Selective serotonin reuptake inhibition modulates response inhibition in Parkinson’s disease.
Brain. 2014-02-27; 137(4): 1145-1155
DOI: 10.1093/brain/awu032
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1. Brain. 2014 Apr;137(Pt 4):1145-55. doi: 10.1093/brain/awu032. Epub 2014 Feb 27.
Selective serotonin reuptake inhibition modulates response inhibition in
Parkinson’s disease.
Ye Z(1), Altena E, Nombela C, Housden CR, Maxwell H, Rittman T, Huddleston C, Rae
CL, Regenthal R, Sahakian BJ, Barker RA, Robbins TW, Rowe JB.
Author information:
(1)1 Department of Clinical Neurosciences, University of Cambridge, Cambridge,
UK.
Impulsivity is common in Parkinson’s disease even in the absence of impulse
control disorders. It is likely to be multifactorial, including a dopaminergic
‘overdose’ and structural changes in the frontostriatal circuits for motor
control. In addition, we proposed that changes in serotonergic projections to the
forebrain also contribute to response inhibition in Parkinson’s disease, based on
preclinical animal and human studies. We therefore examined whether the selective
serotonin reuptake inhibitor citalopram improves response inhibition, in terms of
both behaviour and the efficiency of underlying neural mechanisms. This
multimodal magnetic resonance imaging study used a double-blind randomized
placebo-controlled crossover design with an integrated Stop-Signal and NoGo
paradigm. Twenty-one patients with idiopathic Parkinson’s disease (46-76 years
old, 11 male, Hoehn and Yahr stage 1.5-3) received 30 mg citalopram or placebo in
addition to their usual dopaminergic medication in two separate sessions. Twenty
matched healthy control subjects (54-74 years old, 12 male) were tested without
medication. The effects of disease and drug on behavioural performance and
regional brain activity were analysed using general linear models. In addition,
anatomical connectivity was examined using diffusion tensor imaging and
tract-based spatial statistics. We confirmed that Parkinson’s disease caused
impairment in response inhibition, with longer Stop-Signal Reaction Time and more
NoGo errors under placebo compared with controls, without affecting Go reaction
times. This was associated with less stop-specific activation in the right
inferior frontal cortex, but no significant difference in NoGo-related
activation. Although there was no beneficial main effect of citalopram, it
reduced Stop-Signal Reaction Time and NoGo errors, and enhanced inferior frontal
activation, in patients with relatively more severe disease (higher Unified
Parkinson’s Disease Rating Scale motor score). The behavioural effect correlated
with the citalopram-induced enhancement of prefrontal activation and the strength
of preserved structural connectivity between the frontal and striatal regions. In
conclusion, the behavioural effect of citalopram on response inhibition depends
on individual differences in prefrontal cortical activation and frontostriatal
connectivity. The correlation between disease severity and the effect of
citalopram on response inhibition may be due to the progressive loss of forebrain
serotonergic projections. These results contribute to a broader understanding of
the critical roles of serotonin in regulating cognitive and behavioural control,
as well as new strategies for patient stratification in clinical trials of
serotonergic treatments in Parkinson’s disease.
DOI: 10.1093/brain/awu032
PMCID: PMC3959561
PMID: 24578545 [Indexed for MEDLINE]