The pathophysiological mechanisms of motivational deficits in Parkinson’s disease

&NA; Parkinson's disease (PD) is a progressive degenerative disorder that leads to disabling motor symptoms and a wide variety of neuropsychiatric symptoms. Apathy is the most common psychiatric disorder in the early stages of untreated PD and can be defined as a hypodopaminergic syndrome, which also includes anxiety and depression. Apathy is also considered the core feature of the parkinsonian triad (apathy, anxiety and depression) of behavioural non‐motor signs, including a motivational deficit. Moreover, apathy is recognised as a distinct chronic neuropsychiatric behavioural disorder based on specific diagnostic criteria. Given the prevalence of apathy in approximately 40% of the general Parkinson's disease population, this appears to be a contributing factor to dementia in PD; also, apathy symptoms are factors that potentially contribute to morbidity, leading to a major impairment of health‐related quality of life, thus stressing the importance of understanding the pathophysiology of this disease. Several studies have clearly established a prominent role for DA‐mediated signals in PD apathy. However, synergistic interaction between dopaminergic impairment resulting from the neurodegenerative process and deep brain stimulation of the subthalamic nucleus may cause or exacerbate apathy. Furthermore, serotoninergic mechanism signalling is also likely to be of importance in this pathophysiology. HighlightsApathy is a typical psychiatric feature of Parkinson disease.Standardized diagnostic criteria to identify apathy remain lacking.Mesocorticolimbic system plays a key role in the pathogenesis of apathy.Motivational and affective deficits observed in apathy may occur through subthalamic nucleus deep brain stimulation.Serotoninergic mechanism signaling is involved in the pathophysiology of apathy.

[1]  P. Dombrowski,et al.  Depressive-like behaviors alterations induced by intranigral MPTP, 6-OHDA, LPS and rotenone models of Parkinson's disease are predominantly associated with serotonin and dopamine , 2010, Progress in Neuro-Psychopharmacology and Biological Psychiatry.

[2]  J. Péron,et al.  Apathy in patients with Parkinson disease without dementia or depression , 2012, Neurology.

[3]  J. Péron,et al.  Subthalamic nucleus stimulation in Parkinson disease induces apathy , 2009, Neurology.

[4]  Alan A. Wilson,et al.  Elevated serotonin transporter binding in depressed patients with Parkinson's disease: A preliminary PET study with [11C]DASB , 2008, Movement disorders : official journal of the Movement Disorder Society.

[5]  D. Aarsland,et al.  Neuropsychiatric Symptoms in Parkinson's Disease. , 2015, Journal of Parkinson's disease.

[6]  Jacques Darcourt,et al.  Brain perfusion in Alzheimer's disease with and without apathy: a SPECT study with statistical parametric mapping analysis , 2002, Psychiatry Research: Neuroimaging.

[7]  P. Apicella,et al.  Reward-related neuronal activity in the subthalamic nucleus of the monkey , 2005, Neuroreport.

[8]  L. Tremblay,et al.  The prominent role of serotonergic degeneration in apathy, anxiety and depression in de novo Parkinson's disease. , 2016, Brain : a journal of neurology.

[9]  Y. Liu,et al.  Apathy, depression, and motor symptoms have distinct and separable resting activity patterns in idiopathic Parkinson disease , 2013, NeuroImage.

[10]  J. Salamone,et al.  Nucleus Accumbens Dopamine and the Forebrain Circuitry Involved in Behavioral Activation and Effort-Related Decision Making: Implications for Understanding Anergia and Psychomotor Slowing in Depression , 2006 .

[11]  I Litvan,et al.  Neuropsychiatric symptoms of patients with progressive supranuclear palsy and Parkinson's disease. , 2001, The Journal of neuropsychiatry and clinical neurosciences.

[12]  Bettina Schrader,et al.  Two‐year follow‐up of subthalamic deep brain stimulation in Parkinson's disease , 2003, Movement disorders : official journal of the Movement Disorder Society.

[13]  C. Marsden,et al.  Mood swings associated with the ‘on—off’ phenomenon in Parkinson's disease , 1987, Psychological Medicine.

[14]  M. T. Pellecchia,et al.  Anxiety is associated with striatal dopamine transporter availability in newly diagnosed untreated Parkinson's disease patients. , 2012, Parkinsonism & related disorders.

[15]  M. Savasta,et al.  Loss of dopaminergic nigrostriatal neurons accounts for the motivational and affective deficits in Parkinson’s disease , 2013, Molecular Psychiatry.

[16]  M. Walton,et al.  Comparing the role of the anterior cingulate cortex and 6‐hydroxydopamine nucleus accumbens lesions on operant effort‐based decision making , 2009, The European journal of neuroscience.

[17]  Ewelina Knapska,et al.  A gene for neuronal plasticity in the mammalian brain: Zif268/Egr-1/NGFI-A/Krox-24/TIS8/ZENK? , 2004, Progress in Neurobiology.

[18]  Yasin Temel,et al.  Limbic effects of high-frequency stimulation of the subthalamic nucleus. , 2010, Vitamins and hormones.

[19]  R. Brown,et al.  Behavioural disorders, Parkinson's disease, and subthalamic stimulation , 2002, Journal of neurology, neurosurgery, and psychiatry.

[20]  J. Salamone,et al.  D1 or D2 antagonism in nucleus accumbens core or dorsomedial shell suppresses lever pressing for food but leads to compensatory increases in chow consumption , 2001, Pharmacology Biochemistry and Behavior.

[21]  Simon Hong,et al.  The Globus Pallidus Sends Reward-Related Signals to the Lateral Habenula , 2008, Neuron.

[22]  K. Berridge,et al.  Affective neuroscience of pleasure: reward in humans and animals , 2008, Psychopharmacology.

[23]  S. Nicola,et al.  Dopamine Invigorates Reward Seeking by Promoting Cue-Evoked Excitation in the Nucleus Accumbens , 2014, The Journal of Neuroscience.

[24]  Matthew F. S. Rushworth,et al.  Weighing up the benefits of work: Behavioral and neural analyses of effort-related decision making , 2006, Neural Networks.

