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Helped Or Hurt by Smart Drugs? Insights from Cognitive Neuroscience Cognitive Control [email protected] Helped or hurt by smart drugs? Insights from cognitive neuroscience Cognitive control The ability to adapt flexibly to the constant changes in our environment in a goal-directed manner Cognitive control Dopamine (DA) systems in the human brain DA Stefan et al Smart pills Disorders that implicate dopamine neurobiologie & psychiatrie Attention deficit hyperactivity disorder Parkinson’s disease Drug addiction Food addiction (obesity) Behavioural addictions Dopamine-enhancing drugs neurobiologie & psychiatrie More impulsive Less impulsive How can dopaminergic drugs have such different effects in different individuals? On the paradox of dopamine neurobiologie & psychiatrie Drug effects vary as a function of • Individual (genetic) differences in personality • Baseline levels of dopamine • Task demands and associated neural systems Principle 1 Inter-individual variability of drug effects Drugs can have contrasting effects as a function of (healthy) personality traits This likely reflects individual (genetic) variability in baseline levels of dopamine Rate-dependency neurobiologie & psychiatrie placebo psychostimulant Performance Low impulsive High impulsive Dews 1958; Robbins and Sahakian, 1979; Lyon and Robbins 1975 Predicting drug effects from trait impulsivity neurobiologie & psychiatrie • Stratification by impulsive personality – Putative link with variability in the DA system • > 1200 subjects were prescreened on the self-report Barratt Impulsiveness Scale • High- and low-impulsive subjects were selected from the tail ends • Scanned using fMRI once on placebo and once following the dopamine D2 receptor agonist bromocriptine 11 The paradigm … 13 Interim conclusion neurobiologie & psychiatrie • Bromocriptine enhanced cognitive flexibility in high-impulsive subjects, but (if anything) reduced it in low-impulsive subjects. • These effects were accompanied opposite effects on activity in the striatum Next question neurobiologie & psychiatrie • Why do dopaminergic drugs have opposite effects as a function of trait impulsivity? The danger of pharmacological enhancement - going beyond optimal neurobiologie & psychiatrie 80% 60% DELAYED DELAYED ALTERNATION 40% SCH SAL SCH SKF Zahrt et al., 1997 +SKF Increasing levels of D1 receptor stimulation There is an optimal level of neuromodulation, with both excessive as well as insufficient levels being associated with poor performance Individual differences in striatal dopamine synthesis capacity in healthy volunteers High FMT uptake Low FMT uptake A PET study with the tracer 6-[18F]fluoro-L-m-tyrosine (FMT) In collaboration with Bill Jagust and Mark D’Esposito Cools et al., J Neurosci 2009 Individual differences of in the differences bromocriptine Individual efficacy Drug-effect on shifting Cools et al., J Neurosci 2009 Neurosciet al., J Cools Interim Conclusion neurobiologie & psychiatrie • Dopaminergic drugs like bromocriptine have opposite effects on cognition in high- and low-impulsive subjects • Similar contrasting effects are seen as a function of individual variability in baseline levels of dopamine • This variability likely reflects individual differences in genetic predisposition Principle 2 Intra-individual variability of drug effects, in healthy subjects Drugs can have opposite effects even within the same individual by modulating distinct functions with different ‘chemical needs’ Measuring multiple working memory functions Opposite drug effects on ignoring and updating 100 PPlaceboLC MMethylphenidatePH 90 ) % ( y c 80 a r u c c A 70 60 Ignore Update Fallon and Cools, in prep Opposite drug effects on ignoring and updating 0.2 PLPlaceboC ) MMethylphenidatePH D 0.1 E S ( e g 0 n a h C l −0.1 a n g i S −0.2 % Ignore Update Fallon and Cools, in prep Thus • Ritalin (methylphenidate) can have contrasting effects, even within the same individual, depending on specific task demands • Specifically, ritalin enhances distractor-resistance while impairing updating of working memory • Thus high levels of dopamine in the PFC might be beneficial for cognitive stability but detrimental for cognitive flexibility On the paradox of dopamine neurobiologie & psychiatrie Drug effects vary as a function of • Individual (genetic) differences in personality • Baseline levels of dopamine • Task demands and associated neural systems Conclusion Cognitive processing can be selectively modified by psychopharmacological interventions Such interventions almost certainly involve trade-offs between enhancement of some and impairment of other processing This is not to say that research on psychopharmacological enhancement should be banned. Instead, blurry boundaries between mental health and disease might be recognized & focus should move away from predicting efficacy in ill-defined spectrum disorders towards predicting effects on isolated neurocognitive processes in both ‘health’ and ‘disease’ Progress will depend on the degree to which drugs can be tailored to individuals, component processes and specific molecular events (receptors) This highlights how societal/ethical discussions about human enhancement should take into account knowledge gained from neuroscience Thank you Esther Aarts (postdoc) Marieke van der Schaaf (PhD student) Martine van Schouwenburg (PhD student) Sean Fallon (postdoc) Trevor Robbins Mark D’Esposito Bill Jagust Funding James McDonnell Scholar Award Human Frontiers Research Program Netherlands Organization for Science Dutch Brain Foundation The Royal Society of London National Institute of Health .
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