Presented at the Intentional Inhibition Workshop (London, 2013)

1. Response Inhibition in Parkinson’s Disease:
Towards New Treatments
Z Ye, E Altena, C Nombela-Otero, CR Housden, H Maxwell, T Rittman, C Huddleston,
CL Rae, R Regenthal, BJ Sahakian, RA Barker, TW Robbins, JB Rowe
Contact Dr Rowe
James.Rowe@mrc-cbu.cam.ac.uk
Contact Dr Ye
zy250@medschl.cam.ac.uk
Follow the Rowe Lab
www.brc.cam.ac.uk/principal-
investigators/james-rowe/
Items PD Control P (t test)
Sex (M:F) 11:10 12:8 n.s.
Age 64 (8) 65 (6) n.s.
MMSE 29 (1) 29 (1) n.s.
Years of disease 11 (5) -- --
UPDRS-III motor 21 (8) -- --
Hoehn & Yahr 1.9 (0.4) -- --
L-dopa equivalent dose (mg/day) 632.6 (310.6) -- --
Background & Hypotheses
Parkinson’s disease (PD) causes impulsivity even in the absence of impulse control disorders. Potential mechanisms
underlying PD impulsivity include the loss of monoaminergic projections to the forebrain, including serotonin1.
Increasing central serotoninergic transmission with selective serotonin reuptake inhibitors (SSRIs) might therefore
improve impulsivity. We examined whether the SSRI citalopram improves response inhibition, both behaviourally and in
terms of the frontostriatal neural systems mediating inhibition.
We studied both the prevention of a prepotent response (restraint) and stopping an initiated action (cancellation), using a
NoGo paradigm and Stop-Signal Reaction Time (SSRT) task respectively. Based on preclinical evidence from animal and
human studies2, we proposed that serotonin plays an important role in regulating the neural systems of restraint and
cancellation. We tested three specific hypotheses.
Hypothesis#1: PD impairs both action restraint and cancellation.
Hypothesis#2: The impact of citalopram on behavioural performance depends on individual variation in disease severity.
Hypothesis#3: The behavioural effect relates to the enhancement of inferior frontal cortical activation following citalopram.
Go
(360 trials)
NoGo
(40 trials)
Stop-Signal
(80 trials) Online trackers3
Variable delay
50% Inhibition
Task & Stimuli
Participants (measure means, SDs and group differences)
max. 1000 ms
max. 1000 ms
Design & Drug
• Pharmacological functional magnetic resonance imaging (fMRI)
• Double-blinded randomised placebo-controlled crossover design
• Patients (sessions ≥6 days apart): 30 mg citalopram (CIT) and
placebo (PLA); controls (one session): no drug
• CIT: SSRI that increases extracellular cortical serotonin 4 fold
100
150
200
Control PD-PLA PD-CIT
SSRT(ms)
SSRT
400
500
600
Control PD-PLA PD-CIT
RT(ms)
Go RT
0
0.08
0.16
Control PD-PLA PD-CIT
Errorrate
NoGo error
0
0.08
0.16
Control PD-PLA PD-CIT
Errorrate
Go error
*
* *
Behavioural Data
UPDRS (centred)
∆SSRT(ms)∆NoGo-error
Drug effects
SSRT
NoGo
fMRI Data
Disease effects Disease effects Drug effects
∆SS-activation
SSRT
∆SSRT(ms)
Control PD-PLA
SS>Go NoGo>Go Both
∆NoGo-activation
∆NoGo-error
PD-PLA<Control
(Stop-Signal)
UPDRS (centred)
0 5
T values
NoGo
Conclusion
• PD impairs both action restraint and cancellation.
• Effect of citalopram on behavioural impulsivity depends on the
severity of PD and individual difference in inferior frontal
cortical activation.
• This study indicates the need for patient stratification in clinical
trials and serotonergic treatments of impulsivity in PD. Primarily funded by
References
1. Politis et al. 2010. Neurobiol Disease 40(1): 216-21.
2. Eagle et al. 2008. Psychopharmacology (Berl) 199(3):
439-56.
3. Chamberlain et al. 2007. Biol Psychiatry 62(9): 977-
84.
Methods
Results