Presented at OHBM2013 (Seattle)

1. Citalopram Enhances Action Inhibition Systems in Parkinson’s Disease
Z Ye1, E Altena1, C Nombela-Otero1, C Housden1, H Maxwell1, T Rittman1, C Huddleston1, CL Rae2,
R Regenthal3, BJ Sahakian4, RA Barker1, TW Robbins1,4, JB Rowe1,2,4
1University of Cambridge, UK 2Medical Research Council Cognition and Brain Science Unit, UK
3University of Leipzig, Germany 4Behavioural and Clinical Neuroscience Institute, UK
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James.Rowe@mrc-cbu.cam.ac.uk
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zy250@medschl.cam.ac.uk
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Introduction
Impulsivity in Parkinson’s disease (PD) is highlighted by the severity of
impulse control disorders (ICDs). However, subtler impulsivity is
common even in the absence of ICDs and is likely to be multifactorial.
In addition to dopaminergic ‘overdose’1,2 and structural changes3 in
the frontostriatal circuits for motor control, we propose that changes
in serotonergic projections to the forebrain also exacerbate the
impairment of response inhibition. Enhancing central serotonin
transmission with selective serotonin reuptake inhibitors (SSRIs)
might therefore provide adjunctive treatment for behavioural
impulsivity in Parkinson’s disease.
We investigated whether the SSRI citalopram reduces impulsivity and
enhances the neural systems mediating response inhibition in
Parkinson’s disease. We studied two forms of inhibition: (1) restraint,
using NoGo events; and (2) cancellation, in terms of the Stop-Signal
Reaction Time (SSRT). There is strong preclinical evidence from
animal and human studies that serotonin plays an important role in
regulating action restraint4. In contrast, the link between serotonin
and action cancellation is less well established. We tested three
specific hypotheses.
Hypothesis1: PD impairs both action restraint and cancellation.
Hypothesis2: The effect of citalopram on behavioural performance
depends on patients’ disease severity.
Hypothesis3: The behavioural effect relates to the enhancement of
inferior frontal cortical activation following citalopram.
Methods
Participants
• PD patients (N=21): right-handed.
• Controls (N=20): right-handed; no history of neurological or
psychiatric disorders.
Table 1: Demographic data, clinical features and neuropsychological
measures (means, SDs and p values of two-sample t tests)
Items PD Control P (2-tailed)
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) -- --
Levodopa equivalent dose
(LED, mg/day)
632.6 (310.6) -- --
Beck Depression
Inventory
9.9 (5.5) 3.8 (3.9) < 0.001
Simple reaction time (ms) 294 (53) 314 (72) n.s.
Choice reaction time (ms) 353 (47) 392 (70) < 0.05
Drug and Design
• Double-blind randomised placebo-controlled crossover design
• Patients (sessions ≥6 days apart): 30mg citalopram (CIT) and placebo
(PLA)
• Controls (one session): on drug
• Citalopram: SSRI that increases extracellular cortical serotonin 4 fold
Task and Stimuli
• An integrated Stop-Signal and NoGo paradigm with 360 Go trials
(75%), 40 NoGo trials (8%) and 80 Stop-Signal trials (SS, 17%, with
~50% accuracy).
• Go: Subject responded to a left/right black arrow (1000ms) with their
right hand.
• NoGo: Subjects withheld a response to a red arrow (1000ms) and
auditory tone.
• SS: A button press was cued by the left/right black arrow but
signalled to stop by a colour change (to red) and auditory tone after a
variable delay. An online tracking algorithm maintained approx. 50%
successful inhibition5.
Results
• Behaviour (Table 2 & Fig.1A): Disease effect (Hypothesis1: control
vs. PD-PLA) and drug effect (Hypothesis2: PD under CIT vs. PLA)
were examined respectively with two-sample t-tests and repeated-
measures ANOVAs with disease severity, age, LED, and plasma
concentration of CIT as covariates.
• fMRI (Fig.1B): General linear models estimated brain responses to
correct SS, Go and NoGo trials, commission errors (SS, NoGo and
Go trials), and Go omission errors. Contrast maps of SS>Go and
NoGo>Go were computed for each group and compared between
groups (Hypothesis1). We focused on the RIFG which showed
inhibition-related activations in controls.
• Behaviour-fMRI (Fig.1C): Parameter estimates (betas) were pooled
from the RIFG for correlation tests between changes in behaviour
and changes in frontal activation following citalopram
(Hypothesis3).
Table 2: Disease effect on behavioural performance (means, SDs and p
values of two-sample t tests)
Parameter Control PD-PLA PD-CIT P (1-tailed)
Go RT (ms) 532 (129) 554 (108) 555 (100) n.s.
SSRT (ms) 142 (44) 167 (50) 180 (75) 0.05
NoGo error 0.06 (0.13) 0.14 (0.13) 0.16 (0.18) < 0.05
Go error 0.08 (0.05) 0.14 (0.06) 0.13 (0.08) < 0.001
Fig.1
A. Behavioural
effect of CIT
(changes of SSRT
and NoGo errors)
depended on
disease severity
(p<0.05).
B. The stop-related
RIFG activation
was significantly
weaker in PD-PLA
than in controls
(p<0.05 FWE-
corrected).
C. CIT-induced
changes of SSRT
and NoGo error
correlated with the
changes of inferior
frontal cortical
activation (p<0.05).
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.
References and Funding
1. Voon et al. 2011. Curr Opin Neurol 24(4): 324-30.
2. Rowe et al. 2008. Brain 131(Pt 8): 2094-105.
3. Rae et al. 2012. Neuroimage 62(3): 1675-84.
4. Eagle et al. 2008. Psychopharmacology (Berl) 199(3): 439-56.
5. Chamberlain et al. 2007. Biol Psychiatry 62(9): 977-84.
This work was primarily funded by