You are on page 1of 6

Available online at www.sciencedirect.


Learning and cognitive flexibility: frontostriatal function and

monoaminergic modulation
Angie A Kehagia1,2, Graham K Murray1,3 and Trevor W Robbins1,2

Learning in a constant environment, and adapting flexibly to a last decade has focused on the prefrontal cortex (PFC)
changing one, through changes in reinforcement contingencies and basal ganglia, particularly the striatum, and their
or valence-free cues, depends on overlapping circuitry that interactions through their multiple serial and parallel
interconnects the prefrontal cortex (PFC) with the striatum and loops [1,2], subject to neuromodulatory inputs by the
is subject to several forms of neurochemical modulation. We monoamines (dopamine (DA), serotonin (5-hydroxytryp-
present evidence from recent studies in animals employing tamine, 5-HT) and noradrenaline (NA)).
electrophysiological, pharmacological and lesion techniques,
and neuroimaging, neuropsychological and pharmacological We review developments in recent years that have con-
investigations of healthy humans and clinical patients. tributed to the state of the science, progressing through a
Dopamine (DA) neurotransmission in the medial striatum and conceptual gradient of cognitive processes and paradigms.
PFC is critical for basic reinforcement learning and the First, we address basic reinforcement learning, where
integration of negative feedback during reversal learning, whilst behaviour is critically dependent on environmental sig-
orbitofrontal 5-hydroxytryptamine (5-HT) likely mediates this nals or (reward) feedback. Subsequently, we focus on
type of low level flexibility, perhaps by reducing interference reversal learning, reflecting the ability to switch respond-
from salient stimuli. The role of prefrontal noradrenaline (NA) in ing to a previously non-reinforced exemplar, which relies
higher order flexibility indexed through attentional set-shifting on feedback but critically incorporates flexibility. We
has recently received significant empirical support, and similar proceed to attentional set-shifting, which also indexes
avenues appear promising in the field of task switching. the ability to adapt behaviour flexibly following feedback,
Addresses but pertains to broader stimulus dimensions rather than a
Behavioural and Clinical Neuroscience Institute, University of specific exemplar. Finally, we address task switching, a
Cambridge, Downing Street, Cambridge CB2 3EB, UK relatively purer form of cognitive flexibility uncontami-
Department of Experimental Psychology, University of Cambridge, nated by learning and feedback processing.
Downing Street, Cambridge CB2 3EB, UK
Brain Mapping Unit, Department of Psychiatry, University of
Cambridge, Box 255, Addenbrooke’s Hospital, Cambridge CB2 2QQ, The literature cited represents a corresponding gradient
UK in spatiotemporal scale as a function of the complexity of
cognitive paradigms, and the feasibility of interspecies
Corresponding author: Kehagia, Angie A (,
translation. Basic neuronal and molecular mechanisms of
Murray, Graham K ( and Robbins, Trevor W
( reinforcement learning and low level flexibility emerge
predominantly from animal studies employing invasive
techniques such as single unit recordings, microdialysis
Current Opinion in Neurobiology 2010, 20:199–204 and selective gene knock-out. More cognitively complex
forms of flexibility are tapped mostly through systemic
This review comes from a themed issue on
Cognitive neuroscience
pharmacology (across species), lesion studies in animals
Edited by Earl Miller and Liz Phelps and functional neuroimaging in humans.

Available online 16th February 2010

0959-4388/$ – see front matter Cortico-striatal anatomy

# 2010 Elsevier Ltd. All rights reserved.
Before addressing the cognitive neuroscience of cortico-
DOI 10.1016/j.conb.2010.01.007 striatal interactions, we note developments in the field of
anatomy. The landmark proposal of anatomically and
functionally segregated cortico-striatal loops by Alexan-
der and colleagues is gradually becoming superseded by
Introduction evidence for more complex cross-talk and convergence
The ability to learn, or acquire associations between enabling integration of processing across these circuits
stimuli, actions and environmental outcomes, and flexibly [3,4]. Thus, functional connectivity network effects that
adapt ongoing behaviour according to salient changes in may underpin learning and flexible cognition are consist-
the environment or our current intentions, carries survival ent with new functional models emerging from rodent
value and is arguably fundamental to what cognitive and primate electrophysiology [5], and human neuroima-
agents perceive as voluntary action. Research on neural ging data [6,7]. Together, such studies provide func-
mechanisms subserving learning and flexibility over the tional support to anatomical results demonstrating that Current Opinion in Neurobiology 2010, 20:199–204

