Vigor and the LDR in Parkinson Disease
Phase: PHASE4
Conditions: Parkinson Disease
Sponsor: University of Michigan

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Study Protocol and Statistical Analysis Plan 
 
 
 
 
Official title: Vigor and the LDR in Parkinson Disease 
 
NCT number: NCT04821830 
 
IRB Approval Date: 10/25/2019 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Vigor and the LDR in Parkinson Disease 
PI: Roger L. Albin, MD; Co-I: Taraz Lee, PhD 
 
A. Abstract: 
 
Dopamine replacement therapy (DRT) is the standard and very effective symptomatic treatment for early to 
moderate Parkinson disease (PD). The most important DRT component is the Long Duration Response 
(LDR), a pharmacodynamic effect that builds up over the course of weeks. DRT actions are poorly understood 
and the basis of the LDR is unknown. As the LDR wanes in advancing disease, PD patients develop 
troublesome motor fluctuations and increasing disability. LDR kinetics suggest long-term plastic changes in 
striatal function. Studies of striatal dopamine actions indicate that striatal dopaminergic neurotransmission 
regulates “vigor;” modulation of the velocity, amplitude, force, or frequency of movements. Vigor is closely 
allied with the concept that striatal dopaminergic neurotransmission mediates motivation; assessment of act 
utility and appropriate scaling of actions to perceived rewards. Recent theoretical and experimental results 
suggest that tonic striatal dopamine signaling is a key determinant of movement vigor. Convergent clinical 
pharmacologic and experimental data lead to a strong hypothesis that the LDR results from chronic DRT 
partially restoring movement vigor. This model of the LDR requires stable “records” of action values. Recent 
non-human primate work on saccadic eye movement vigor indicates the existence of striatal dopaminergic 
neurotransmission stably encoding motor behavior values for prolonged periods – a potential mechanism for 
the LDR. Prior experiments examining vigor in PD did not take the LDR into account, resulting in incomplete 
examinations of the role of vigor deficits in PD. Our long-term goal is to understand the clinically relevant 
actions of DRT. The primary objective of our proposal is to test the hypothesis that the LDR results from 
partial restoration of normal movement vigor-motivation. Our secondary objective is to evaluate a potential 
mechanism underlying the LDR. The rationale for these experiments is that better understanding of the LDR, 
a clinically crucial component of DRT action, will lead to improved symptomatic therapy. We will study 
recently diagnosed PD subjects. All subjects will undergo standard evaluations of clinical, cognitive, and 
motivational features.  Subjects will perform incentive motivation tasks assessing movement vigor – 
motivation coupling to assess    our primary hypothesis. A task assessing saccadic eye movement vigor in 
response to stable value signals   will be employed to evaluate our secondary hypothesis. They will perform 
all tasks before and after LDR induction in both the “practical off” and post-acute treatment states. Validation 
of our hypotheses would have considerable impact by identifying the functional process underlying the LDR 
and providing information for uncovering the mechanisms of the LDR. This would facilitate research into LDR 
mechanisms, provide a rational basis for developing valid animal models of the LDR, and open a new path 
towards improved symptomatic management of PD. 
 
B. Specific Aims 
Dopamine replacement therapy (DRT) is the standard symptomatic treatment for early to moderate Parkinson 
disease (PD). In early to moderate PD, the most important DRT component is the Long Duration Response 
(LDR), a pharmacodynamic effect that builds up over the course of days-weeks and can be induced by 
dopamine agonists. Despite its effectiveness, DRT actions are poorly understood and the basis of the LDR is 
unknown.  As the LDR wanes in advancing disease, PD patients develop troublesome motor fluctuations and 
increasing disability. Improved understanding of the LDR has the potential to prolong the duration of its 
effects and could have a significant positive effect on clinical practice. 
 
The kinetics of the LDR suggest long-term plastic changes in striatal function. Recent studies of striatal 
dopamine actions in PD subjects and experimental animals indicate that striatal dopaminergic 
neurotransmission regulates “vigor,” the force, velocity, or amplitude of actions.  Vigor is closely allied to the 
concept that striatal dopaminergic neurotransmission mediates motivation, which involves the assessment of 
act utility and the appropriate scaling of actions to perceived rewards. Recent theoretical and experimental 
results suggest that tonic striatal dopamine signaling, mimicked by dopamine agonist administration, is a key 
determinant of movement vigor.  Convergent clinical pharmacologic and experimental data lead to a strong 
hypothesis that the LDR results from chronic DRT partially restoring motivational coupling of effort to 
perceived reward and movement vigor.  Prior experiments examining vigor in PD subjects did not take the 
LDR into account, resulting in incomplete examinations of the role of vigor deficits in PD. 

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Recent non-human primate work on the control and vigor of saccadic eye movements indicates the existence 
of basal ganglia circuit changes that stably encode motor action values for prolonged periods.  Striatal 
dopaminergic neurotransmission is critical for establishing this remarkably stable form of value-action 
coupling. This phenomenon is a plausible circuit level mechanism underlying the LDR. 
Our long-term goal is to understand the clinically relevant actions of DRT. The primary objective of our 
proposal is to test the hypothesis that the LDR results from partial restoration of normal action vigor by 
reinstating the link between motivation and effort. Our secondary objective is to explore potential 
mechanisms underlying the LDR. The rationale for these experiments is that better understanding of the 
LDR, a clinically crucial component of DRT action, will lead to improved symptomatic therapy. 
 
