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Roshan Cools – roshan.cools@gmail Behavioural and Clinical Neuroscience Institute

Wednesday, 11 July 2007 Summer school of Neuroscience - Catania Dopaminergic modulation of cognitive function in Parkinson’s disease. Roshan Cools – roshan.cools@gmail.com Behavioural and Clinical Neuroscience Institute University of Cambridge. Dopamine (DA) systems in the human brain.

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Roshan Cools – roshan.cools@gmail Behavioural and Clinical Neuroscience Institute

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  1. Wednesday, 11 July 2007Summer school of Neuroscience - CataniaDopaminergic modulation of cognitive function in Parkinson’s disease Roshan Cools – roshan.cools@gmail.com Behavioural and Clinical Neuroscience Institute University of Cambridge

  2. Dopamine (DA) systems in the human brain Cognition PREFRONTAL Attention deficit Hyperactivity disorder Movement STRIATUM Parkinson’s disease DA Reward & Motivation LIMBIC Drug Abuse Stefan et al

  3. Cortico-striatal circuits Movement CognitionMotivation Salloway et al Alexander et al

  4. Contrasting effects of dopaminergic drugs As a function of (i) Task demands and associated neural systems (ii) Baseline levels of dopamine

  5. 80% 60% 40% SCH SAL SCH SKF +SKF Dopaminergic drugs in experimental animals Both insufficient as well as excessive DA receptor stimulation impairs performance DELAYED ALTERNATION Increasing levels of D1 receptor stimulation Zahrt et al., 1997

  6. Ventral striatal- Ventral frontal circuitry Dorsolateral PFC TOO Dorsal striatum LOW GPi SNpr DOPAMINE LEVEL VA MD Parkinson’s disease – an imbalance of dopamine Dorsal striatal- Dorsal frontal circuitry OPTIMAL Ventral Striatum Dorsal Striatum Alexander et al., 1986 ‘Cold’ Cognition‘Hot’ cognition Ventral PFC Ventral striatum Gpi SNpr VA MD

  7. ‘Dorsal’ ‘Ventral’ Dopamine over-dose hypothesis • L-DOPA doses necessary to remedy the dopamine lack in the dorsal striatum may ‘over-dose’ any area where dopamine levels are relatively intact, namely the ventral striatum. TOO HIGH OPTIMAL TOO LOW DOPAMINE LEVEL

  8. LETTER NUMBER K4 7A 3# U2 Response: ‘K’ ‘A’ ‘3’ ‘2’ Dorsolateral fronto-striatal function => Task-Switching

  9. Dorsolateral PFC Dorsal striatum K4 GPi SNpr TOO HIGH 7A OPTIMAL VA MD TOO LOW 3# DOPAMINE U2 LEVEL ‘Dorsal’ Task-Switching • Implicates dorsal striatum and strongly connected dorsolateral prefrontal cortex (Meyer et al., 1998; Sohn et al., 2000; MacDonald et al., 2000)

  10. CORRECT! WRONG! Ventral/limbic fronto-striatal function => reversal learning

  11. TOO HIGH OPTIMAL TOO LOW DOPAMINE LEVEL ‘Ventral’ Reversal learning • Implicates ventral striatum and strongly connected ventral prefrontal cortex Ventral PFC Ventral striatum Gpi SNpr VA MD (Divac et al., 1967; Dias et al., 1996; Fellow and Farah, 2003; Cools et al., 2002; Hampton et al., 2007

  12. 840 790 740 690 640 590 Task switching: between well-learned task-rules PD ON PD OFF CS Mean Reaction Times (ms) switch non-switch Trial-type Cools et al., 2001, Cerebral Cortex; replicated Cools et al., 2003, Neuropsychologia

  13. 100 80 60 40 20 0 Reversal Learning based on changes in reward and punishment values Percentage of people completing (%) PD ON PD OFF CS acquisition reversal Stage Cools et al., 2001, Cerebral Cortex

  14. ‘Dorsal’ ‘Ventral’ Interim conclusion • In mild PD patients, dopamine-enhancing medication improved task-switching, but impaired reversal learning. • Consistent with the ‘DA overdose hypothesis’ TOO HIGH OPTIMAL TOO LOW DOPAMINE LEVEL Cools et al., 2001, Cereb Cortex