[25]  N. Volkow,et al.  Imaging dopamine's role in drug abuse and addiction , 2009, Neuropharmacology.

[26]  A. Benabid,et al.  Bilateral subthalamic nucleus stimulation for severe Parkinson's disease , 1995, Movement disorders : official journal of the Movement Disorder Society.

[27]  Scott J. Russo,et al.  The brain reward circuitry in mood disorders , 2013, Nature Reviews Neuroscience.

[28]  Z. Kiss,et al.  Behavioral effects of subthalamic deep brain stimulation in Parkinson's disease , 2009, Neuropsychologia.

[29]  J. Nielsen,et al.  Analysis of the Human Tissue-specific Expression by Genome-wide Integration of Transcriptomics and Antibody-based Proteomics* , 2013, Molecular & Cellular Proteomics.

[30]  Rudolf Morgenstern,et al.  Deep brain stimulation of subthalamic neurons increases striatal dopamine metabolism and induces contralateral circling in freely moving 6-hydroxydopamine-lesioned rats , 2002, Neuroscience Letters.

[31]  M. T. Pellecchia,et al.  Apathy and striatal dopamine transporter levels in de-novo, untreated Parkinson's disease patients. , 2015, Parkinsonism & related disorders.

[32]  A. Benabid,et al.  Long‐Term Electrical Inhibition of Deep Brain Targets in Movement Disorders , 2008, Movement disorders : official journal of the Movement Disorder Society.

[33]  P. Krack,et al.  Deep brain stimulation: from neurology to psychiatry? , 2010, Trends in Neurosciences.

[34]  Albert Gjedde,et al.  Mapping neuroreceptors at work: on the definition and interpretation of binding potentials after 20 years of progress. , 2005, International review of neurobiology.

[35]  Philip J. Hahn,et al.  Network perspectives on the mechanisms of deep brain stimulation , 2010, Neurobiology of Disease.

[36]  D. Grandjean,et al.  Subthalamic nucleus stimulation affects limbic and associative circuits: a PET study , 2010, European Journal of Nuclear Medicine and Molecular Imaging.

[37]  Angelo Antonini,et al.  The PRIAMO study: A multicenter assessment of nonmotor symptoms and their impact on quality of life in Parkinson's disease , 2009, Movement disorders : official journal of the Movement Disorder Society.

[38]  B. Dubois,et al.  Apathy and the functional anatomy of the prefrontal cortex-basal ganglia circuits. , 2006, Cerebral cortex.

[39]  A. Strafella,et al.  Apathy and Impulse Control Disorders: Yin & Yang of Dopamine Dependent Behaviors. , 2015, Journal of Parkinson's disease.

[40]  M. Mega,et al.  The Neuropsychiatric Inventory , 1994, Neurology.

[41]  H. Bergman,et al.  Goal-directed and habitual control in the basal ganglia: implications for Parkinson's disease , 2010, Nature Reviews Neuroscience.

[42]  G. Juckel,et al.  Lesions of dopaminergic neurons in the substantia nigra pars compacta and in the ventral tegmental area enhance depressive-like behavior in rats , 2007, Behavioural Brain Research.

[43]  M. Ghilardi,et al.  Apathy, but Not Depression, Reflects Inefficient Cognitive Strategies in Parkinson's Disease , 2011, PloS one.

[44]  Bogdan Draganski,et al.  Dopamine reverses reward insensitivity in apathy following globus pallidus lesions , 2013, Cortex.

[45]  L. Hazrati,et al.  Functional anatomy of the basal ganglia , 1995 .

[46]  Y. Temel,et al.  High-frequency stimulation of the subthalamic nucleus inhibits the firing of juxtacellular labelled 5-HT-containing neurones , 2011, Neuroscience.

[47]  E. Granieri,et al.  Explosive-aggressive behavior related to bilateral subthalamic stimulation. , 2004, Parkinsonism & related disorders.

[48]  Y. Agid,et al.  Does bilateral stimulation of the subthalamic nucleus aggravate apathy in Parkinson’s disease? , 2005, Journal of Neurology Neurosurgery & Psychiatry.

[49]  D. Brooks,et al.  Tremor in Parkinson’s disease and serotonergic dysfunction , 2003, Neurology.

[50]  J. Salamone,et al.  Activational and effort-related aspects of motivation: neural mechanisms and implications for psychopathology. , 2016, Brain : a journal of neurology.

[51]  L. Tremblay,et al.  Abnormal influences of passive limb movement on the activity of globus pallidus neurons in parkinsonian monkeys , 1988, Brain Research.

[52]  Abdelhamid Benazzouz,et al.  Emerging dysfunctions consequent to combined monoaminergic depletions in parkinsonism , 2012, Neurobiology of Disease.

[53]  D J Brooks,et al.  Personality correlates of [18F]dopa striatal uptake: results of positron-emission tomography in Parkinson's disease. , 1995, The Journal of neuropsychiatry and clinical neurosciences.

[54]  P Sockeel,et al.  The Lille apathy rating scale (LARS), a new instrument for detecting and quantifying apathy: validation in Parkinson’s disease , 2006, Journal of Neurology, Neurosurgery & Psychiatry.

[55]  L. Defebvre,et al.  Apathy in Parkinson's disease is associated with nucleus accumbens atrophy: A magnetic resonance imaging shape analysis , 2014, Movement disorders : official journal of the Movement Disorder Society.

[56]  J. Salamone,et al.  Effort-related functions of nucleus accumbens dopamine and associated forebrain circuits , 2007, Psychopharmacology.

[57]  J. Jankovic,et al.  Cognitive declines following bilateral subthalamic nucleus deep brain stimulation for the treatment of Parkinson’s disease , 2007, Journal of Neurology, Neurosurgery, and Psychiatry.

[58]  M. C. Campbell,et al.  Dopamine pathway loss in nucleus accumbens and ventral tegmental area predicts apathetic behavior in MPTP-lesioned monkeys , 2012, Experimental Neurology.