We will study recently diagnosed PD subjects. All subjects will undergo standard evaluations of clinical, 
cognitive, and motivational features. Subjects will perform incentive motivation tasks assessing movement 
vigor in response to monetary incentives. Two complementary tasks, one based on modulation of movement 
velocity and one based on modulation of grip strength, will be employed.   To assess whether the recently 
described stable action-value coupling for saccades is relevant to the LDR, subjects will perform a task that 
measures saccadic eye movement vigor in response to stable value signals learned prior to LDR induction. 
Subjects will perform all tasks before and after LDR induction in both the “practical off” and post-acute 
treatment states. 
Specific Aim 1: To use incentive motivation tasks to evaluate the coupling between motivation and movement 
vigor in recently treated PD subjects before and after LDR induction. 
Hypothesis 1A:  LDR induction will result in partial restoration of movement vigor in response to monetary 
incentives in PD subjects in the “practical off” state. 
Hypothesis 1B: The magnitude of partially restored movement vigor in response to monetary incentives will 
correlate with reduced bradykinesia in PD subjects in the “practical off” state. 
Hypothesis 1C:  Identical effects will be found with an incentive motivation task based on movement 
amplitude and one based on grip strength. 
Specific Aim 2: To use a saccadic eye movement task to assess saccadic eye movement vigor in 
response to stable value signals in recently treated PD subjects before and after LDR induction. 
Hypothesis 2:  LDR induction will result in partial restoration of saccadic eye movement vigor in response to 
previously learned stable value signals in PD subjects in the “practical off” state. 
Validation of our hypotheses would have considerable impact by identifying a specific functional process 
underlying the LDR and a potential mechanism of the LDR. This will facilitate research into LDR mechanisms, 
provide a rational basis for developing valid animal models of the LDR, and open a new path towards improved 
symptomatic management of PD. 
 
C. Research Strategy 
 
The Long Duration Response in Parkinson disease:  Parkinson disease (PD) is the second most common 
neurodegenerative disorder, affecting approximately 1 million Americans. PD is defined by a constellation of 
motor features – bradykinesia, rigidity, resting tremor, and postural instability. Bradykinesia, which includes 
slowed movements and progressive decrements of movement speed and amplitude with movement 
repetition, is regarded as the core deficit of PD.1   Motor dysfunction in PD results from reduced striatal 
dopamine (DA) signaling accompanying degeneration of the DAergic nigrostriatal projection. 
DA replacement therapy (DRT) is the cornerstone of PD treatment and is generally very effective in mild to 
moderate PD. The most effective and commonly used treatment is the DA precursor L-dopa.  Synthetic DA 
agonists, with longer half-lives, are used for monotherapy and as adjunctive agents.  These are primarily D2 
receptor selective agents, are less potent, and exhibit significantly higher rates of serious side effects. 
There are 2 major components of patient response to L-dopa treatment – the Short Duration Response 
(SDR) and the Long Duration Response (LDR).2-4   L-dopa has a half-life of approximately 1 hour in blood. 
With typical oral administration schedules (3-4x/day), plasma L-dopa levels are very low at the end of dose 
intervals. The SDR begins quickly, lasts minutes to hours, and then declines, with clinical effects 
approximately paralleling plasma L-dopa levels. The LDR is sustained improvement following chronic 

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treatment which builds up over days to weeks and declines over similar intervals with treatment suspension. 
The LDR is the major component of treatment response in early PD and is responsible for the fact that many 
early phase PD patients experience little or no decrement in performance if they miss L-dopa doses. 
Pharmacodynamic modeling studies suggest that the half-life of the LDR is approximately 8 days, with 
plausible suggestions of longer half- lives.5,6 
 
The LDR wanes with disease progression with increasing importance of the SDR.7,8   This results in motor 
fluctuations, including wearing off of drug effect and dyskinesias. Patients require increasing L-dopa doses, 
frequent regimen adjustments, and adjunctive agents. There is significantly increased incidence of 
troublesome medication side-effects.  Many need Deep Brain 
Stimulation (DBS) surgery to obtain adequate quality of life. 
 
Initial hypotheses about LDR mechanisms suggested that its existence reflected a brain “buffer” compartment 
taking up and storing L-dopa and/or DA for subsequent release. This hypothesis was falsified by several 
experiments demonstrating that DA agonists can initiate and sustain the LDR.5.9-11   In addition, LDR kinetics 
are identical in patients with Dopa Responsive Dystonia, a rare disorder of deficient DA synthesis highly 
responsive to L-dopa treatment.12   These individuals have normal nigrostriatal terminals and normal DA 
storage capacity. 
 
The mechanism(s) underlying the LDR are unknown as there have been no subsequent studies investigating 
the underpinnings of the LDR. 
 
Phasic Dopamine Signaling Does Not Explain the LDR: Striatal DA actions have been the focus of intense 
study over the past generation. Striatal DAergic neurotransmission is described as mediating a number of 
important processes, including reinforcement learning, habit formation, action selection, action vigor, and 
motivation (for discussion of vigor and motivation, see Approach below).  The best characterized aspect of 
striatal DA signaling is its role in reinforcement learning.  Considerable evidence indicates that rapid (100-300 
msec), phasic bursting of nigrostriatal neurons, resulting in discrete boluses of striatal DA, provides a Reward 
Prediction Error signal for reinforcement learning.13-15   Observed originally in seminal non-human primate 
experiments by Wolfram Schultz, studies of this aspect of striatal DAergic signaling dominate the literature on 
striatal DA actions. 
 
