Bahlmann, J, Aarts E, D'Esposito M.  2015.  Influence of motivation on control hierarchy in the human frontal cortex., 2015 Feb 18. The Journal of neuroscience : the official journal of the Society for Neuroscience. 35(7):3207-17. Abstract

The frontal cortex mediates cognitive control and motivation to shape human behavior. It is generally observed that medial frontal areas are involved in motivational aspects of behavior, whereas lateral frontal regions are involved in cognitive control. Recent models of cognitive control suggest a rostro-caudal gradient in lateral frontal regions, such that progressively more rostral (anterior) regions process more complex aspects of cognitive control. How motivation influences such a control hierarchy is still under debate. Although some researchers argue that both systems work in parallel, others argue in favor of an interaction between motivation and cognitive control. In the latter case it is yet unclear how motivation would affect the different levels of the control hierarchy. This was investigated in the present functional MRI study applying different levels of cognitive control under different motivational states (low vs high reward anticipation). Three levels of cognitive control were tested by varying rule complexity: stimulus-response mapping (low-level), flexible task updating (mid-level), and sustained cue-task associations (high-level). We found an interaction between levels of cognitive control and motivation in medial and lateral frontal subregions. Specifically, flexible updating (mid-level of control) showed the strongest beneficial effect of reward and only this level exhibited functional coupling between dopamine-rich midbrain regions and the lateral frontal cortex. These findings suggest that motivation differentially affects the levels of a control hierarchy, influencing recruitment of frontal cortical control regions depending on specific task demands.

Wittmann, BC, D'Esposito M.  2014.  Levodopa administration modulates striatal processing of punishment-associated items in healthy participants., 2014 Jun 13. Psychopharmacology. Abstract

Appetitive and aversive processes share a number of features such as their relevance for action and learning. On a neural level, reward and its predictors are associated with increased firing of dopaminergic neurons, whereas punishment processing has been linked to the serotonergic system and to decreases in dopamine transmission. Recent data indicate, however, that the dopaminergic system also responds to aversive stimuli and associated actions.

Vytlacil, J, Kayser A, Miyakawa A, D'Esposito M.  2014.  An approach for identifying brainstem dopaminergic pathways using resting state functional MRI., 2014. PloS one. 9(1):e87109. Abstract

Here, we present an approach for identifying brainstem dopaminergic pathways using resting state functional MRI. In a group of healthy individuals, we searched for significant functional connectivity between dopamine-rich midbrain areas (substantia nigra; ventral tegmental area) and a striatal region (caudate) that was modulated by both a pharmacological challenge (the administration of the dopaminergic agonist bromocriptine) and a dopamine-sensitive cognitive trait (an individual's working memory capacity). A significant inverted-U shaped connectivity pattern was found in a subset of midbrain-striatal connections, demonstrating that resting state fMRI data is sufficiently powerful to identify brainstem neuromodulatory brain networks.

Stelzel, C, Fiebach CJ, Cools R, Tafazoli S, D'Esposito M.  2013.  Dissociable fronto-striatal effects of dopamine D2 receptor stimulation on cognitive versus motor flexibility., 2013 Apr 11. Cortex; a journal devoted to the study of the nervous system and behavior. Abstract2013_stelzel.pdf

Genetic and pharmacological studies suggest an important role of the dopamine D2 receptor (DRD2) in flexible behavioral adaptation, mostly shown in reward-based learning paradigms. Recent evidence from imaging genetics indicates that also intentional cognitive flexibility, associated with lateral frontal cortex, is affected by variations in DRD2 signaling. In the present functional magnetic resonance imaging (MRI) study, we tested the effects of a direct pharmacological manipulation of DRD2 stimulation on intentional flexibility in a task-switching context, requiring switches between cognitive task rules and between response hands. In a double blind, counterbalanced design, participants received either a low dose of the DRD2 agonist bromocriptine or a placebo in two separate sessions. Bromocriptine modulated the blood-oxygen-level-dependent (BOLD) signal during rule switching: rule-switching-related activity in the left posterior lateral frontal cortex and in the striatum was increased compared to placebo, at comparable performance levels. Fronto-striatal connectivity under bromocriptine was slightly increased for rule switches compared to rule repetitions. Hand-switching-related activity, in contrast, was reduced under bromocriptine in sensorimotor regions. Our results provide converging evidence for an involvement of DRD2 signaling in fronto-striatal mechanisms underlying intentional flexibility, and indicate that the neural mechanisms underlying different types of flexibility (cognitive vs motor) are affected differently by increased dopaminergic stimulation.