200 Cognitive neuroscience

the various cortico-striatal loops inter-relate in a partially emerge from studies in brain slices from transgenic mice.
overlapping, mediolateral gradient. Previously, it was hypothesized that, within the striatum,
D1 receptor-type medium spiny neurons (MSNs) express
Reinforcement learning LTP at the glutamatergic synapse, and D2 receptor-type
For some years it has been clear that both the striatum and MSNs express LDP. It is now evident that both types of
the frontal cortex play key roles in learning, being active MSN are subject to both types of synaptic plasticity,
during the expectation of reward and following its deliv- although they exhibit opposite effects in terms of LTP
ery, as well as coding prediction error during learning and LDP in the context of stimulation and in its absence
[8,9]. Beyond the postulated role of synaptic plasticity [19].
[10], monkey cell recording suggests that changes in
dynamic network states of caudate and lateral PFC Reversal learning
neurons may also be critical for learning [11]. These Deficits in reversal learning, the ability to switch respond-
regions exhibit sustained activity during simple learning ing to a previously non-reinforced stimulus, are present
and reversal learning, when contingencies are reversed. not just in chronic illness but also in the early stages of
This activity persists over the course of several seconds disorders such as Parkinson’s disease (PD) [20], schizo-
following the outcome of a behavioural trial to influence phrenia and bipolar disorder [21,22]. Catecholamines,
behaviour on the subsequent one. specifically cortico-striatal DA, and indoleamines, in
particular orbitofrontal (OFC) 5-HT, are considered
At the neurochemical level, research which illustrated critical for this type of flexibility. Reversal learning is
that primary prefrontal lesions can cause secondary impaired not only following infusions of a D2 agonist into
impairments in striatal DA function [12] has been influ- the rat medial striatum by reducing prefrontal cortical
ential, for example, in models of schizophrenia patho- input [23], but also following serotonergic depletion in
physiology. In a re-examination of the causal relationship the OFC in monkeys [24], which causes specific deficits
between striatal D2 receptor activity and frontal function, in serial reversal learning that are underpinned by a
Bach et al. showed that mesolimbic/mesostriatal hyper- failure to inhibit responding to the previously rewarded
function can also lead to frontal dysfunction [13,14]. stimulus, rather than proactive interference or enhanced
Over-expression of striatal D2 receptors caused frontal- learned avoidance [25]. Work from the same laboratory
like cognitive deficits (working memory and go/no-go has gone on to clarify the roles of OFC and medial
conditional associative learning), possibly mediated by (associative) striatum in learning and contingency reversal
altered D1 receptor activation (see [15]; working memory [26]. Whilst discrete OFC lesions impair learning reward
deficits remediated by D1 agonist administration), and contingencies by disrupting reversal following both
decreased DA turnover in PFC consequent upon the positive and negative reinforcement, striatal lesions
striatal abnormality. impaired reversal following negative feedback only,
suggesting abnormal prediction error processing. A recent
Although rodent behavioural pharmacology has been rat electrophysiological study also supports the role of the
dominated by studies in rats, a number of key exper- medial striatum in reversal learning: medial but not
iments have recently been performed in genetically ventral striatal activity changes preceded go/no-go beha-
modified mice to elucidate the role of phasic DA in viour upon reversal [27].
learning. A novel procedure employed by Zweifel et al.
[16] examined the differential effects of tonic and phasic The finding that striatal lesions impair reversal behaviour
DA neuron activity, by eliminating the latter through the following negative reinforcement suggests that DA may
inactivation of NMDA receptors on DA neurons. These crucially modulate this form of behavioural flexibility by
mice were slower to reach criterion on free operant virtue of its role in basic reinforcement learning. Indeed, a
learning and develop food conditioned place preference, recent microdialysis study demonstrated increased rever-
and were impaired on cue-driven learning in the Morris sal-related DA, but not NA, efflux in rat medial PFC
water maze. The role of burst DA firing in learning is (which is interconnected with the medial striatum), an
corroborated by a fascinating optogenetics study demon- effect that was particularly pronounced on early but not
strating that phasic activation of ascending VTA dopa- late reversals [28]. Research in humans has further illu-
minergic neurons is sufficient to drive conditioned place minated the importance of D2 receptors in mediating
preference [17]. Cellular mechanisms underlying negative reinforcement during reversal learning. Using
reinforcement learning have also been elucidated by fMRI, Jocham et al. [29] showed that individuals with a
Stuber et al. [18]. Striatal DA release in response to genotype that predisposes to lower striatal D2 receptor
reward-predicting cues and enhanced synaptic strengths expression exhibit reduced recruitment of the ventral
with VTA DA neurons develop during learning; specifi- striatum and lateral OFC, which in association with
cally, cue-reward learning was mediated by greater abnormal rostral cingulate activation observed following
AMPA receptor currents impacting on DA neurons. negative feedback, underpins their subtle reversal learn-
Further insights into the plasticity underpinning learning ing deficits. These results complement behavioural