As pointed out by Schultz and others, restoration of phasic nigrostriatal DA signaling is unlikely to occur with L- 
dopa treatment and cannot account for the effects of L-dopa treatment in PD.2,16,17   At onset of symptomatic 
PD, patients have already experienced massive, >60% loss, of motor striatum nigrostriatal terminals.18 
Accompanying nigrostriatal terminal degeneration is loss of dopamine transporters (DAT) located uniquely on 
DAergic terminals.  DAT activity is the primary mechanism for clearing DA from the synaptic cleft. Massive 
nigrostriatal terminal loss results in both diminished DA release and increased DA extracellular residence time, 
degrading phasic DA signaling.19,20   Other components of striatal DA signaling must account for the 
effectiveness of L-dopa in PD.  Schultz suggested that some form(s) of tonic striatal DA signaling accounts for 
L-dopa effectiveness.16   LDR kinetics suggests long-term plastic changes in striatal DA actions. 
 
Approach Overview: Our primary objective is to test the hypothesis that the LDR results from partial 
restoration of a critical aspect of striatal DA signaling: mediation of vigor and motivation (Specific Aim 1). 
Confirmation of our hypothesis would connect the LDR to a fundamental feature of striatal DA action. The 
burgeoning preclinical and human experimental literature in this area would provide a solid foundation for 
mechanistic studies of the LDR. Our secondary objective is to evaluate a potential LDR circuit level 
mechanism (Specific Aim 2). 
 
The proposed work is based on collaboration between investigators with strongly complementary expertise. 
Dr. Albin is a Movement Disorder neurologist and experienced PD clinical researcher. Dr. Lee is a Cognitive 
Neuroscientist focused on the interactions between cognitive control, motivation, and action. We engaged 
expert collaborative consultants for critical aspects of the proposed experiments.  Dr. Joshua Dudman 
(HHMI- Janelia Farms) is a leading expert on striatal dopamine signaling and vigor modulation. Dr. 
Dudman developed the movement amplitude task deployed for SA1, a human adaptation of the task his lab 

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used in influential murine experiments demonstrating DAergic modulation of movement vigor.  Dr. Brian 
Anderson (Texas A&M) is an expert on the task deployed for SA2.  Drs. Dudman and Anderson agreed to 
advise us on implementation of these tasks and data interpretation (see attached LOS). 
Specific Aim 1: To use incentive motivation tasks to evaluate the coupling between motivation and 
movement vigor in recently treated PD subjects before and after LDR induction. 
Hypothesis 1A:  LDR induction will result in partial restoration of movement vigor in response to monetary 
incentives in PD subjects in the “practical off” state. 
Hypothesis 1B: The magnitude of partially restored movement vigor in response to monetary incentives will 
correlate with reduced bradykinesia in PD subjects in the “practical off” state. 
Hypothesis 1C:  Identical effects will be found with an incentive motivation task based on movement 
amplitude and one based on grip strength. 
 
Rationale: A substantial body of data indicates that striatal DAergic neurotransmission mediates vigor – the 
speed, amplitude, force, or frequency of actions.21-25   These different aspects of vigor have in common 
modultion of effort, ultimately the degree of energy expenditure required to accomplish actions.  Vigor 
modulation is closely linked to the motivational role of striatal DAergic neurotransmission. Salamone and 
others argue persuasively that striatal DAergic neurotransmission is critical for efficient effort allocation by 
proportioning actions to perceived rewards – the fundamental process of motivation.21-23   Several studies 
implicate aberrant movement vigor modulation as the underlying mechanism of PD bradykinesia. An 
influential experiment by Mazzoni et al. indicates that PD subjects exhibit aberrant estimation of effort-reward 
tradeoffs of movements.26   These results were replicated by several groups using a variety of paradigms to 
assess movement vigor in PD subjects.27-29   These paradigms generally isolate modulation of movement 
velocity, force (e.g., grip strength), or amplitude as outcome measures. These outcome variables all reflect 
effort and in most paradigms, the chosen outcome variable (e.g., amplitude of reaching) is co-linear with 
other potential outcome variables (e.g., force of reaching). 
 