Yoon, JH, Minzenberg MJ, Raouf S, D'Esposito M, Carter CS.  2013.  Impaired Prefrontal-Basal Ganglia Functional Connectivity and Substantia Nigra Hyperactivity in Schizophrenia., 2013 Jan 3. Biological psychiatry. Abstract2013_yoon.pdf

BACKGROUND: The theory that prefrontal cortex (PFC) dysfunction in schizophrenia leads to excess subcortical dopamine has generated widespread interest because it provides a parsimonious account for two core features of schizophrenia, cognitive deficits and psychosis, respectively. However, there has been limited empirical validation of this model. Moreover, the identity of the specific subcortical brain regions and circuits that may be impaired as a result of PFC dysfunction and mediate its link to psychosis in schizophrenia remains unclear. We undertook this event-related functional magnetic resonance imaging study to test the hypothesis that PFC dysfunction is associated with altered function of and connectivity with dopamine regulating regions of the basal ganglia. METHODS: Eighteen individuals with schizophrenia or schizoaffective disorder and 19 healthy control participants completed event-related functional magnetic resonance imaging during working memory. We conducted between-group contrasts of task-evoked, univariate activation maps to identify regions of altered function in schizophrenia. We also compared the groups on the level of functional connectivity between a priori identified PFC and basal ganglia regions to determine if prefrontal disconnectivity in patients was present. RESULTS: We observed task-evoked hyperactivity of the substantia nigra that occurred in association with prefrontal and striatal hypoactivity in the schizophrenia group. The magnitude of prefrontal functional connectivity with these dysfunctional basal ganglia regions was decreased in the schizophrenia group. Additionally, the level of nigrostriatal functional connectivity predicted the level of psychosis. CONCLUSIONS: These results suggest that functional impairments of the prefrontal striatonigral circuit may be a common pathway linking the pathogenesis of cognitive deficits and psychosis in schizophrenia.

Kimberg, DY, Aguirre GK, Lease J, D’Esposito.  2001.  Cortical effects of bromocriptine, a D-2 dopamine receptor agonist, in human subjects, revealed by fMRI., 2001 Apr. Human brain mapping. 12:246-57. Abstractbromo.pdf

Studies of human subjects performing cognitive tasks on and off dopaminergic drugs have suggested a specific role of dopamine in cognitive processes, particularly in working memory and prefrontal "executive" functions. However, the cortical effects of these drugs have been poorly understood. We used functional magnetic resonance imaging (fMRI) to examine both task-specific and general changes in cortical activity associated with bromocriptine, a selective agonist for D-2 dopamine receptors. Bromocriptine resulted in task-specific modulations of task-related activity in three cognitive tasks. Across tasks, the overall effect of the drug was to reduce task-related activity. We also observed drug effects on behavior that correlated with individual differences in memory span. We argue that bromocriptine may show both task-specific modulation and task-general inhibition of neural activity due to dopaminergic neurotransmission.