Current Opinion in Neurobiology 2010, 20:199–204

Frontostriatal substrates of learning and flexibility Kehagia, Murray and Robbins 201

effects associated with a D2 polymorphism [30] and injections into medial PFC [40]. Lapiz et al. followed this
reports from human pharmacological fMRI that DA-ergic up with a demonstration of attentional set-shifting
manipulations modulate striatal reversal-related activity benefits following chronic administration of desipramine,
[31]. Using positron emission tomography (PET), Clat- a selective NA reuptake inhibitor [41]. Moreover, lesions
worthy et al. demonstrated that reversal learning perform- of the DNAB produce attentional set-shifting deficits in
ance correlated with methylphenidate-induced DA the rat [42]. McGaughy et al. [43] showed that NA-ergic
release in the medial striatum [32]. Similarly, methyl- but not cholinergic deafferentiation of rat medial PFC led
phenidate induced blood oxygen level dependent to specific EDS deterioration, indicative of an overly
(BOLD) changes in the striatum during reversals follow- focused attentional set, rather than an intrinsic deficit
ing negative feedback [33], presumably as a consequence in ignoring irrelevant stimuli, which was intact in the
of its blocking action on the DA transporter. lesioned animals. Results from the same laboratory
extended these findings to the beneficial effects of ato-
The open question of the precise contributions of DA and moxetine, a NA reuptake inhibitor used for the treatment
5-HT in the OFC to conditioned reinforcement and of attention deficit/hyperactivity disorder (ADHD),
reversal learning has recently been addressed by Walker which at the low doses employed in that study only
et al. [34]. Collectively, the doubly dissociable deficit augments cortical NA [44]. These findings are of
patterns exhibited by marmosets with either DA or 5-HT particular importance to the attentional set-shifting def-
depletion in the OFC implicate DA in basic associative icits of PD that have hitherto been found to be insensitive
processes of reward, and possibly in prediction error to DA-ergic medication and which we are currently
signalling (the absence of which leads to a remarkable investigating in a pharmacological study on the effects
persistence of responding in extinction), and 5-HT in of acute atomoxetine administration (see also below).
maintaining a flexible response set in the face of distract-
ing salient stimuli. In the rat, a similar function of redu- Task switching
cing distractibility from irrelevant stimuli during reversal Task switching addresses cognitive flexibility divorced
learning is ascribed to the anterior cingulate cortex: from the ability to adapt ongoing behaviour to feedback,
although 2-choice reversal behaviour remains intact fol- hence unconfounding it from the learning mechanisms
lowing lesions to this region, its inactivation by muscimol that underlie attentional set-shifting. It involves switch-
microinfusion impairs four-choice reversal by increasing ing between rules that determine well-learned stimulus
never-reinforced distracter errors [35]. and response (S–R) mappings, on the basis of cues. Task
switching deficits are seen in neurodegenerative disease
Attentional set-shifting such as PD [45] and psychiatric illness, for example,
In contrast to reversal learning which pertains to a specific OCD [46], since frontoparietal areas and the basal ganglia
exemplar, attentional set-shifting (extra-dimensional contribute to different aspects of a switch. For example,
shifting (EDS)) refers to switching between higher order whilst the human anterior cingulate underlies more gen-
modalities (e.g. from lines to shapes, from texture to eral motivational updating of the goal state on a switch of
odour) on the basis of feedback. The neural correlates task, the dorsolateral PFC is thought to be involved in
of attentional set-shifting in humans were elucidated specifically resolving interference from irrelevant task
using fMRI [36], associating OFC with reversal learning sets [47]. A coordinating role has recently been proposed
and ventrolateral PFC (vlPFC) with EDS. In the rat, a for the inferior parietal region on the basis of switch-
well-controlled lesion study of strategy shifting demon- specific signal change, which precedes that seen in PFC
strated dissociable roles for the parallel pathways from the [48]. The basal ganglia have been implicated in response
mediodorsal thalamic nucleus to the nucleus accumbens selection, particularly under conditions of increased
and medial PFC: the former is central in eliminating response interference [49] but are thought to be involved
inappropriate strategies, the latter in signalling the need in tonic fluctuations in flexibility rather than transient
to shift and the cortico-striatal projection in integrating switch-specific processes [50].
reinforcement with instrumental behaviour [37].
Remarkably few pharmacological studies have been
Although NA traditionally has been linked to attention, conducted on task switching. Ketamine induced switch-
arousal and exploration/exploitation trade-offs as a func- ing deficits in a marmoset analogue of task switching
tion of phasic and tonic firing in the locus coeruleus (LC), [51], indicating a central role of glutamate neurotrans-
the principal source of NA neurons in the dorsal nor- mission analogous to its role in attentional set-shifting
adrenergic ascending bundle (DNAB) (e.g. [38,39]), bur- [52]. Furthermore, caffeine (1,3,7-trimethylxanthine),
geoning evidence now directly implicates it in attentional an adenosine receptor antagonist that elevates central
set-shifting. One of the earlier studies in the rat reported catecholamines including DA and NA, enhances task
EDS enhancing effects of systemic atipamezole, an a2- switching in humans [53]. Indeed, the role of DA in
adrenergic autoreceptor antagonist, which were reversed dorsal cortico-striatal circuits during task switching
by a1-adrenergic but not b-adrenergic antagonist micro- has been supported primarily by the detrimental effect Current Opinion in Neurobiology 2010, 20:199–204

