Thesis submitted in fulfillment of the degree of Doctor of Philosophy Reta Lila Weston Institute of Neurological Studies UCL Institute of Neurology University College London 2013 Atbin Djamshidian-Tehrani 1 I, Atbin Djamshidian-Tehrani confirm that the work presented in this thesis is my own. Where information has been derived from other sources, I confirm that this has been indicated in the thesis. Signed: Date: 2 Abstract The phenomenology of impulsive compulsive behaviours in patients with Parkinson’s disease (PD) treated with dopaminergic therapy has been reviewed. Neuropsychological studies have been conducted to explore the behavioural mechanisms responsible for these socially devastating disorders, which affect a substantial proportion of treated patients. Results demonstrated that poor information sampling and impaired working memory capacity, especially when mental manipulation of information was required, distinguish PD patients with impulsive compulsive behaviours from those without. A direct comparison to non PD-patients with addictions revealed that impulsive PD patients closely resembled illicit drug abusers, whereas non-impulsive PD patients treated with a dopamine agonist performed similarly to pathological gamblers. PD patients who were not taking dopamine agonists performed as well as healthy volunteers, even when treated with deep brain stimulation. Therefore, dopamine agonists are the single most important risk factor for impulsive choice in PD. Conversely, response inhibition and feedback learning were intact in medicated PD patients with impulsive compulsive behaviours. Furthermore, all PD patients became more risk prone after dopaminergic medication, but greater salivary cortisol release only correlated with risk taking behaviour in the PD group with behavioural addictions. Cortisol plays also a prominent role in stress regulation. Therefore, the literature was reviewed to explore links between emotional stress and PD. 3 Papers associated with this thesis 1) Djamshidian A, Cardoso F, Grossett D, Bowden-Jones H, Lees A. “Pathological Gambling in Parkinson’s disease. A review of the literature”. Mov Disord. 2011 Sep;26(11):1976-84. 2) Djamshidian A, Averbeck BB, Lees A, O'Sullivan SS. “Clinical aspects of impulsive compulsive behaviours in Parkinson’s disease”. J Neurol Sci. 2011 Nov 15;310(1- 2):183-88. 3) Djamshidian A, Jha A, O'Sullivan SS, Silveira-Moriyama L, Jacobson C, Brown P, Lees A, Averbeck BB. “Risk and learning in impulsive and non- impulsive patients with Parkinson's disease”. Mov Disord. 2010 Oct 15;25(13):2203-10. 4) Djamshidian A, O'Sullivan SS, Doherty KM, Lees A, Averbeck BB. ”Altruistic punishment in patients with Parkinson’s disease with and without impulsive behaviour”. Neuropsychologia 2011 Jan;49(1):103-37. 5) Djamshidian A, O'Sullivan SS, Lees A, Averbeck BB. “Stroop test performance in impulsive and non-impulsive patients with Parkinson’s disease”. Parkinsonism Relat Disord. 2011 Mar;17(3):212-14. 6) Djamshidian A, O'Sullivan SS, Wittmann B. Lees A, Averbeck BB. “Novelty seeking behaviour in Parkinson's disease”. Neuropsychologia. 2011 Jul;49(9):2483-88. 7) Djamshidian A, O'Sullivan SS, Sanotsky Y, Sharman S, Matviyenko Y, Foltynie T, Michalczuk R ,Aviles-Olmos I, Fedoryshyn L, Doherty KM, Filts Y, Selikhova M, Bowden-Jones H, Joyce E, Lees A, Averbeck BB. ” Decision making impulsivity and addictions: Do Parkinson’s disease patients jump to conclusions?” Mov Disord. 2012 Aug;27(9):1137-45. 4 8) Djamshidian A, O'Sullivan SS, Foltynie T, Aviles-Olmos I, Limousin P, Zrinzo L, Lees A, Averbeck BB. “Dopamine agonists cause reflection impulsivity in Parkinson’s disease, not Deep Brain Stimulation”. Journal of Parkinson’s disease 2013 3(2):139-44. 9) Djamshidian A, Sanotsky Y, Matviyenko Y, O;Sullivan SS, Sharman S, Selikova M, Fedoryshyn L, Filts Y, Bearn J, Lees A, Averbeck BB. “Increased reflection impulsivity in patients with ephedrone induced Parkinsonism”. Addiction 2012. Dec.11. 10) Djamshidian A, O'Sullivan SS, Papadopoulos A, Bassett P, Shaw K, Averbeck BB, Lees A. “Salivary cortisol levels in Parkinson's disease and its correlation to risk behaviour”. J Neurol Neurosurg Psychiatry. 2011 Oct;82(10):1107-11. Related publications during the degree period 1) Djamshidian A, O'Sullivan SS, Lees A, Averbeck BB. “Effects of dopamine on sensitivity to social bias in Parkinson's disease”. PLoS One. 2012;7(3).e32889. 2) Averbeck BB, Djamshidian A, O'Sullivan SS, Housden CR, Roiser JP, Lees AJ. “Uncertainty about mapping future actions into rewards may underlie performance on multiple measures of impulsivity in behavioral addiction: evidence from Parkinson's disease”.Behav Neurosci. 2013 Apr;127(2):245-55. 