Consistent with Schultz’s suggestion that some form of tonic striatal DA action is critical for treatment of PD, 
LDR induction by dopamine agonists suggests tonic striatal DA signaling in the LDR. Theoretical and recent 
experimental evidence indicates that tonic striatal DA signaling is an important mediator of vigor.  Niv et al. 
elaborated a model of reinforcement learning in which subjects make choices about action selection and vigor 
with the goal of maximizing the net value of rewards per unit time.30   Faster or more intense movements are 
more costly.30,31   Optimal performance requires an effort-reward (cost-benefit) analysis including the costs of 
action vigor. Simulations with this model recapitulate results of typical animal experiments examining 
response vigor.  In this model, a mechanism is needed to provide a long-term account of the prior average 
rate of rewards. Niv et al. predicted that tonic striatal dopamine signaling provides the necessary history of 
prior rate of reward.  Zhuang and colleagues tested this hypothesis with partial DAT knockdown (pDATKD) 
mice.32,33 These mice manifest chronic, moderate elevation of striatal DA but exhibit normal nigrostriatal 
neuron phasic activity and normal reinforcement learning.  pDATKD mice work more vigorously than control 
mice for equivalent rewards, exhibiting distorted effort-reward coupling. Panigraphi et al. examined forelimb 
movement vigor in MitoPark mice, a model of adult-onset, selective nigrostriatal neuron degeneration with 
slowly progressive bradykinesia.34   In clever experiments, they demonstrated normal reward contingency 
learning but impaired ability to scale forelimb movements appropriately. Panigraphi et al. also demonstrated 
significant improvements in MitoPark mice movement vigor with L-dopa treatment. Remarkably, improved 
movement vigor did not occur with acute treatment, but only with weeks of daily treatment, a possible LDR 
analogue. 
Converging theoretical work, preclinical experiments, and clinical experiments suggest that DRT improves 
bradykinesia via partial restoration of normal striatal vigor modulation and that the LDR is the manifestation of 
improved vigor modulation via partially restored tonic dopamine signaling. There is, however, a critical gap in 
the chain of data.  None of the human experiments adequately controlled for DRT treatment effects. The 
Mazzoni et al. study was performed in chronically treated PD subjects.26   Several other experiments 
evaluated PD subjects during DRT and after withholding DRT for 10-12 hours (the “practical off” state) and 
obtained analogous results.28,29   These experiments report reduced vigor modulation in the “practical off” 
state. The PD subjects in these studies were inevitably beneficiaries of the LDR, confounding comparison of 

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performance of PD subjects evaluated in the “practical off” state with control subject performances.  
Rigorous evaluation of the concept that PD bradykinesia results from aberrant modulation of vigor requires 
human experiments that control for LDR effects. A well designed experiment will assess whether the LDR is 
correlated with improved vigor, as predicted by our hypothesis. 
 
Procedures: 
a) We will study newly diagnosed PD subjects recruited from the Movement Disorders clinics at the 
University of Michigan. We see approximately 1300 PD patients annually.  Subjects must meet Movement 
Disorder Society (MDS) criteria for PD.1   Only H&Y1-2 subjects will be enrolled.  Exclusion criteria include 
significant cognitive impairment (Montreal Cognitive Assessment score <24), significant depression 
(Geriatric Depression Scale [GDS] >5), stimulant use, dopamine agonist treatment, or confounding other 
neurologic or medical disorders. Subjects will be characterized at each testing condition with standard 
scales: Parkinsonism – MDS- Unified Parkinson Disease Rating Scale (UPDRS); Mood – GDS; Apathy – 
Lille Apathy Rating Scale; Cognition – a short battery of selected domain specific tests used previously.35   
Bradykinesia will be quantified with a tapping task used extensively by Nutt et al. in prior LDR studies (see 
section c below).7,8 
 
b) Subjects will be studied at pre-treatment baseline and 2-3 months after L-dopa treatment initiation and 
regimen stabilization. We will only enroll drug-naïve subjects about to start treatment with L-dopa.  
Subjects will be studied in OFF and ON acute treatment states at baseline and after LDR induction. There 
will be 4 measurement states: at baseline prior to chronic treatment initiation (OFF-No LDR); at baseline 
after a standard, acute oral dose (25/250 carbidopa/L-dopa) of L-dopa (ON-No LDR), 2 months after initiation 
of chronic, stable L-dopa treatment but with no L-dopa for 10-12 hours prior to evaluation (Practical OFF– 
LDR), and after subjects’ usual L-dopa dose (ON-LDR) (Table 1). 
Table 1: 
 
Practical ON and OFF state measurements will be counterbalanced across individuals. We will recruit both 
male and female PD subjects, though we expect more male subjects as PD is more common in men. This is 
a within subjects design and randomization per se is not used. Blinding of study conditions is not feasible.  
It would be potentially interesting to include a placebo LDR induction arm, but denying PD subjects effective 
treatment is not ethical. Data analysis will be blinded. It would also be interesting to include a normal subject 
arm, but this is ethically problematic as it would involve chronic L-dopa treatment. If, however, we obtain 
results confirming our hypotheses, we will explore inclusion of normal controls in the next phase of 
experiments. 
 
c) LDR magnitude will be measured by reduction of bradykinesia between the initial OFF-No LDR state and the 
Practical OFF-LDR state. Comparisons of the On-No LDR state and OFF-No LDR state, and the Practical 
OFF-LDR and ON-LDR states will measure the SDR.  As a measure of bradykinesia, we will use the well-
validated tapping task used by Nutt et al. in their experiments defining LDR kinetics.7,8   With the hand most 
affected by PD, subjects are instructed to alternately tap 2 manual counters spaced 20 cm apart as rapidly as 
possible for 1 minute.  Subjects will practice several times until they feel comfortable  with the task. They will 
perform 5 trials spaced ~3-4 minutes apart with the initial trial discarded to reduce variation secondary to 
anxiety.  Results of the remaining 4 trials will be averaged       to generate a tapping speed (taps/min) for each 
subject in each condition. This is very similar to the approach used by Nutt et al. (JG Nutt, personal 
communication). 
d) Vigor modulation will be evaluated with two separate incentive motivation tasks; one based on modulation 
of movement amplitude and one based on modulation of grip strength. The latter is similar to a task used 
previously in PD subjects by Schmidt et al.36   It is implemented in the Lee laboratory.  This task was chosen 
because it is relatively easy to use and implement, is compatible with functional neuroimaging, and results in 
PD subjects were replicated using a very similar task by Chong et al.28   Briefly, subjects will be tasked with 
modulating their grip strength in response to monetary incentives. With the hand most affected by          PD 
OFF-No LDR 
Baseline - Treatment Naïve Subject 
ON-No LDR 
Baseline - Treatment Naïve Subject After Acute L-Dopa 
OFF-LDR 
Chronically Treated – “Practical Off” State 
ON-LDR 
Chronically Treated – After Usual L-Dopa 