202 Cognitive neuroscience

of L-DOPA withdrawal in PD patients (e.g. [54]) and 2. Haber SN, Fudge JL, McFarland NR: Striatonigrostriatal
pathways in primates form an ascending spiral from the shell
that of sulpiride administration in healthy subjects [55]. to the dorsolateral striatum. J Neurosci 2000, 20:2369-2382.
However, we have recently shown that task switching 3. Draganski B, Kherif F, Kloppel S, Cook PA, Alexander DC,
deficits in PD, which profoundly affects not only DA but Parker GJ, Deichmann R, Ashburner J, Frackowiak RS: Evidence
for segregated and integrative connectivity patterns in the
also NA transmission (because of LC degeneration), are human basal ganglia. J Neurosci 2008, 28:7143-7152.
a function of disease severity and not all types of
4. Haber SN, Kim KS, Mailly P, Calzavara R: Reward-related
switching deficit stem from DA dysfunction [45]. We cortical inputs define a large striatal region in primates that
have proposed that task switching may exhibit distinct interface with associative cortical connections, providing a
substrate for incentive-based learning. J Neurosci 2006,
neurochemical profiles depending on the abstraction of 26:8368-8376.
the rule that governs a task set, similarly to those during
5. Kasanetz F, Riquelme LA, Della-Maggiore V, O’Donnell P,
attentional set-shifting: switching between simple S–R Murer MG: Functional integration across a gradient of
mappings governed by lower order rules may rely on DA corticostriatal channels controls UP state transitions in the
dorsal striatum. Proc Natl Acad Sci U S A 2008, 105:8124-8129.
(similarly to reversal learning and intradimensional set-
shifting, see Dias et al. [24]) whilst switching between 6. Di Martino A, Scheres A, Margulies DS, Kelly AM, Uddin LQ,
 Shehzad Z, Biswal B, Walters JR, Castellanos FX, Milham MP:
higher order rules pertaining to categories of stimuli may Functional connectivity of human striatum: a resting state
have a NA-ergic substrate (similarly to EDS). In support FMRI study. Cereb Cortex 2008, 18:2735-2747.
The authors addressed correlations in BOLD signal low frequency activa-
of this proposed role of NA in cognitive flexibility, tion patterns in resting state fMRI obtained from healthy volunteers to
phasic LC signals were modelled in a recent pharma- confirm patterns of functional connectivity suggested by recent anato-
mical studies. Whereas the inferior ventral striatum is functionally con-
cological fMRI study of the effects of modafinil on nected to the medial OFC, the superior ventral region connects to lateral
switching S–R mappings [56]. Modafinil was associ- OFC and dlPFC. Functional connectivity was also established between
ated with task-independent deactivation in the LC (a dorsal caudate and cognitive control regions such as the dlPFC and
anterior cingulate, whilst putamen additionally connects to motor cortex.
reduction in tonic firing), but increased activation (tonic
7. Postuma RB, Dagher A: Basal ganglia functional connectivity
firing) in the LC and cognitive control regions including based on a meta-analysis of 126 positron emission
dlPFC when subjects prepared to overcome a prepotent tomography and functional magnetic resonance imaging
response. publications. Cereb Cortex 2006, 16:1508-1521.
8. O’Doherty JP, Dayan P, Friston K, Critchley H, Dolan RJ:
Temporal difference models and reward-related learning in
Conclusions the human brain. Neuron 2003, 38:329-337.
Recent advances in understanding the contributions of
9. Schultz W, Dayan P, Montague PR: A neural substrate of
neurons in the striatum, orbital and prefrontal regions of prediction and reward. Science 1997, 275:1593-1599.
the frontal cortex to learning and flexibility reflect devel- 10. Pfister JP, Gerstner W: Triplets of spikes in a model of spike
opments in methods and techniques in animal and human timing-dependent plasticity. J Neurosci 2006, 26:9673-9682.
experimentation. The roles of cortico-striatal DA and 11. Histed MH, Pasupathy A, Miller EK: Learning substrates in the
orbitofrontal 5-HT in basic forms of learning and flexi- primate prefrontal cortex and striatum: sustained activity
bility have received growing support, and their contri- related to successful actions. Neuron 2009, 63:244-253.