[59]  H. Caci,et al.  Striatal dopamine transporter levels correlate with apathy in neurodegenerative diseases A SPECT study with partial volume effect correction , 2008, Clinical Neurology and Neurosurgery.

[60]  Kae Nakamura,et al.  Predictive Reward Signal of Dopamine Neurons , 2015 .

[61]  L. Defebvre,et al.  Influence of chronic bilateral stimulation of the subthalamic nucleus on cognitive function in Parkinson's disease , 2001, Journal of Neurology.

[62]  A. Dickinson,et al.  Parallel and interactive learning processes within the basal ganglia: Relevance for the understanding of addiction , 2009, Behavioural Brain Research.

[63]  Paul Krack,et al.  Parkinsonian apathy responds to dopaminergic stimulation of D2/D3 receptors with piribedil. , 2013, Brain : a journal of neurology.

[64]  H. Caci,et al.  The Apathy Inventory: assessment of apathy and awareness in Alzheimer's disease, Parkinson's disease and mild cognitive impairment , 2002, International journal of geriatric psychiatry.

[65]  K. Dujardin,et al.  Apathy and anhedonia rating scales in Parkinson's disease: Critique and recommendations , 2008, Movement disorders : official journal of the Movement Disorder Society.

[66]  J. Saint-Cyr,et al.  Neuropsychological consequences of chronic bilateral stimulation of the subthalamic nucleus in Parkinson's disease. , 2000, Brain : a journal of neurology.

[67]  Janet B W Williams,et al.  Diagnostic and Statistical Manual of Mental Disorders , 2013 .

[68]  M. Savasta,et al.  Implication of dopamine D3 receptor activation in the reversion of Parkinson's disease-related motivational deficits , 2014, Translational Psychiatry.

[69]  J. Morris,et al.  The association of ventral tegmental area histopathology with adult dementia. , 1988, Archives of neurology.

[70]  J. Salamone,et al.  The behavioral pharmacology of effort-related choice behavior: dopamine, adenosine and beyond. , 2012, Journal of the experimental analysis of behavior.

[71]  H. Tachibana,et al.  Clinical correlates of anhedonia in patients with Parkinson's disease , 2013, Clinical Neurology and Neurosurgery.

[72]  Mario F. Mendez,et al.  Neurobehavioral changes associated with caudate lesions , 1989, Neurology.

[73]  D. Schaid,et al.  Anxiety disorders and depressive disorders preceding Parkinson's disease: A case‐control study , 2000, Movement disorders : official journal of the Movement Disorder Society.

[74]  D. Joel,et al.  High frequency stimulation and pharmacological inactivation of the subthalamic nucleus reduces ‘compulsive’ lever-pressing in rats , 2009, Experimental Neurology.

[75]  Jens Volkmann,et al.  Neuropsychiatric effects of subthalamic neurostimulation in Parkinson disease , 2010, Nature Reviews Neurology.

[76]  M. Husain,et al.  Characterization of reward and effort mechanisms in apathy , 2015, Journal of Physiology-Paris.

[77]  A. Benabid,et al.  Five-year follow-up of bilateral stimulation of the subthalamic nucleus in advanced Parkinson's disease. , 2003, The New England journal of medicine.

[78]  M. Buonocore,et al.  Posterior cingulate cortex activation by emotional words: fMRI evidence from a valence decision task , 2003, Human brain mapping.

[79]  J. Duffy The Neural Substrates of Motivation , 1997 .

[80]  J. Nutt,et al.  Mood and anxiety fluctuation in Parkinson's disease associated with levodopa infusion: Preliminary findings , 1995, Movement disorders : official journal of the Movement Disorder Society.

[81]  Rudolf Morgenstern,et al.  High‐frequency stimulation of the subthalamic nucleus enhances striatal dopamine release and metabolism in rats , 2003, Journal of neurochemistry.

[82]  D. Brooks,et al.  Fatigue in Parkinson's disease is linked to striatal and limbic serotonergic dysfunction. , 2010, Brain : a journal of neurology.

[83]  Richard G. Brown,et al.  Negative symptoms: the ‘pathology’ of motivation and goal-directed behaviour , 2000, Trends in Neurosciences.

[84]  M. Amalric,et al.  SK channel blockade reverses cognitive and motor deficits induced by nigrostriatal dopamine lesions in rats. , 2014, The international journal of neuropsychopharmacology.

[85]  D. Bowers,et al.  The trajectory of apathy after deep brain stimulation: from pre-surgery to 6 months post-surgery in Parkinson's disease. , 2011, Parkinsonism & related disorders.

[86]  E. Moro,et al.  Chronic subthalamic nucleus stimulation reduces medication requirements in Parkinson’s disease , 1999, Neurology.

[87]  H. Tachibana,et al.  Apathy and Depression in Parkinson Disease , 2010, Journal of geriatric psychiatry and neurology.

[88]  R. Brown,et al.  Apathy in Parkinson’s disease , 2002, Journal of neurology, neurosurgery, and psychiatry.

[89]  Yen F. Tai,et al.  Compulsive drug use linked to sensitized ventral striatal dopamine transmission , 2006, Annals of neurology.

[90]  J. Kulisevsky,et al.  Apathy in Parkinson's Disease: Neurophysiological Evidence of Impaired Incentive Processing , 2014, The Journal of Neuroscience.

[91]  Ryan D Ward,et al.  Dissociation of Hedonic Reaction to Reward and Incentive Motivation in an Animal Model of the Negative Symptoms of Schizophrenia , 2012, Neuropsychopharmacology.

[92]  Y. Agid,et al.  Biochemical substrates of mental disturbances in Parkinson's disease. , 1984, Advances in neurology.

[93]  C. Da Cunha,et al.  Emotional, cognitive and neurochemical alterations in a premotor stage model of Parkinson's disease , 2008, Neuroscience.

[94]  Erwan Bezard,et al.  Chronic dopaminergic stimulation in Parkinson's disease: from dyskinesias to impulse control disorders , 2009, The Lancet Neurology.