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symptoms, they will be asked to squeeze a hand dynamometer at the outset of the experiment to measure 
the strength of their maximum voluntary contraction (MVC).  All grip strength targets will be scaled to this  
value.  Subsequently, subjects will undergo a series of trials in which they will be presented with an incentive 
cue that indicates the level of reward for that trial. They will be informed that on each of these trials they will 
earn a percentage of the incentive shown that is directly proportional to how hard they squeeze on that trial. 
While healthy individuals generally increase grip strength with increasing incentive values on this task, 
previous work has shown that PD patients are impaired in their ability to modulate their grip strength in this                
way.  To ensure that any deficits found are due to motivational vigor and not simply a reflection of impaired 
muscle power, we will incorporate control trials in which PD subjects are instructed to increase grip strength 
to similar target levels of force without monetary incentives. 
We will use a variant of the mouse task used in Panigrahi et al.34 This task was inspired by tasks used in 
human PD studies.26,27 A spring loaded joystick that returns to a center position if no force is applied is used. 
Application of force to the joystick displaces it from the center and is monitored to detect the real-time 
trajectory of the movement. A water reward is delivered 1 second after the joystick passes a specified 
amplitude threshold.  For human equivalent tasks, a flexible range of manipulanda (varying the force 
requirements) and flexible visuomotor feedback during training and/or testing are deployed. Varying force 
requirements for reward measure reward-effort coupling.  Use of 2 incentive motivation tasks is 
complementary and provides a more stringent test of our hypothesis.  As these tasks are different measures 
of movement vigor modulation, we should obtain similar and strongly correlated results. Confirmation of our 
hypothesis with the amplitude modulation task will provide reassurance that we are studying the same vigor 
modulation phenomenon studied in basic investigations. The grip strength modulation task is better suited to 
functional imaging experiments and will be a valuable platform for future experiments. 
e) Analysis Plan:  Hypothesis 1A; Our primary comparisons will be performance on the incentive motivation 
tasks before and after LDR induction. We predict that improved performance on the incentive motivation 
tasks will be apparent between the OFF-No LDR and Practical OFF-LDR conditions but not in comparisons 
between the other conditions. Data will be analyzed via 2-Way Repeated Measures ANOVA followed by 
post-hoc tests with incentive level and treatment condition as the factors and multiple comparison 
adjustments. Based on the Schmidt et al. data36, we estimate that achieving power of 0.9 at an effect size of 
η2 = 0.15 requires complete data from 16 subjects.  Based on experience with complex, serial imaging 
studies, we project a 10% dropout rate (~2 subjects). To compensate for dropouts, we will recruit 20 
subjects.  Hypothesis 1B; We will correlate changes in performance on the incentive motivation task with the 
change in tapping rates with Pearson or Spearman correlation tests. Hypothesis 1C: We will correlate the 
results of the amplitude modulation based and grip strength based incentive motivation tasks with Pearson or 
Spearman correlation tests. 
Interpretations and Potential Problems:  If our predictions are correct, we will validate the connection between 
the LDR and partial restoration of vigor modulation. Falsifying this hypothesis will be equally valuable as it 
would direct research on the LDR towards different features of striatal DA action. We may, for example, find a 
relationship between the SDR and improved vigor modulation, which would direct research towards the 
mechanisms of the SDR.  As discussed above, prior experiments evaluating vigor modulation in PD have not 
taken the LDR into account. We may find no clear relationship between vigor modulation and bradykinesia. 
This would be important as it would cast doubt on the widely accepted concept that PD bradykinesia is the 
consequence of altered vigor modulation, and potentially re-direct research in this field. 
Subject recruitment is a potential obstacle to study completion. Our clinics follow ~1300 PD subjects with 
~200 new PD patient visits per year. Our group successfully recruited for trials requiring untreated PD 
patients such as STEADY-PD and SURE-PD.  Our group expanded this past summer with the addition of 2 
faculty  Movement Disorder specialists primarily committed to clinical practice. Treatment with dopamine 
agonists is an exclusion criterion and will not affect recruitment. Our Movement Disorders group is 
conservative in terms      of treatment recommendations and the overwhelming majority of our patients initiate 
therapy with L-dopa monotherapy.  If recruitment lags, we will recruit through the Michigan Parkinson 
Foundation, the major lay PD organization in Michigan with 71 affiliated support groups and a mailing-email 
list of ~15,000 (see attached LOS). These experiments are straightforward, using simple behavioral tasks.  A 
potential problem is that some patients experience nausea with initial L-dopa treatment, which could 

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complicate the ON-No LDR assessment. We will reduce the possibility of nausea by 48 hour pretreatment 
with the peripheral decarboxylase inhibitor carbidopa.  Another potential problem is enrollment of subjects 
with one of the PD mimics (Multiple System Atrophy, etc.).  An advantage of our design is that we will be 
evaluating subjects after treatment initiation, allowing us to gauge treatment responses. Subjects not 
improving with L-dopa treatment, defined by the MDS criteria of > 30% improvement in MDS-UPDRSIII score, 
will be excluded. 
Specific Aim 2: To use a saccadic eye movement task to assess saccadic eye movement vigor in 
response to stable value signals in recently treated PD subjects before and after LDR induction. 
Hypothesis 2:  LDR induction will result in partial restoration of saccadic eye movement vigor in response to 
previously learned stable value signals in PD subjects in the “practical off” state. 
 