bution to different cognitive subprocesses has been 12. Pycock CJ, Kerwin RW, Carter CJ: Effect of lesion of cortical
dopamine terminals on subcortical dopamine receptors in
relatively well demarcated. Conversely, the NA-ergic rats. Nature 1980, 286:74-76.
substrate of higher order flexibility represents a nascent
13. Bach ME, Simpson EH, Kahn L, Marshall JJ, Kandel ER,
field of scientific inquiry, with promise of therapeutic  Kellendonk C: Transient and selective overexpression of D2
potential in neurodegenerative and psychiatric disease, receptors in the striatum causes persistent deficits in
conditional associative learning. Proc Natl Acad Sci U S A 2008,
which future studies should explore. 105:16027-16032.
This group had previously shown that frontal-like working memory dys-
function in mice could be secondary to developmental striatal over-
Acknowledgements expression of D2 receptors. Here they demonstrate that this same striatal
This work was supported by a Wellcome Trust Programme Grant (076274/Z/ abnormality can also lead to deficient associative learning (learning to
04/Z) to TWR, BJ Everitt, AC Roberts and BJ Sahakian and was completed at lever press to one tone and withhold responding to a different tone) as a
the University of Cambridge Behavioural and Clinical Neuroscience Institute result of perseveration — a deficit also seen in mice following lesions of
supported by a joint award from the Medical Research Council and the the medial PFC which included the anterior cingulate cortex.
Wellcome Trust (G00001354). AAK holds an Isaac Newton fellowship and is
additionally supported by the Parkinson’s Disease Society. GKM is supported 14. Kellendonk C, Simpson EH, Polan HJ, Malleret G, Vronskaya S,
by the Medical Research Council and NARSAD (National Alliance for Winiger V, Moore H, Kandel ER: Transient and selective
Research on Schizophrenia and Depression). overexpression of dopamine D2 receptors in the striatum
causes persistent abnormalities in prefrontal cortex
functioning. Neuron 2006, 49:603-615.
References and recommended reading 15. Castner SA, Williams GV, Goldman-Rakic PS: Reversal of
Papers of particular interest, published within the period of review, antipsychotic-induced working memory deficits by short-term
have been highlighted as:
dopamine D1 receptor stimulation. Science 2000,
 of special interest
 of outstanding interest 16. Zweifel LS, Parker JG, Lobb CJ, Rainwater A, Wall VZ, Fadok JP,
Darvas M, Kim MJ, Mizumori SJ, Paladini CA et al.: Disruption of
NMDAR-dependent burst firing by dopamine neurons
1. Alexander GE, DeLong MR, Strick PL: Parallel organization of provides selective assessment of phasic dopamine-
functionally segregated circuits linking basal ganglia and dependent behavior. Proc Natl Acad Sci U S A 2009,
cortex. Annu Rev Neurosci 1986, 9:357-381. 106:7281-7288.