[95]  R. Wise Dopamine and reward: The anhedonia hypothesis 30 years on , 2008, Neurotoxicity Research.

[96]  Jean-Michel Deniau,et al.  High Frequency Stimulation of the Subthalamic Nucleus , 2005 .

[97]  J. Salamone,et al.  Motivational views of reinforcement: implications for understanding the behavioral functions of nucleus accumbens dopamine , 2002, Behavioural Brain Research.

[98]  S. Ikemoto,et al.  Role of Dopamine D1 and D2 Receptors in the Nucleus Accumbens in Mediating Reward , 1997, The Journal of Neuroscience.

[99]  Yulia Worbe,et al.  Behavioral and movement disorders induced by local inhibitory dysfunction in primate striatum. , 2009, Cerebral cortex.

[100]  P. Amarenco,et al.  Tremor in Parkinson's disease and serotonergic dysfunction An 11 C-WAY 100635 PET study , 2003 .

[101]  E. Bézard,et al.  Initial clinical manifestations of Parkinson's disease: features and pathophysiological mechanisms , 2009, The Lancet Neurology.

[102]  J. Péron,et al.  Subthalamic nucleus stimulation affects orbitofrontal cortex in facial emotion recognition: a pet study , 2008, Brain : a journal of neurology.

[103]  K. Amirdelfan,et al.  High-Frequency Stimulation , 2018 .

[104]  I. Katz,et al.  Striatal dopamine transporter imaging correlates with anxiety and depression symptoms in Parkinson's disease. , 2005, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[105]  M. Husain,et al.  Reward Pays the Cost of Noise Reduction in Motor and Cognitive Control , 2015, Current Biology.

[106]  A. Dagher,et al.  Amphetamine-Induced Increases in Extracellular Dopamine, Drug Wanting, and Novelty Seeking: A PET/[11C]Raclopride Study in Healthy Men , 2002, Neuropsychopharmacology.

[107]  H. Steinbusch,et al.  Premature responding following bilateral stimulation of the rat subthalamic nucleus is amplitude and frequency dependent , 2004, Brain Research.

[108]  R. Marin Differential diagnosis and classification of apathy. , 1990, The American journal of psychiatry.

[109]  P. Mertens,et al.  Bilateral subthalamic nucleus stimulation in advanced Parkinson’s disease: Five year follow-up , 2009, Journal of Neurology.

[110]  H. Braak,et al.  Staging of brain pathology related to sporadic Parkinson’s disease , 2003, Neurobiology of Aging.

[111]  Junchao Tong,et al.  Preferential loss of serotonin markers in caudate versus putamen in Parkinson's disease. , 2007, Brain : a journal of neurology.

[112]  D. Brooks,et al.  [123I]β-CIT SPECT imaging of dopamine and serotonin transporters in Parkinson’s disease and multiple system atrophy , 2003, Nuklearmedizin.

[113]  A. Nieoullon,et al.  Dopamine: a key regulator to adapt action, emotion, motivation and cognition , 2003, Current opinion in neurology.

[114]  J. Salamone,et al.  The Mysterious Motivational Functions of Mesolimbic Dopamine , 2012, Neuron.

[115]  Dany Paleressompoulle,et al.  Reducing the desire for cocaine with subthalamic nucleus deep brain stimulation , 2009, Proceedings of the National Academy of Sciences.

[116]  Ethan S. Bromberg-Martin,et al.  Dopamine in Motivational Control: Rewarding, Aversive, and Alerting , 2010, Neuron.

[117]  E. Murray,et al.  A role for primate subgenual cingulate cortex in sustaining autonomic arousal , 2014, Proceedings of the National Academy of Sciences.

[118]  T. Robbins,et al.  Neurobehavioural mechanisms of reward and motivation , 1996, Current Opinion in Neurobiology.

[119]  Claire Haegelen,et al.  Fear recognition is impaired by subthalamic nucleus stimulation in Parkinson's disease , 2005, Neuropsychologia.

[120]  D. Aarsland,et al.  Apathy in drug-naïve patients with incident Parkinson’s disease: the Norwegian ParkWest study , 2010, Journal of Neurology.

[121]  M. Savasta,et al.  Pramipexole reverses Parkinson's disease‐related motivational deficits in rats , 2014, Movement disorders : official journal of the Movement Disorder Society.

[122]  P. Barone,et al.  Apathy in Parkinson’s Disease: Diagnosis, Neuropsychological Correlates, Pathophysiology and Treatment , 2013, Behavioural neurology.

[123]  William W. McDonald,et al.  Depression rating scales in Parkinson's disease: Critique and recommendations , 2007, Movement disorders : official journal of the Movement Disorder Society.

[124]  H. Mayberg,et al.  Reliability, validity, and clinical correlates of apathy in Parkinson's disease. , 1992, The Journal of neuropsychiatry and clinical neurosciences.

[125]  F. Durif,et al.  Evaluation des troubles comportementaux hyper- et hypodopaminergiques dans la maladie de Parkinson Assessment of hyper- and hypodopaminergic behaviors in Parkinson's disease , 2014 .

[126]  K. Berridge The debate over dopamine’s role in reward: the case for incentive salience , 2007, Psychopharmacology.

[127]  L. Wilkins Dissociating apathy and depression in Parkinson disease , 2006, Neurology.

[128]  J. Daunizeau,et al.  Computational Dissection of Dopamine Motor and Motivational Functions in Humans , 2016, The Journal of Neuroscience.

[129]  J. Bogousslavsky,et al.  The acute behavioral syndrome of anterior thalamic infarction: A prospective study of 12 cases , 2000, Annals of neurology.

[130]  A. Strafella,et al.  Apathy in Parkinson's disease: clinical features, neural substrates, diagnosis, and treatment , 2015, The Lancet Neurology.

[131]  Michael Okun,et al.  Startling facts about emotion in Parkinson's disease: blunted reactivity to aversive stimuli. , 2006, Brain : a journal of neurology.

[132]  Georg Juckel,et al.  High frequency stimulation of the subthalamic nucleus modulates neurotransmission in limbic brain regions of the rat , 2008, Experimental Brain Research.