Rationale: The long half-life of the LDR indicates that it is based on long-term DA mediated striatal plasticity. 
The computational model of Niv et al. suggests that accurate vigor modulation requires a striatal DA signaling 
“recording” the long-term prior average value of rewards.  Rodent and non-human primate lesion experiments 
suggest that the striatum mediates estimates of prior reward histories.37,38   Studying saccadic eye movements 
in non-human primates, Hikosaka and colleagues described a basal ganglia mechanism stably encoding 
values of visual stimuli to modulate the vigor of saccadic eye movements.39,40   Hikosaka et al. presented 
animals with a large set of fractal images, training them to associate a subset with rewards. Weeks to months 
later and in unrewarded conditions, animals are exposed to groups of fractal images containing some images 
associated previously with rewards.  Saccadic eye movement vigor was measured. Images associated 
previously with rewards evoked greater saccadic vigor.  In detailed physiologic experiments, Hikosaka et al. 
established that activity of DAergic nigrostriatal neurons projecting to the caudate nucleus tail are critical for 
this phenomenon. This demonstration of long-term stable action-value association has features required of 
a DAergic mechanism “recording” reward history and underpinning vigor modulation. 
If this phenomenon underpins vigor modulation, then DRT partial restoration of DAergic signaling in this 
circuit is a plausible substrate for the LDR. LDR induction is predicted to improve saccadic eye movement 
vigor in tasks analogous to that used by Hikosaka et al. 
Procedures:  Subject recruitment, characterization, and test conditions are as described in Specific Aim 1. 
It is not feasible to train PD subjects on hundreds of fractal images. We will use an analogous task validated 
well in humans; value driven attentional oculomotor capture (VDAOC).41-43 A probabilistic learning task is used 
to train subjects to associate a salient visual stimulus (color) with reward. In a test phase, the previously 
rewarded stimulus is presented in task-irrelevant context as a distractor.  Saccades to the test phase target 
and distractor are assessed, including percentage of saccades to distractor or target, saccade latency, and 
saccade duration.  Previously rewarded distractor stimuli capture initial saccades and the magnitude of 
VDAOC is assessed. This task is accompanied by striatal dopamine release.44   Subjects are trained in a 
single session and attentional capture is remarkably durable; it persists in test phase experiments months 
after a single training session.45 To duplicate the approach used by Hikosaka et al., PD subjects will be 
trained on reward-color association prior to initiation of L-dopa therapy.  VDAOC will be measured in 4 
measurement states described above (Table 1).  Saccades will be evaluated with an Eyelink tracker with a 
sampling rate of 250 Hz. If we again assume a modest effect size of η2 = 0.15, 16 subjects will be sufficient to 
achieve a power of 0.9. To guard against dropouts, we will target enrolling 20 subjects.  Data analysis 
approach will be similar to that proposed for Specific Aim 1. 
Interpretations and Potential Problems:  Straightforward interpretation of this experiment presupposes 
validation of our hypothesis that LDR induction is associated with improved modulation of vigor as tested in 
Specific Aim 1 experiments. Assuming validation of our primary hypothesis, we predict that LDR induction 
will be associated with improved saccadic eye movement vigor (VDOAC magnitude). The analysis approach 
will be similar to that used for Specific Aim 1 experiments. The primary comparison will be between 
saccadic      vigor in OFF-No LDR and Practical OFF-LDR conditions.  If LDR induction is associated with 
improved saccadic vigor in the context of successful Specific Aim 1 experiments, we will have evidence 
supporting the hypothesis that the stable striatal DAergic signaling described by Hikosaka’s group underpins 
the LDR.  This would be an excellent point of departure for future experiments on LDR mechanisms. This 
experiment will have value even if we falsify Hypothesis 1.  Regardless of the outcome of the SA1 

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experiments, success with this experiment would support the existence in humans of the interesting and 
potentially important phenomenon described by Hikosaka et al. in monkeys. It’s possible that we might 
validate Hypothesis 1 but falsify Hypothesis 2. That result would certainly point away from the mechanism 
described by Hikosaka et al. as underlying the LDR. An alternative interpretation then would be that the 
dopamine deficient (PD) state    impairs value encoding. This could be evaluated in subsequent experiments 
in which different colors are associated with reward in different training sessions during each of our 
measurement conditions. 
Potential obstacles and responses to problems associated with this experiment are those outlined above for 
Specific Aim 1 experiments. This task has not been used in a patient population and a more prolonged 
training phase may be needed. Initial experiments will assess this potential issue. 
D. Recruitment and Retention: 
 
Subjects will include 30-40 with Parkinson disease (PD). For experiments for SA1 and SA2, our power 
estimates indicate that 16 participants will be adequate for each experiment. We project recruiting 20 subjects 
for each experiment to compensate for possible dropouts. A number of subjects will participate in both SA1 and 
SA2 experiments. 
 