Current Opinion in Neurobiology 2010, 20:199–204

Frontostriatal substrates of learning and flexibility Kehagia, Murray and Robbins 203

17. Tsai HC, Zhang F, Adamantidis A, Stuber GD, Bonci A, de Lecea L, 32. Clatworthy PL, Lewis SJ, Brichard L, Hong YT, Izquierdo D,
Deisseroth K: Phasic firing in dopaminergic neurons is  Clark L, Cools R, Aigbirhio FI, Baron JC, Fryer TD et al.:
sufficient for behavioral conditioning. Science 2009, Dopamine release in dissociable striatal subregions
324:1080-1084. predicts the different effects of oral methylphenidate on
reversal learning and spatial working memory. J Neurosci
18. Stuber GD, Klanker M, de Ridder B, Bowers MS, Joosten RN, 2009, 29:4690-4696.
Feenstra MG, Bonci A: Reward-predictive cues enhance Using a PET molecular imaging technique, this study examined changes
excitatory synaptic strength onto midbrain dopamine in D2 receptor binding of the [11C]-raclopride radioligand induced by the
neurons. Science 2008, 321:1690-1692. DA-releasing agent methylphenidate administered to healthy subjects.
Reversal learning performance assessed outside the PET camera corre-
19. Shen W, Flajolet M, Greengard P, Surmeier DJ: Dichotomous lated with DA release induced by methylphenidate in the associative
dopaminergic control of striatal synaptic plasticity. Science striatum.
2008, 321:848-851.
33. Dodds CM, Muller U, Clark L, van Loon A, Cools R, Robbins TW:
20. Peterson DA, Elliott C, Song DD, Makeig S, Sejnowski TJ, Methylphenidate has differential effects on blood oxygenation
Poizner H: Probabilistic reversal learning is impaired in level-dependent signal related to cognitive subprocesses of
Parkinson’s disease. Neuroscience 2009, 163:1092-1101. reversal learning. J Neurosci 2008, 28:5976-5982.
21. Leeson VC, Robbins TW, Matheson E, Hutton SB, Ron MA, 34. Walker SC, Robbins TW, Roberts AC: Differential contributions
 Barnes TR, Joyce EM: Discrimination learning, reversal, and  of dopamine and serotonin to orbitofrontal cortex function in
set-shifting in first-episode schizophrenia: stability over six the marmoset. Cereb Cortex 2009, 19:889-898.
years and specific associations with medication type and This study systematically addressed the roles of DA and 5-HT in the OFC
disorganization syndrome. Biol Psychiatry 2009, 66:586-593. in mediating basic learning and low level cognitive flexibility. Marmosets
A longitudinal study of the course of learning deficits in a large cohort of with 5-HT or DA depletion were both impaired at responding with con-
first-episode schizophrenia patients in whom notable reversal learning ditioned reinforcement. In addition, 5-HT depleted marmosets were
deficits were documented. Interestingly, these correlated with disorga- biased towards the previously reinforced response during extinction,
nization symptoms. Performance did not deteriorate substantially over but exhibited no overall resistance to extinction. Conversely, the DA-
the first six years of illness. depleted animals failed to extinguish responding to the discriminative
22. Murray GK, Cheng F, Clark L, Barnett JH, Blackwell AD,
 Fletcher PC, Robbins TW, Bullmore ET, Jones PB: Reinforcement 35. Ragozzino ME, Rozman S: The effect of rat anterior cingulate
and reversal learning in first-episode psychosis. Schizophr Bull inactivation on cognitive flexibility. Behav Neurosci 2007,
2008, 34:848-855. 121:698-706.
This study reports deficits in simple discrimination and reversal learning,
which are seen as early as the first episode of psychosis. Roughly equal 36. Hampshire A, Owen AM: Fractionating attentional control using
impairments emerged in affective and non-affective psychosis.  event-related fMRI. Cereb Cortex 2006, 16:1679-1689.
This attentional set-shifting experiment adapted for functional magnetic
23. Goto Y, Grace AA: Dopaminergic modulation of limbic and resonance imaging (fMRI) employed compound stimuli of faces and
cortical drive of nucleus accumbens in goal-directed houses in a design that was driven by subjects’ own responses rather
behavior. Nat Neurosci 2005, 8:805-812. than experimental instructions. This study isolated the contributions of