[133]  M. Amalric,et al.  The subthalamic nucleus exerts opposite control on cocaine and 'natural' rewards , 2005, Nature Neuroscience.

[134]  Mathias Pessiglione,et al.  Disconnecting force from money: effects of basal ganglia damage on incentive motivation. , 2008, Brain : a journal of neurology.

[135]  Rita Z. Goldstein,et al.  Motivation Deficit in ADHD is Associated with Dysfunction of the Dopamine Reward Pathway , 2010, Molecular Psychiatry.

[136]  J. Deniau,et al.  Deep brain stimulation mechanisms: beyond the concept of local functional inhibition , 2010, The European journal of neuroscience.

[137]  L. Defebvre,et al.  Apathy may herald cognitive decline and dementia in Parkinson's disease , 2009, Movement disorders : official journal of the Movement Disorder Society.

[138]  Z. Tong,et al.  Up-regulation of tyrosine hydroxylase mRNA in a sub-population of A10 dopamine neurons in Parkinson's disease. , 2000, Brain research. Molecular brain research.

[139]  R. Bressan,et al.  Increased dopamine transporter density in Parkinson's disease patients with social anxiety disorder , 2011, Journal of the Neurological Sciences.

[140]  Y. Smith,et al.  The Corticostriatal and Corticosubthalamic Pathways: Two Entries, One Target. So What? , 2011, Front. Syst. Neurosci..

[141]  A. Benabid,et al.  Long term effects of bilateral subthalamic nucleus stimulation on cognitive function, mood, and behaviour in Parkinson’s disease , 2004, Journal of Neurology, Neurosurgery & Psychiatry.

[142]  G. Fénelon,et al.  Attempted and completed suicides after subthalamic nucleus stimulation for Parkinson’s disease , 2008, Journal of Neurology, Neurosurgery, and Psychiatry.

[143]  W. Schultz Behavioral dopamine signals , 2007, Trends in Neurosciences.

[144]  Karl Herholz,et al.  Regional cerebral metabolism in early Alzheimer’s disease with clinically significant apathy or depression , 2005, Biological Psychiatry.

[145]  M Baulac,et al.  Pure psychic akinesia with bilateral lesions of basal ganglia. , 1984, Journal of neurology, neurosurgery, and psychiatry.

[146]  L. Fellows,et al.  A Longitudinal View of Apathy and Its Impact After Stroke , 2009, Stroke.

[147]  A. Barceló,et al.  Effect of electrical and chemical stimulation of the subthalamic nucleus on the release of striatal dopamine , 2010, Synapse.

[148]  P. Jerabek,et al.  Regional metabolic effects of fluoxetine in major depression: serial changes and relationship to clinical response , 2000, Biological Psychiatry.

[149]  C. Benkelfat,et al.  Cocaine craving, euphoria, and self-administration: a preliminary study of the effect of catecholamine precursor depletion. , 2005, Behavioral neuroscience.

[150]  R. Wise Roles for nigrostriatal—not just mesocorticolimbic—dopamine in reward and addiction , 2009, Trends in Neurosciences.

[151]  L. Defebvre,et al.  Validation of diagnostic criteria for apathy in Parkinson's disease. , 2010, Parkinsonism & related disorders.

[152]  R. Marconi,et al.  Anhedonia and cognitive impairment in Parkinson's disease: Italian validation of the Snaith-Hamilton Pleasure Scale and its application in the clinical routine practice during the PRIAMO study. , 2009, Parkinsonism & related disorders.

[153]  K. Berridge,et al.  What is the role of dopamine in reward: hedonic impact, reward learning, or incentive salience? , 1998, Brain Research Reviews.

[154]  J. Boulenger,et al.  [Evolution of the concept of apathy: the need for a multifactorial approach in schizophrenia]. , 2013, L'Encephale.

[155]  H. de Wit,et al.  Amping Up Effort: Effects of d-Amphetamine on Human Effort-Based Decision-Making , 2011, The Journal of Neuroscience.

[156]  Eric Seigneuret,et al.  Subthalamic stimulation in Parkinson's disease: restoring the balance of motivated behaviours. , 2012, Brain : a journal of neurology.

[157]  Jens Volkmann,et al.  Depression and Parkinson’s disease , 2004, Journal of Neurology.

[158]  D. Kupfer,et al.  Amphetamine-induced dopamine release in human ventral striatum correlates with euphoria , 2001, Biological Psychiatry.

[159]  S. Houle,et al.  Increased striatal dopamine release in Parkinsonian patients with pathological gambling: a [11C] raclopride PET study. , 2009, Brain : a journal of neurology.

[160]  H. Steinbusch,et al.  Inhibition of 5-HT neuron activity and induction of depressive-like behavior by high-frequency stimulation of the subthalamic nucleus , 2007, Proceedings of the National Academy of Sciences.

[161]  A. Kupsch,et al.  High frequency stimulation of the subthalamic nucleus infuences striatal dopaminergic metabolism in the naive rat , 2000, Neuroreport.

[162]  V. Preedy,et al.  Unified Parkinson's Disease Rating Scale , 2010 .

[163]  Wu Zhou,et al.  Monetary reward speeds up voluntary saccades , 2014, Front. Integr. Neurosci..

[164]  T. Hatano,et al.  Anhedonia and its correlation with clinical aspects in Parkinson's disease , 2017, Journal of the Neurological Sciences.

[165]  J. Salamone,et al.  Neurobiological basis of motivational deficits in psychopathology , 2015, European Neuropsychopharmacology.

[166]  Masud Husain,et al.  Impulsivity and apathy in Parkinson's disease. , 2013, Journal of neuropsychology.

[167]  John Hilton,et al.  Positron emission tomography of striatal serotonin transporters in Parkinson disease. , 2003, Archives of neurology.

[168]  D. Zald,et al.  Dopaminergic Mechanisms of Individual Differences in Human Effort-Based Decision-Making , 2012, The Journal of Neuroscience.