Subjects will be recruited from the UMHS Movement Disorders Clinics. The UMHS Movement Disorders clinic 
follows a population of about 1300 clinically well-defined patients with PD, and evaluates approximately 200 
new PD patients per year.  Dr. Albin, Co-Director of the UMHS Movement Disorders clinic, will be in charge 
of subject recruitment. The UM Movement Disorders group is one of the largest in the nation with 13 faculty 
and actively involved in clinical research. We successfully recruit simultaneously for major clinical trials such 
as STEADY-PD and other clinical research projects involving complex protocols such a multiple imaging 
studies. Movement Disorders group faculty work closely on recruitment with all members of the group 
committed to assisting with recruitment of study subjects. We have a weekly email notification of studies 
actively recruiting and a well established system for directing patients identified in clinics as potential 
research subjects to the attention of study coordinators. The Movement Disorders group is expanded this 
past summer with the addition of 2 additional, primarily clinical, faculty. We also have 2 clinical fellows. 
 
In addition, we will apply to the UM IRB for a waiver of consent for screening and recruitment purposes only. 
Our study coordinator (SC) will use the electronic medical record (EMR) to screen all subjects scheduled for 
clinic visits and will maintain a password-protected screening log. The SC will contact possibly eligible 
subjects by phone in advance of their Neurology clinic appointment—so that subjects can discuss the study 
with their physician and so that our team can be available at that time to answer any questions—and will 
introduce them to the study, the ardor and nature of the study procedures, and to review inclusion/exclusion 
criteria. Subjects who are interested in participating will be scheduled for a baseline testing visit. 
 
If recruitment lags, we will recruit regionally through the Michigan Parkinson Foundation (MPF; see attached 
letter of support).  MPF is the major service organization for PD in Michigan.  It supports dozens of local 
chapters and has a newsletter with circulation in the thousands. 
 
Retention is clearly critical in studies of this type. Our experience with complex studies is reassuring.  For 
multiple PET imaging studies our group has performed, often involving anywhere from 2 – 4 PET studies 
(plus MRI imaging) and serial evaluations, including follow-up PET studies, we have had little difficulty with 
retention. Dropout rates are <10%. Our study plan budgets for potential dropouts. To enhance retention, our 
SC will contact subjects via phone on a regular basis throughout the period from study entry to completion. 
This type of personal contact is usually effective in maintaining study participation. We will provide 
reimbursement for travel expenses and a modest volunteer fee on study completion. 
 
Inclusion Criteria: PD diagnosis will be based on the recent Movement Disorder Society criteria.  
a) PD subjects >45 years and <81 will be studied. 
b) H&Y1-2 (early PD) subjects will be recruited. 
c) Only subjects about to initiate treatment with L-dopa preparations will be enrolled.  
 

10 
 
Exclusion Criteria: 
a) The presence of other neurologic disease or neurologic findings on examination. 
b) Cognitive Impairment: Montreal Cognitive Assessment (MoCA) score <24. 
c) Depression: Geriatric Depression Scale (GDS) score >5. 
d) Use of dopamine agonists or stimulants. 
e) Evidence of a stroke or mass lesion on prior structural brain imaging (CT or MRI). 
f) Evidence of any confounding medical or psychiatric problem that would preclude task participation. 
 
Sources of Materials: 
Information gathered specifically for this research project includes test results from clinical test scales, 
standardized neuropsychological measures and from experimental cognitive tests, neurobehavioral rating 
scales, clinical motor data, questionnaires, standardized interview, and data derived from structural and 
functional MRI. 
 
Potential Risks: 
Confidentiality of Research Information: The research data to be collected from subjects will consist of 
confidential information relating to clinical, neuropsychological, mood, neuroanatomical, and neurochemical 
functions. These research data are not intended for entry into the subjects’ clinical medical records. 
However, the data remain potentially discoverable. This may lead to violation of privacy and embarrassment 
of the subject. 
 
Clinical and Behavioral Testing: Risks in regard to the behavioral assessment are limited to fatigue, frustration 
and momentary embarrassment that may occur when one experiences difficulty disclosing information or 
during task performance.  The overnight “off” state may result in discomfort and transient worsening of 
parkinsonism symptoms.   
 
Adequacy of Protection Against Risks: 
 
Recruitment and Informed Consent: 
Subjects will be recruited from the UM Movement Disorders clinic and by advertisement. Individuals willing to 
participate will be scheduled for the research procedures at which time the nature and risks of the procedures 
will again be review d with the subjects and a written informed consent form will be obtained by one of the 
study investigators. One copy of the signed consent form will be given to the subject, one will be placed in the 
patient’s medical record and a third will be kept in the patient’s study binder kept at the patient’s research site. 
Study visits will be conducted in Dr. Lee’s laboratory in East Hall at the University of Michigan. 
 
Protection Against Risk: 
Confidentiality of Research Information: The possibility of unintended disclosure of medical or research data is 
minimal, but not entirely impossible. We will employ stringent safeguards against unintended and inappropriate 
discovery and dissemination of personal medical and research data in our subjects by a multi-layered 
approach. All data bearing potential subject identifiers will reside solely in locked files in the offices of the study 
investigators. Original data collection documents will be maintained in secure files under the control of the 
investigators. Entries regarding details of the research project and its results will not be submitted to clinical 
medical databases. Electronic databases in the project will employ subject codes that cannot be linked directly 
to participants without a “key”, possessed only by the study investigators in a secure location, and maintained 
separately from the databases. Databases will be housed on protected UM servers. Personal information   
that would directly identify study subjects will not be used in any publications or presentations resulting        
from this research study, unless separate written permission is given by the subject (or proxy). Any superfluous 
records will be shredded. 
Clinical and Behavioral Testing: Care will be taken to minimize distress. The study protocol is designed with 
the minimum number of procedures and tasks, so as to minimize participant burden.  Subjects will be 
addressed in a courteous manner that does not infringe the patient’s dignity. These individuals are 
prepared to respond to patient anxiety, concern and other behavioral changes as appropriate to the 
situation. Offering breaks and 

11 
 
reassuring subjects will further minimize risks when necessary.  All study visits will occur in the morning.  
Subjects studied in the overnight “off state” will take their medication as soon as study procedures are 
concluled.   
 