vlPFC to switching between stimulus dimensions, and lateral and medial
24. Dias R, Robbins TW, Roberts AC: Dissociation in prefrontal OFC to reversals following negative and positive feedback, respectively,
cortex of affective and attentional shifts. Nature 1996, consistent with earlier work in the marmoset (Dias et al. [24]). Posterior
380:69-72. parietal activation was associated with changes in S–R mappings, whilst
25. Clarke HF, Walker SC, Dalley JW, Robbins TW, Roberts AC: dlPFC was active throughout solution search.
Cognitive inflexibility after prefrontal serotonin depletion is 37. Block AE, Dhanji H, Thompson-Tardif SF, Floresco SB: Thalamic-
behaviorally and neurochemically specific. Cereb Cortex 2007, prefrontal cortical-ventral striatal circuitry mediates
17:18-27. dissociable components of strategy set shifting. Cereb Cortex
26. Clarke HF, Robbins TW, Roberts AC: Lesions of the medial 2007, 17:1625-1636.
striatum in monkeys produce perseverative impairments 38. Aston-Jones G, Cohen JD: An integrative theory of locus
during reversal learning similar to those produced by lesions coeruleus-norepinephrine function: adaptive gain and optimal
of the orbitofrontal cortex. J Neurosci 2008, 28:10972-10982. performance. Annu Rev Neurosci 2005, 28:403-450.
27. Kimchi EY, Laubach M: Dynamic encoding of action selection 39. Nieuwenhuis S, Aston-Jones G, Cohen JD: Decision making, the
by the medial striatum. J Neurosci 2009, 29:3148-3159. P3, and the locus coeruleus-norepinephrine system. Psychol
Bull 2005, 131:510-532.
28. van der Meulen JA, Joosten RN, de Bruin JP, Feenstra MG:
Dopamine and noradrenaline efflux in the medial prefrontal 40. Lapiz MD, Morilak DA: Noradrenergic modulation of cognitive
cortex during serial reversals and extinction of instrumental function in rat medial prefrontal cortex as measured by
goal-directed behavior. Cereb Cortex 2007, 17:1444-1453. attentional set shifting capability. Neuroscience 2006,
29. Jocham G, Klein TA, Neumann J, von Cramon DY, Reuter M,
 Ullsperger M: Dopamine DRD2 polymorphism alters reversal 41. Lapiz MD, Bondi CO, Morilak DA: Chronic treatment with
learning and associated neural activity. J Neurosci 2009, desipramine improves cognitive performance of rats in an
29:3695-3704. attentional set-shifting test. Neuropsychopharmacology 2007,
This neurogenetic study examined the neural correlates of subtle reversal 32:1000-1010.
learning deficits exhibited by carriers of the A1+ allele of a DA receptor
gene polymorphism, leading to reduced expression of striatal D2 recep- 42. Tait DS, Brown VJ, Farovik A, Theobald DE, Dalley JW,
tors. Carriers of the A1+ allele were impaired at sustaining a newly Robbins TW: Lesions of the dorsal noradrenergic bundle
rewarded response upon reversal and exhibited a more general tendency impair attentional set-shifting in the rat. Eur J Neurosci 2007,
to maintain rewarded responses. Deficient feedback integration was 25:3719-3724.
correlated with abnormal rostral cingulate activation (seen following
negative feedback) and reduced recruitment of the ventral striatum 43. McGaughy J, Ross RS, Eichenbaum H: Noradrenergic, but not
and lateral OFC. cholinergic, deafferentation of prefrontal cortex impairs
attentional set-shifting. Neuroscience 2008, 153:63-71.
30. Cohen MX, Krohn-Grimberghe A, Elger CE, Weber B: Dopamine
gene predicts the brain’s response to dopaminergic drug. Eur 44. Newman LA, Darling J, McGaughy J: Atomoxetine reverses
J Neurosci 2007, 12:3652-3660.  attentional deficits produced by noradrenergic
deafferentation of medial prefrontal cortex.
31. Cools R, Lewis SJ, Clark L, Barker RA, Robbins TW: L-DOPA Psychopharmacology (Berl) 2008, 200:39-50.
disrupts activity in the nucleus accumbens during reversal A well-controlled pharmacological study demonstrating the effects of
learning in Parkinson’s disease. Neuropsychopharmacology (relatively) selective noradrenergic reuptake inhibition with atomoxetine.
2007, 32:180-189. Atomoxetine reversed EDS deficits in noradrenergically lesioned rats, but Current Opinion in Neurobiology 2010, 20:199–204