[169]  J. Deniau,et al.  Cortical inputs to the subthalamus: intracellular analysis , 1981, Brain Research.

[170]  M. Mimura,et al.  Dysthymia and Apathy: Diagnosis and Treatment , 2011, Depression research and treatment.

[171]  P. Pollak,et al.  [Assessment of hyper- and hypodopaminergic behaviors in Parkinson's disease]. , 2009, Revue neurologique.

[172]  C. Hamani,et al.  Effects of Repeated Deep Brain Stimulation on Depressive- and Anxiety-Like Behavior in Rats: Comparing Entopeduncular and Subthalamic Nuclei , 2013, Brain Stimulation.

[173]  L. Defebvre,et al.  The Lille Apathy Rating Scale: Validation of a caregiver‐based version , 2008, Movement disorders : official journal of the Movement Disorder Society.

[174]  K. Berridge,et al.  Pleasure Systems in the Brain , 2015, Neuron.

[175]  R. Marin,et al.  Reliability and validity of the apathy evaluation scale , 1991, Psychiatry Research.

[176]  M Emre,et al.  Neuropsychiatric symptoms in patients with Parkinson’s disease and dementia: frequency, profile and associated care giver stress , 2006, Journal of Neurology, Neurosurgery & Psychiatry.

[177]  J. Péron,et al.  Does subthalamic nucleus stimulation induce apathy in Parkinson’s disease? , 2006, Journal of Neurology.

[178]  M. Husain,et al.  Reduced pupillary reward sensitivity in Parkinson’s disease , 2015, npj Parkinson's Disease.

[179]  J. Zarranz,et al.  Impact of psychiatric symptoms and sleep disorders on the quality of life of patients with Parkinson’s disease , 2011, Journal of Neurology.

[180]  G. Malandain,et al.  Perfusion Brain SPECT and Statistical Parametric Mapping Analysis Indicate That Apathy Is a Cingulate Syndrome: A Study in Alzheimer's Disease and Nondemented Patients , 2001, NeuroImage.

[181]  B. Borroni,et al.  Pattern of behavioral disturbances in corticobasal degeneration syndrome and progressive supranuclear palsy , 2009, International Psychogeriatrics.

[182]  Y. Smith,et al.  Microcircuitry of the direct and indirect pathways of the basal ganglia. , 1998, Neuroscience.

[183]  S. Engelborghs,et al.  Loss of psychic self-activation after paramedian bithalamic infarction. , 2000, Stroke.

[184]  G. Chiara,et al.  SCH 23390 blocks drug-conditioned place-preference and place-aversion: anhedonia (lack of reward) or apathy (lack of motivation) after dopamine-receptor blockade? , 1989, Psychopharmacology.

[185]  M. Lanotte,et al.  Apathy and verbal fluency in STN-stimulated PD patients , 2007, Journal of Neurology.

[186]  C. Marsden,et al.  The behavioural and motor consequences of focal lesions of the basal ganglia in man. , 1994, Brain : a journal of neurology.

[187]  M. Le Moal,et al.  Mesocorticolimbic dopaminergic network: functional and regulatory roles. , 1991, Physiological reviews.

[188]  Jeffrey L. Cummings,et al.  Neuropsychiatric aspects of progressive supranuclear palsy , 1996, Neurology.

[189]  B Mazoyer,et al.  Obsessive-compulsive and other behavioural changes with bilateral basal ganglia lesions. A neuropsychological, magnetic resonance imaging and positron tomography study. , 1989, Brain : a journal of neurology.

[190]  K. Dujardin,et al.  A multicentre study on suicide outcomes following subthalamic stimulation for Parkinson's disease. , 2008, Brain : a journal of neurology.

[191]  A. Kupsch,et al.  Striatal dopaminergic metabolism is increased by deep brain stimulation of the subthalamic nucleus in 6-hydroxydopamine lesioned rats , 2001, Neuroscience Letters.

[192]  R. V. D. Mast,et al.  Psychopathology in verified Huntington's disease gene carriers. , 2007, The Journal of neuropsychiatry and clinical neurosciences.

[193]  G. Fisone,et al.  A mouse model of non-motor symptoms in Parkinson's disease: focus on pharmacological interventions targeting affective dysfunctions , 2014, Front. Behav. Neurosci..

[194]  H. Yin,et al.  The role of the basal ganglia in habit formation , 2006, Nature Reviews Neuroscience.

[195]  Nora Turjanski,et al.  Depression in Parkinson's disease: loss of dopamine and noradrenaline innervation in the limbic system. , 2005, Brain : a journal of neurology.

[196]  D. Aarsland,et al.  The spectrum of neuropsychiatric symptoms in patients with early untreated Parkinson’s disease , 2009, Journal of Neurology, Neurosurgery, and Psychiatry.

[197]  Mark Hallett,et al.  Impulse control disorders in Parkinson's disease: recent advances. , 2011, Current opinion in neurology.

[198]  Y. Agid,et al.  Stimulation of subterritories of the subthalamic nucleus reveals its role in the integration of the emotional and motor aspects of behavior , 2007, Proceedings of the National Academy of Sciences.

[199]  T. Robinson,et al.  Subthalamic Nucleus Lesions Enhance the Psychomotor-Activating, Incentive Motivational, and Neurobiological Effects of Cocaine , 2005, The Journal of Neuroscience.

[200]  S. Raffard,et al.  Évolution du concept d’apathie : nécessité d’une approche multifactorielle dans la schizophrénie , 2013 .

[201]  N. White Reward: What Is It? How Can It Be Inferred from Behavior? , 2011 .

[202]  Paul Krack,et al.  Deep brain stimulation: Neuropsychological and neuropsychiatric issues , 2006, Movement disorders : official journal of the Movement Disorder Society.

[203]  V. Voon,et al.  Medication-related impulse control and repetitive behaviors in Parkinson disease. , 2007, Archives of neurology.

[204]  P. Fox,et al.  Differential limbic–cortical correlates of sadness and anxiety in healthy subjects: implications for affective disorders , 2000, Biological Psychiatry.