3) O'Sullivan SS, Wu K, Politis M, Lawrence AD, Evans AH, Bose SK, Djamshidian A, Lees AJ, Piccini P.” Cue-induced striatal dopamine release in Parkinson's disease- associated impulsive-compulsive behaviours.” Brain. 2011 Apr;134(Pt 4):969-78. 4) O'Sullivan SS, Djamshidian A, Ahmed Z, Evans AH, Lawrence AD, Holton JL, Revesz T, Lees AJ. ” Impulsive-compulsive spectrum behaviors in pathologically confirmed progressive supranuclear palsy”. Mov Disord. 2010 Apr 15;25(5):638-42. 5 5) O'Sullivan SS, Djamshidian A, Evans AH, Loane CM, Lees AJ, Lawrence AD. “Excessive hoarding in Parkinson's disease”. Mov Disord. 2010 Jun 15;25(8):1026-33. 6 List of abbreviations ACC Anterior cingulate cortex AM Amygdala ANOVA Analysis Of Variance BOLD Blood-Oxygen-Level Dependent C Congruent CG Cingulate gyrus CO Control CO-O Elderly Controls CO-Y Young Controls COMT Catechol-O-Methyl Transferase DA Dopamine Agonists DAT Dopamine Transporter Scan DBS Deep Brain Stimulation DDS Dopamine Dysregulation Syndrome DRT Dopamine Replacement Therapy DSM-IV Diagnostic and Statistical Manual, 4th Edition FAB Frontal Assessment Battery fMRI functional Magnetic Resonance Imaging HC Hippocampus HIP Hippocampus HPA Hypothalamo-Pituitary-adrenal Axis I Incongruent IBS Irritable Bowel Syndrome ICBs Impulsive Compulsive Behaviours IGT Iowa Gambling Task I.V. Intravenous KHZ Kilohertz KMNO4 Potassium Permanganate 7 L-DOPA Levodopa LEU L-dopa Equivalent Unit LRRK2 Leucine- Rich Repeat-Kinase type 2 MAO-B Monoamine Oxidase B MMSE Mini Mental State Examination MPTP 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine MRI Magnetic Resonance Imaging MS Multiple Sclerosis MSA Multiple System Atrophy NAc Nucleus accumbens NEG Negative NMDA N-Methyl D-Aspartate NS Not Significant 6-OHDA 6-Hydroxydopamine OCD Obsessive Compulsive Disorder OFC Orbitofrontal cortex PFC Prefrontal cortex PPA Phenylpropranolamine PANAS Positive and Negative Affect Schedule PD Parkinson’s disease PD+ICB PD patients with Impulsive Compulsive Behaviours PD-ICB PD patients without Impulsive Compulsive Behaviours PD+PG PD patients with Pathological Gambling PET Positron Emission Tomography PG Pathological Gambling POS Positive PSP Progressive Supranuclear Palsy QUIP Questionnaire for Impulsive Compulsive Disorders in Parkinson’s disease RAC Raclopride RLS Restless Legs Syndrome 8 RT Reaction Time SD Standard Deviation SE Standard Error SEM Standard Error of the Mean SPECT Single-Photon Emission Computed Tomography SSRI Selective Serotonin Reuptake Inhibitor STN Subthalamic Nucleus UCLH University College London Hospitals UK United Kingdom UPDRS Unified Parkinson’s disease Rating Scale VTA Ventral tegmental area WM Working memory YRS Years 9 Table of contents Abstract ............................................................................................................................................................................... 3 Papers associated with this thesis .......................................................................................................................... 4 Related publications during the degree period ................................................................................................ 5 List of abbreviations ...................................................................................................................................................... 7 Table of contents ...........................................................................................................................................................10 List of tables ....................................................................................................................................................................14 List of figures ..................................................................................................................................................................15 Chapter 1 - Introduction to Parkinson’s disease .......................................................... 17 Overview and research aims....................................................................................................................................17 Clinical features of Parkinson’s disease..............................................................................................................18 Diagnosis of Parkinson’s disease ...........................................................................................................................19 Environmental factors................................................................................................................................................22 Pharmacological treatment of Parkinson’s disease and motor complications ...............................24 Chapter 2 - Addictive behaviours in Parkinson’s disease ..........................................