204 Cognitive neuroscience

impaired intact animals, highlighting the importance of a noradrenergic 50. Leber AB, Turk-Browne NB, Chun MM: Neural predictors of
optimum in higher order cognitive flexibility. moment-to-moment fluctuations in cognitive flexibility. Proc
Natl Acad Sci U S A 2008, 105:13592-13597.
45. Kehagia AA, Cools R, Barker RA, Robbins TW: Switching
 between abstract rules reflects disease severity but not 51. Stoet G, Snyder LH: Effects of the NMDA antagonist ketamine
dopaminergic status in Parkinson’s disease. Neuropsychologia on task-switching performance: evidence for specific
2009, 47:1117-1127. impairments of executive control. Neuropsychopharmacology
A neuropsychological study which addressed the effects of disease 2006, 31:1675-1681.
severity in early PD (Hoehn and Yahr stages I–II) on a novel task switching
design which employed switching between abstract rules and switches in 52. Stefani MR, Groth K, Moghaddam B: Glutamate receptors in the
both stimulus and response sets. Disease severity was a significant rat medial prefrontal cortex regulate set-shifting ability. Behav
predictor of switching deficits. Furthermore, L-DOPA withdrawal had Neurosci 2003, 117:728-737.
no effect on task switching performance in a Hoehn and Yahr stage I
subgroup. These findings indicate that switching between abstract rules 53. Tieges Z, Snel J, Kok A, Plat N, Ridderinkhof R: Effects of caffeine
is DA-independent and that this type of PD deficit may reflect extranigral on anticipatory control processes: evidence from a cued task-
pathology. switch paradigm. Psychophysiology 2007, 44:561-578.

46. Gu BM, Park JY, Kang DH, Lee SJ, Yoo SY, Jo HJ, Choi CH, 54. Cools R, Barker RA, Sahakian BJ, Robbins TW: Mechanisms of
Lee JM, Kwon JS: Neural correlates of cognitive inflexibility cognitive set flexibility in Parkinson’s disease. Brain 2001,
during task-switching in obsessive–compulsive disorder. 124:2503-2512.
Brain 2008, 131:155-164. 55. Mehta MA, Manes FF, Magnolfi G, Sahakian BJ, Robbins TW:
47. Hyafil A, Summerfield C, Koechlin E: Two mechanisms for Impaired set-shifting and dissociable effects on tests of
task switching in the prefrontal cortex. J Neurosci 2009, spatial working memory following the dopamine D2 receptor
29:5135-5142. antagonist sulpiride in human volunteers. Psychopharmacology
(Berl) 2004, 176:331-342.
48. Bode S, Haynes JD: Decoding sequential stages of task
preparation in the human brain. Neuroimage 2009, 45:606-613. 56. Minzenberg MJ, Watrous AJ, Yoon JH, Ursu S, Carter CS:
 Modafinil shifts human locus coeruleus to low-tonic, high-
49. Yehene E, Meiran N, Soroker N: Basal ganglia play a unique role phasic activity during functional MRI. Science 2008,
 in task switching within the frontal-subcortical circuits: 322:1700-1702.
evidence from patients with focal lesions. J Cogn Neurosci Pharmacological fMRI study of the effects of modafinil on cognitive
2008, 20:1079-1093. control. Modafanil (which weakly inhibits the NA and DA transporters
A study comparing the neuropsychological effects of lesions to the basal thus putatively elevating levels of both neurotransmitters) was associated
ganglia, prefrontal cortex and thalamus. Patients with basal ganglia with task-independent deactivation in the locus coeruleus, which the
lesions exhibited a unique profile of behavioural deficits highlighting authors argue stems from NA stimulation of autoreceptors, leading to
the role of this region in response selection: greater error rates on decreased baseline LC firing. During incongruent trials where subjects
incongruent trials which drew on response selection based on rule were required to overcome a prepotent response, modafanil was asso-
selection, as well as longer RTs on switch trials requiring response ciated with increased activation in the LC and various cognitive control
repetition. regions such as dlPFC, as well as increased LC-frontal connectivity.

Current Opinion in Neurobiology 2010, 20:199–204