[205]  C. Baunez,et al.  Alcohol Preference Influences the Subthalamic Nucleus Control on Motivation for Alcohol in Rats , 2008, Neuropsychopharmacology.

[206]  R. Wise Voluntary ethanol intake in rats following exposure to ethanol on various schedules , 2004, Psychopharmacologia.

[207]  F. Windels,et al.  High Frequency Stimulation of the Subthalamic Nucleus Increases the Extracellular Contents of Striatal Dopamine in Normal and Partially Dopaminergic Denervated Rats , 2001, Journal of neuropathology and experimental neurology.

[208]  A. Lang,et al.  Levodopa‐related motor complications—Phenomenology , 2008, Movement disorders : official journal of the Movement Disorder Society.

[209]  A. Verma Compulsive Drug Use Linked to Sensitized Ventral Striatal Dopamine TransmissionEvans AH, Pavese N, Lawrence AD, et al (Reta Lila Weston Inst of Neurological Studies; Imperial College, London; MRC Cognition and Brain Sciences Unit, Cambridge, England) Ann Neurol 59:852–858, 2006§ , 2007 .

[210]  J. Aharon-Peretz,et al.  Novelty seeking and harm avoidance in Parkinson’s disease: effects of asymmetric dopamine deficiency , 2004, Journal of Neurology, Neurosurgery & Psychiatry.

[211]  C. Degueldre,et al.  Orbitofrontal Dysfunction Related to Both Apathy and Disinhibition in Frontotemporal Dementia , 2006, Dementia and Geriatric Cognitive Disorders.

[212]  Paul Krack,et al.  Mirthful laughter induced by subthalamic nucleus stimulation , 2001, Movement disorders : official journal of the Movement Disorder Society.

[213]  G. Rebec,et al.  Subthalamic and striatal neurons concurrently process motor, limbic, and associative information in rats performing an operant task. , 2007, Journal of neurophysiology.

[214]  Xu-dong Zhao,et al.  Long term high frequency stimulation of STN increases dopamine in the corpus striatum of hemiparkinsonian rhesus monkey , 2009, Brain Research.

[215]  S. Starkstein,et al.  Apathy and Parkinson’s Disease , 2011, Current treatment options in neurology.

[216]  S. Kish,et al.  Uneven pattern of dopamine loss in the striatum of patients with idiopathic Parkinson's disease. Pathophysiologic and clinical implications. , 1988, The New England journal of medicine.

[217]  R. Dolan,et al.  Dopamine and Effort-Based Decision Making , 2011, Front. Neurosci..

[218]  K. Berridge,et al.  Parsing reward , 2003, Trends in Neurosciences.

[219]  Timothy Edward John Behrens,et al.  Individual Differences in Premotor Brain Systems Underlie Behavioral Apathy , 2015, Cerebral cortex.

[220]  M. Molliver Serotonergic Neuronal Systems: What Their Anatomic Organization Tells Us about Function , 1987, Journal of clinical psychopharmacology.

[221]  H. Steinbusch,et al.  A combined in vivo neurochemical and electrophysiological analysis of the effect of high-frequency stimulation of the subthalamic nucleus on 5-HT transmission , 2012, Experimental Neurology.

[222]  E. Bézard,et al.  The dopamine D3 receptor: a therapeutic target for the treatment of neuropsychiatric disorders. , 2006, CNS & neurological disorders drug targets.

[223]  H. Kita,et al.  Efferent projections of the subthalamic nucleus in the rat: Light and electron microscopic analysis with the PHA‐L method , 1987, The Journal of comparative neurology.

[224]  B. Dubois,et al.  Motivation, reward, and Parkinson’s disease: influence of dopatherapy , 2002, Neuropsychologia.

[225]  G. M. Halliday,et al.  Loss of brainstem serotonin- and substance P-containing neurons in Parkinson's disease , 1990, Brain Research.

[226]  D. Aarsland,et al.  Prevalence and clinical correlates of apathy in Parkinson's disease: a community-based study. , 2009, Parkinsonism & related disorders.

[227]  K. Dujardin,et al.  Proposed diagnostic criteria for apathy in Alzheimer’s disease and other neuropsychiatric disorders , 2009, European Psychiatry.

[228]  J. H. Friedman,et al.  Fatigue in Parkinson's disease: a nine‐year follow‐up , 2001, Movement disorders : official journal of the Movement Disorder Society.

[229]  M. Savasta,et al.  Mechanisms of High Frequency Stimulation of the Subthalamic Nucleus in Parkinson's Disease: From Local to Distal Effects on the Basal Ganglia Network , 2011 .

[230]  L. Tremblay,et al.  Role of serotonergic 1A receptor dysfunction in depression associated with Parkinson's disease , 2012, Movement disorders : official journal of the Movement Disorder Society.

[231]  M. Savasta,et al.  High‐frequency stimulation of the subthalamic nucleus prolongs the increase in striatal dopamine induced by acute l‐3,4‐dihydroxyphenylalanine in dopaminergic denervated rats , 2007, The European journal of neuroscience.

[232]  L. Defebvre,et al.  Characteristics of apathy in Parkinson's disease , 2007, Movement disorders : official journal of the Movement Disorder Society.

[233]  Brian Knutson,et al.  Reward system activation in schizophrenic patients switched from typical neuroleptics to olanzapine , 2008, Psychopharmacology.

[234]  D. Brooks,et al.  Staging of serotonergic dysfunction in Parkinson's Disease: An in vivo 11C-DASB PET study , 2010, Neurobiology of Disease.

[235]  Dagmar Verbaan,et al.  Non-motor symptoms in Parkinson's disease , 2009 .

[236]  Y. Agid,et al.  Apathy following subthalamic stimulation in Parkinson disease: A dopamine responsive symptom , 2008, Movement disorders : official journal of the Movement Disorder Society.

[237]  H. Berendse,et al.  Interventions for fatigue in Parkinson's disease. , 2015, The Cochrane database of systematic reviews.

[238]  M. Husain,et al.  Dopamine enhances willingness to exert effort for reward in Parkinson's disease , 2015, Cortex.

