Successfully reported this slideshow.
We use your LinkedIn profile and activity data to personalize ads and to show you more relevant ads. You can change your ad preferences anytime.

Response Inhibition in Parkinson's Disease: Towards New Treatments

344 views

Published on

Presented at the Intentional Inhibition Workshop (London, 2013)

Published in: Health & Medicine
  • Be the first to comment

  • Be the first to like this

Response Inhibition in Parkinson's Disease: Towards New Treatments

  1. 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

×