  15. Assessing the neural mechanisms of L-DOPA effects in PD

  16. Reversal learning  Correct  Correct Comparison of interest: final reversal errors minus correct responses  Final Reversal Error  Reversal Error  Reversal Error Reversal  Correct  Correct  Correct Correct  Probabilistic Error  Correct Correct 

  17. Ventral and orbital frontal cortex Ventral striatum Reversal-related activity irrespective of medication Front Left Right Back Cools et al. Neuropsychopharmacology, 2007 Plots thresholded at P = 0.001 uncorrected

  18. Ventral Striatum Effect of L-DOPA on reversal-related activity in PD T-value

  19. L-Dopa reduced reversal-related activity in the ventral striatum * 0.6 0.5 0.4 PD OFF 0.3 Mean Signal Change PD ON 0.2 0.1 0 Correct Responses Punishment switch trials

  20. L-DOPA altered activity in ventral, but not dorsal striatum during reversal learning Cools et al., 2007, Neuropsychopharmacology

  21. ‘Dorsal’ ‘Ventral’ Interim Conclusion Reversal learning Task switching Ventral Dorsal TOO HIGH OPTIMAL TOO LOW DOPAMINE LEVEL

  22. WRONG! ‘Dorsal’ ‘Ventral’ Decomposing the overdose effect on reversal learning TOO HIGH CORRECT! OPTIMAL Reversal learning requires us to change behaviour based on • unexpected punishment • unexpected reward TOO LOW DOPAMINE LEVEL

  23. Decomposing the overdose effect on reversal learning

  24. PD OFF PD ON Dopaminergic medication impairs reversal signalled by punishment 0.4 0.35 0.3 0.25 Mean proportion of errors 0.2 CS 0.15 0.1 0.05 0 punishment reward Cools et al., 2006; Neuropsychologia

  25. Dopaminergic medication & neuropsychological gambling

  26. Impulsive responding in the Cambridge Gamble Task * 40 35 30 25 20 Impulsivity score 15 10 5 0 PD ON PD OFF CONTROLS Patients place their bets more impulsively when they are ON medication compared with when they are OFF medication and compared with controls. Cools et al., 2003, Neuropsychologia

  27. Dorsolateral PFC Dorsal striatum GPi SNpr TOO HIGH OPTIMAL VA MD TOO LOW DOPAMINE LEVEL ‘Dorsal’ The beneficial effects of dopaminergic medication

  28. Effect of bromocriptine in healthy volunteers on task-switching

  29. Switch-related brain activity in the dorsal striatum (fMRI) Dorsal striatum * Striatal BOLD activity

  30. Dorsolateral fronto-striatal function => Spatial working memory

  31. Spatial working memory in Parkinson’s disease 45 Mild PD patients 40 Control 35 30 25 Between Search Errors 20 15 10 5 0 4 Boxes 6 Boxes 8 Boxes Difficulty Owen et al., 1997

  32. L-DOPA remediates spatial working memory deficit in PD 40 35 on' L-Dopa 30 off' L-Dopa 25 20 Between Search Errors 15 10 5 0 2 3 4 6 8 Difficulty (no. of boxes)

  33. L-Dopa normalizes blood flow in the dorsolateral PFCduring working memory PD on 2 PD off 1.5 CS 1 0.5 0 Size of effect [38 28 22] Control Memory -0.5 T-value -1 -1.5 -2 Task

  34. General Conclusion • Contrasting effects of L-DOPA as a function of task demands and underlying (ventral vs dorsal) neural systems • The striatum and the PFC may mediate dopaminergic effects on distinct cognitive function (i.e. task-switching and working memory)

  35. Catania July 2007 Thank you CambridgeUC Berkeley Trevor Robbins Mark D’Esposito Roger Barker Richard Ivry Luke Clark Lee Altamirano Simon Lewis Emily Jacobs Barbara Sahakian Margaret Sheridan Elizabeth Kelley The Royal Society of London National Institute of Health Medical Research Council American PD Association Welcome Trust Parkinson’s disease Society of the UK

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