[239]  Didier Grandjean,et al.  Author's Personal Copy Neuroscience and Biobehavioral Reviews Subthalamic Nucleus: a Key Structure for Emotional Component Synchronization in Humans Author's Personal Copy , 2022 .

[240]  Kevin J Black,et al.  Levodopa Challenge Neuroimaging of Levodopa-Related Mood Fluctuations in Parkinson's Disease , 2005, Neuropsychopharmacology.

[241]  K. Chaudhuri,et al.  Non-motor symptoms of Parkinson's disease: dopaminergic pathophysiology and treatment , 2009, The Lancet Neurology.

[242]  T. Ono,et al.  Altered accumbens neural response to prediction of reward associated with place in dopamine D2 receptor knockout mice , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[243]  A. Björklund,et al.  Serotonin Neuron Loss and Nonmotor Symptoms Continue in Parkinson’s Patients Treated with Dopamine Grafts , 2012, Science Translational Medicine.

[244]  A. Antonini,et al.  Functional abnormalities underlying pathological gambling in Parkinson disease. , 2008, Archives of neurology.

[245]  Y Agid,et al.  Is the mesocortical dopaminergic system involved in Parkinson disease? , 1980, Neurology.

[246]  H. Groenewegen,et al.  [Impulse control disorders in Parkinson's disease]. , 2011, Tijdschrift voor psychiatrie.

[247]  Joseph James Duffy,et al.  Apathy: a treatable syndrome. , 1995, The Journal of neuropsychiatry and clinical neurosciences.

[248]  R. Marin,et al.  Apathy: a neuropsychiatric syndrome. , 1991, The Journal of neuropsychiatry and clinical neurosciences.

[249]  T. Sesia,et al.  Cognitive and limbic effects of deep brain stimulation in preclinical studies. , 2009, Frontiers in bioscience.

[250]  T. Robbins,et al.  Bilateral high‐frequency stimulation of the subthalamic nucleus on attentional performance: transient deleterious effects and enhanced motivation in both intact and parkinsonian rats , 2007, The European journal of neuroscience.

[251]  M. Merello,et al.  The Unified Parkinson's Disease Rating Scale: Validation study of the mentation, behavior, and mood section , 2007, Movement disorders : official journal of the Movement Disorder Society.

[252]  P. Barone,et al.  Relationship between depression and cognitive dysfunctions in Parkinson’s disease without dementia , 2009, Journal of Neurology.

[253]  T. Chase Apathy in Neuropsychiatric Disease: Diagnosis, Pathophysiology, and Treatment , 2011, Neurotoxicity Research.

[254]  K. Chaudhuri,et al.  Non-motor symptoms of Parkinson's disease: diagnosis and management , 2006, The Lancet Neurology.

[255]  L. Tremblay,et al.  Non-motor dopamine withdrawal syndrome after surgery for Parkinson's disease: predictors and underlying mesolimbic denervation. , 2010, Brain : a journal of neurology.

[256]  I. Appollonio,et al.  Clinical, neuropsychological, and morphometric correlates of apathy in Parkinson's disease , 2002, Movement disorders : official journal of the Movement Disorder Society.

[257]  A. Benabid,et al.  Acute psychotropic effects of bilateral subthalamic nucleus stimulation and levodopa in Parkinson's disease , 2003, Movement disorders : official journal of the Movement Disorder Society.

[258]  P. Barone,et al.  The effect of pramipexole on mood and motivational symptoms in Parkinson's disease: a meta-analysis of placebo-controlled studies. , 2009, Clinical therapeutics.

[259]  M. Raichle,et al.  Emotion-induced changes in human medial prefrontal cortex: II. During anticipatory anxiety. , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[260]  A. Chaudhuri,et al.  Fatigue in neurological disorders , 2004, The Lancet.

[261]  R. Palmiter Dopamine Signaling in the Dorsal Striatum Is Essential for Motivated Behaviors , 2008, Annals of the New York Academy of Sciences.

[262]  Rita Z. Goldstein,et al.  Addiction: Pulling at the Neural Threads of Social Behaviors , 2011, Neuron.

[263]  A. Nambu A new dynamic model of the cortico-basal ganglia loop. , 2004, Progress in brain research.

[264]  M. Amalric,et al.  High frequency stimulation of the subthalamic nucleus has beneficial antiparkinsonian effects on motor functions in rats, but less efficiency in a choice reaction time task , 2003, The European journal of neuroscience.

[265]  M. Savasta,et al.  Subthalamic deep brain stimulation differently alters striatal dopaminergic receptor levels in rats , 2015, Movement disorders : official journal of the Movement Disorder Society.

[266]  T. Robbins,et al.  Neural systems of reinforcement for drug addiction: from actions to habits to compulsion , 2005, Nature Neuroscience.

[267]  Jean-Jacques Lemaire,et al.  Contact dependent reproducible hypomania induced by deep brain stimulation in Parkinson's disease: clinical, anatomical and functional imaging study , 2010, Journal of Neurology, Neurosurgery & Psychiatry.

[268]  D. Brooks,et al.  Depressive symptoms in PD correlate with higher 5-HTT binding in raphe and limbic structures , 2010, Neurology.

[269]  A. Parent,et al.  Functional anatomy of the basal ganglia. I. The cortico-basal ganglia-thalamo-cortical loop , 1995, Brain Research Reviews.

[270]  Y Agid,et al.  Transient acute depression induced by high-frequency deep-brain stimulation. , 1999, The New England journal of medicine.

[271]  J. Salamone,et al.  Mesolimbic Dopamine and the Regulation of Motivated Behavior. , 2015, Current topics in behavioral neurosciences.

[272]  Alan A. Wilson,et al.  Brain serotonin transporter binding in non‐depressed patients with Parkinson's disease , 2007, European journal of neurology.

[273]  Wim E J Weber,et al.  Neuroanatomical correlates of apathy in Parkinson's disease: A magnetic resonance imaging study using voxel‐based morphometry , 2010, Movement disorders : official journal of the Movement Disorder Society.