Impulsivity in Parkinson Disease By Imran Rafi Ahmed Abdullah Punekar Submitted in Partial ...

290 Pages·2015·1.87 MB·English

by  Imran Punekar

Impulsivity in Parkinson Disease
By
Imran Rafi Ahmed Abdullah Punekar

Submitted in Partial Fulfillment of the
Requirements for the Degree
Doctor of Philosophy

Supervised by
Professor Jonathan Mink

Department of Neurobiology and Anatomy
University of Rochester
Rochester, New York
2015
ii

Dedication

To my mother, my untiring supporter, and my father, my eternal hero.
iii

Biographical Sketch
Imran Rafi Ahmed Abdullah Punekar was born in Al-Baha, Saudi Arabia. He grew up
there, in the United Kingdom and then in New York City. He attended Stuyvesant High
School in Manhattan and the Mining and Mechanical Institute in Pennsylvania for High
School. He attended Villanova University from 2002-2005 where he completed a B.S.
and B.S.H. in Biology and Bioethics with minors in Cognitive Science and Philosophy.
He was awarded a Fulbright Scholarship to study Cultural Competence and Islamic
Bioethics at the Faculty of Medical Sciences, UAE University, UAE. He joined the
MSTP program at the University of Rochester in 2006 and began his doctoral studies
under the supervision of Dr. Jonathan Mink in the Departments of Neurology and
Neurobiology and Anatomy in 2008. He received a Master of Science degree in
Neuroscience in 2010.
iv

Acknowledgments
I would like to sincerely acknowledge my Advisor, Dr. Jonathan Mink. Without his
support, faith in me, and extraordinary patience, none of this would have been possible.
Time and again through roadblock and failure, he proved to be my strongest ally.
I would also like to acknowledge my Committee members, particularly
Dr. Robert Schor whose dedication to teach and mentor was phenomenal.
Also instrumental in this work was the inspiration, dedication and assistance of Dr.
Michelle Burack, someone whom I am continually in awe of and thoroughly indebted to.
I would also like to acknowledge my family and all the friends who supported me during
these years and have helped to make them truly memorable.
v

Abstract
Parkinson Disease (PD) is a degenerative neurological disease characterized by the loss
of nigrostriatal dopamine neurons. Cardinal symptoms of the disease include resting
tremor, rigidity, bradykinesia and postural instability which can be seen as symptoms of
over-inhibition. When treated with dopaminergic medications (MEDS) or subthalamic
nucleus deep brain stimulation (STN DBS) PD patients may develop one or more
Impulse Control Disorders (ICDs) such as pathological gambling or hypersexuality.
While the precise etiology of these disorders is not known, they have been characterized
as failures of inhibition.
We hypothesized that both forms of therapy increase impulsive behavior even in PD
subjects without clinically apparent ICD’s. We employed three tasks designed to
investigate response selection, inhibition, and impulsive choice: a Go/No-Go task, a Stop
Signal Task (SST) and a Delay Discounting (DD) task. We further aimed to clarify the
relationships between task performance and a number of measures including disease
severity, apathy, and self-perceived autonomy.
We report that both MEDS and STN DBS contribute to impulsivity in PD and shift the
balance towards habitual behavior over than goal-directed behavior, although in distinct
and dissociable ways. MEDS result in the nonselective reinforcement of frontal-
subcortical and direct pathway circuits, undermining experience and self-control, and
resulting in increased discounting and improved Reaction Times. STN DBS impairs the
ability of the STN to integrate frontal and striatal inputs and reduces STN output, thereby
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improving Movement Times, impairing switching behavior and resulting in decreased
STN-induced slowing in high-conflict situations. Our results highlight the contributions
of, and communication between, the Basal Ganglia and the Frontal Cortex in response
inhibition and impulsive choice. Furthermore, we discuss the bioethical challenges and
imperatives to treating impulsivity in the context of PD.
vii

Contributors and Funding Sources
This work was supervised by a dissertation committee consisting of Professors
Jonathan Mink (Advisor, Department of Neurology), Richard Dees (Department of
Philosophy), Mark Mapstone (Department of Neurology), Liz Romanski, and Robert
Schor ((Department of Neurobiology and Anatomy). All data collection and analysis was
completed independently by the student. This work was funded by NIH Grant #
P01NS048328 and # R01NS039821.
viii

