 3116-3121
        • Nambu A.
        Somatotopic organization of the primate basal ganglia.
        Front Neuroanat. 2011; 5: 26
        • Parent A.
        • Côté P.Y.
        • Lavoie B.
        Chemical anatomy of primate basal ganglia.
        Prog Neurobiol. 1995; 46: 131-197
        • Paz-Alonso P.M.
        • Navalpotro-Gomez I.
        • Boddy P.
        • Dacosta-Aguayo R.
        • Delgado-Alvarado M.
        • Quiroga-Varela A.
        • et al.
        Functional inhibitory control dynamics in impulse control disorders in Parkinson’s disease.
        Mov Disord. 2020; 35: 316-325