E. Safety Monitoring: 
 
Review of study procedures and adverse effects will be performed on a monthly basis. The PI will be 
responsible for monitoring any break in confidentiality and for reporting any adverse events following 
University of Michigan IRB guidelines. For purposes of this study, an AE is defined as any unfavorable or 
unintended change in structure, function, signs, or symptoms temporally associated with participation in this 
study, whether or not a causal relationship with the study has been established. Clinically significant 
abnormalities may be considered an AE if deemed appropriate by the PI. Unexpected worsening of a pre-
existing condition is also considered an AE, as is the discovery of an abnormal finding during physical exam 
that was not included in the medical history. Breaches of confidentiality will be considered related to the 
research whenever they occur and will be reported. Withdrawals from the study and the reason for these 
withdrawals will also be reported. 
 
The PI and Co-I are in daily contact with the project research staff testing the participants, scoring and entering 
data, and will monitor their procedures to ensure that confidentiality is maintained. The PI will ensure that the 
IRB is notified of any adverse event following the IRB guidelines. Expected and unexpected serious (including 
fatal) adverse reactions and major unresolved disputes between the research investigator(s) and the research 
participant or between research investigator(s) will be expeditiously reported to the IRB of the University of 
Michigan. At the time of renewal, the IRB will be provided with a summary indicating the frequency of the 
monitoring, cumulative adverse event data, information regarding participant safety or ethics changes, 
confidentiality issues, benefit-to-risk changes and recommendations on continuing, changing or terminating the 
study. 
 
For independent oversight, Dr. Kelvin Chou, a Movement Disorder neurologist with considerable trial 
experience, will act as a DSMB. Dr. Chou will meet with the study team to review the protocol prior to study 
initiation, 6 months after study initiation, and then yearly. Dr. Chou will receive a study charter that empowers 
him to recommend significant study changes, including study termination. All AEs will be immediately 
communicated to Dr. Chou for review. 
 
Definitions: 
An Adverse Event is any undesirable experience occurring in a subject during a clinical trial, whether or not 
considered related to the investigational protocol. For reporting purposes, we will distinguish among pre-existing 
conditions and trial-emergent adverse events. 
Pre-Existing Conditions (i.e., undesirable experiences, signs, or symptoms that begin prior to Study Procedures) 
will not be reported as adverse events unless they worsen in intensity or frequency after study entry (i.e., satisfy 
definition of Trial-Emergent, below). 
Trial-Emergent Adverse Events are undesirable experiences, signs or symptoms that begin or worsen in intensity 
or frequency after the Screening Visit, and prior to administration of study drug at the Imaging Visit. These will 
be reported as adverse events. 
Serious Adverse Event: A serious adverse event is an adverse event that is fatal or life-threatening, or results in 
hospitalization, prolongation of hospitalization, persistent or significant disability/incapacity, or a congenital 
anomaly/birth defect. A life-threatening adverse event is an adverse event that, in the view of the investigators, 
places the subject at immediate risk of death from the reaction, as it occurred. 
Unexpected Adverse Event: An unexpected adverse event is an experience not previously reported or an 
adverse event that occurs with specificity, severity or frequency that is not consistent with the investigator’s prior 
experience with the research methods. 
Relationship to Research Protocol: The assessment of the relationship of an adverse event to the study protocol 
(none, remote, possible, and probable) is a clinical decision based on all available information at the time of 
resolution or stabilization. The following definitions of the relationship between the study procedures and the 
adverse event (including serious adverse events) will be considered: 

12 
 
Remote (unlikely, doubtful, improbable): The time course of the study procedure(s) and the occurrence or 
worsening of the adverse event makes a causal relationship unlikely and another cause is probable. 
 
Possible: The time course of the study procedure(s) and the occurrence or worsening of the adverse event is 
consistent with a causal relationship, but another cause cannot be ruled out. OR The time course of the study 
procedure(s) and the occurrence or worsening of the adverse event is not consistent with a causal relationship 
but no alternative cause can be identified.  If the Investigators are unable to assess causality, the adverse event 
will be considered “Possible” by definition and not “Remote.”  
Probable: The time course of the study procedure(s) and the occurrence or worsening of the adverse event is 
consistent with a causal relationship, and no other cause can be identified. 
Intensity/Severity of an Adverse Event: In addition to assessing the relationship of the administration of the 
investigational product/procedure to adverse events, an assessment is required of the intensity (severity) of the 
event. The following classifications will be used: 
Mild: A mild adverse event is usually transient in nature and generally does not interfere with normal activities. 
Moderate: A moderate adverse event is sufficiently discomforting to interfere with normal activities. 
Severe: A severe adverse event is incapacitating and prevents normal activities. However, a severe event is not 
necessarily a serious event.  Nor must a serious event necessarily be severe. 
 
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