Table of Contents

Dedication .......................................................................................................................ii
Biographical Sketch ...................................................................................................... iii
Acknowledgments .......................................................................................................... iv
Abstract ........................................................................................................................... v
Contributors and Funding Sources ................................................................................. vii
Table of Contents .........................................................................................................viii
List of Tables ............................................................................................................... xiv
List of Figures ............................................................................................................... xv
CHAPTER I .................................................................................................................... 1
PARKINSON DISEASE ............................................................................................. 1
An Overview of Parkinson Disease .......................................................................... 1
History of Parkinson Disease .................................................................................... 2
Role of Dopamine .................................................................................................... 3
Dopamine and Reward ............................................................................................. 4
Dopamine pathways ................................................................................................. 5
Definition of Impulsivity .......................................................................................... 6
Impulse Control Disorders in Parkinson Disease ...................................................... 8
Etiology of Impulse Control Disorders in Parkinson Disease .................................... 9
Assessment of Impulse Control Disorders in Parkinson Disease ............................. 10
Our Hypothesis of How Parkinson Disease Therapy Leads to Impulsivity .............. 11
APPROACHES TO MEASURING IMPULSIVITY ...................................................... 13
GO/NO-GO TASK ..................................................................................................... 13
Basal Ganglia Modulation of Reaction Time .......................................................... 13
Signal Encoding ..................................................................................................... 14
Decision Time ........................................................................................................ 17
Response Output .................................................................................................... 19
THE STOP SIGNAL TASK ......................................................................................... 23
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Overview of the Stop Signal Task .......................................................................... 23
Prior Studies ........................................................................................................... 27
Overview of Delay Discounting ............................................................................. 34
Brain Mechanisms Involved in Delay Discounting ................................................. 39
How Delay Discounting is useful to the study of ICD’s in PD ................................ 42
Prior Studies ........................................................................................................... 43
A Case Study of Pathological Gambling in PD ....................................................... 46
The 4 Principle Approach to Bioethics ................................................................... 46
Respect for Autonomy ............................................................................................ 47
Nonmaleficence ..................................................................................................... 49
Beneficence ............................................................................................................ 50
Justice .................................................................................................................... 51
Our Goal in Discussing Bioethics ........................................................................... 52
CHALLENGES AND OPPORTUNITY IN PARKINSON DISEASE ............................. 53
CHAPTER II ................................................................................................................. 55
GENERAL METHODS .............................................................................................. 55
Subjects ..................................................................................................................... 55
Hardware .................................................................................................................. 57
Task Description ........................................................................................................ 58
Go Trials ................................................................................................................ 59
No-Go Trials .......................................................................................................... 60
Stop Trials .............................................................................................................. 60
Delay Discounting Trials ........................................................................................ 62
Additional Measures .............................................................................................. 63
The Frontal Systems Behavior Scale (FrSBE) ........................................................ 63
The Treatment Self-Regulation Questionnaire (TSRQ) ........................................... 64
Measured Outcomes ............................................................................................... 65
From the LabVIEW Testing Computer: .................................................................. 65
From the VICON camera system: ........................................................................... 66
Calculated Outcomes ................................................................................................. 67
GO Trial Performance ............................................................................................ 67
x

Stop Signal Reaction Times.................................................................................... 68
k-values (see Table 5.1, Figure 5.1) ........................................................................ 70
Kinematic Data ...................................................................................................... 71
Analysis ................................................................................................................. 72
CHAPTER III ............................................................................................................... 73
GO/NO-GO Chapter ................................................................................................... 73
INTRODUCTION ......................................................................................................... 73
Encoding of Visual Stimulus .................................................................................. 74
Response Output .................................................................................................... 74
Our Go/No-Go Task ............................................................................................... 74
METHODS................................................................................................................ 75
Analysis ................................................................................................................. 78
RESULTS ................................................................................................................. 79
Participants ............................................................................................................ 79
Go/No-Go Task ......................................................................................................... 83
Movement Parameters ............................................................................................ 83
Go/No-Go Accuracy .............................................................................................. 86
UPDRS and Additional Measures ........................................................................... 88
DISCUSSION............................................................................................................ 92
Summary of Findings ............................................................................................. 92
Dopaminergic Medication improves Reaction Time but not Movement Time. ........ 92
STN DBS improves Movement Time but not Reaction Time.................................. 93
STN DBS and Dopaminergic Medication do not affect Go Success Rates, or Wrong
Hand errors. ........................................................................................................... 95
STN DBS alone does not affect No-Go Success Rates or Wrong Hand errors. ........ 95
STN DBS and Dopmainergic Medication together synergistically worsen No-Go
Success, but not No-Go Wrong Hand errors. .......................................................... 95
Go/No-Go measures do not correlate to UPDRSIII, MOCA, or FRSBE scores ....... 96
Go/No-Go Accuracy correlates to some TSRQ subscores ....................................... 97
Conclusions ............................................................................................................ 99
CHAPTER IV ............................................................................................................. 101