Gibbs, SE, D’Esposito.  2005.  A functional MRI study of the effects of bromocriptine, a dopamine receptor agonist, on component processes of working memory., 2005 Aug. Psychopharmacology. 180:644-53. Abstractgibbs2005_a_functional_mri_study_ofthe_effects_of_bromocriptine_a_dopamine_receptor_agonist_on_component_processes_of_working_memory.pdf

RATIONALE: Dopamine is abundant in the prefrontal cortex and striatum, regions implicated in working memory processes. Monkey studies suggest that subpopulations of prefrontal neurons are sensitive to component processes of working memory, and that dopaminergic actions at D1 and D2 receptors differentially affect these neurons. However, it is not known to what extent the effects of dopaminergic stimulation may differ in human subjects across the processing stages of working memory, and whether these effects are found throughout the network of task-related brain regions. OBJECTIVE: In this study we tested the effects of the D2 dopamine agonist bromocriptine during the performance of a delayed recognition task using functional magnetic resonance imaging (fMRI). METHODS: We measured blood oxygenation level dependent (BOLD) signals as subjects performed a spatial and object delayed recognition task. Subjects were scanned twice, once following 1.25 mg of bromocriptine and once following lactose placebo in a randomized double-blind design. Using an event-related design allowed for separate investigation of encoding, delay, and response period effects of dopaminergic stimulation. RESULTS: A group analysis revealed that bromocriptine treatment decreased activity in the task network at encoding and increased activity at response. There was no clear pattern of change in the delay period network. Across subjects, these BOLD signal changes were accompanied by reductions in accuracy and increases in response time during delayed recognition for spatial and object information. CONCLUSIONS: Decreased activity during encoding suggests that hyperdopaminergic stimulation may have reduced stimulus encoding processes, contributing to impaired performance.

Gibbs, SE, D’Esposito.  2005.  Individual capacity differences predict working memory performance and prefrontal activity following dopamine receptor stimulation., 2005 Jun. Cognitive, affective & behavioral neuroscience. 5:212-21. Abstractgibbs2005_individual_capacity_differences_predict_working_memory_performance_and_prefrontal_activity_following_dopamine_receptor_stimulation.pdf

Dopamine receptors are abundant in the prefrontal cortex (PFC), a critical region involved in working memory. This pharmacological fMRI study tested the relationships between dopamine, PFC function, and individual differences in working memory capacity. Subjects performed a verbal delayed-recognition task after taking either the dopamine receptor agonist bromocriptine or a placebo. Behavioral effects of bromocriptine treatment depended on subjects’ working memory spans, with the greatest behavioral benefit for lower span subjects. After bromocriptine, PFC activity was positively correlated with a measure of cognitive efficiency (RT slope) during the probe period of the task. Less efficient subjects with slower memory retrieval rates had greater PFC activity, whereas more efficient subjects had less activity. After placebo, these measures were uncorrelated. These results support the role of dopamine in verbal working memory and suggest that dopamine may modulate the efficiency of retrieval of items from the contents of working memory. Individual differences in PFC dopamine receptor concentration may thus underlie the behavioral effects of dopamine stimulation on working memory function.

Gibbs, SE, D’Esposito.  2006.  A functional magnetic resonance imaging study of the effects of pergolide, a dopamine receptor agonist, on component processes of working memory., 2006 Apr 28. Neuroscience. 139:359-71. Abstract2006gibbsfmristudyoftheeffectsofpergolide.pdf

Working memory is an important cognitive process dependent on a network of prefrontal and posterior cortical regions. In this study we tested the effects of the mixed D1-D2 dopamine receptor agonist pergolide on component processes of human working memory using functional magnetic resonance imaging (fMRI). An event-related trial design allowed separation of the effects on encoding, maintenance, and retrieval processes. Subjects were tested with spatial and object memoranda to investigate modality-specific effects of dopaminergic stimulation. We also measured baseline working memory capacity as previous studies have shown that effects of dopamine agonists vary with working memory span. Pergolide improved reaction time for high-span subjects and impaired reaction time for low-span subjects. This span-dependent change in behavior was accompanied by span-dependent changes in delay-related activity in the premotor cortex. We also found evidence for modality-specific effects of pergolide only during the response period. Pergolide increased activity for spatial memoranda and decreased activity for object memoranda in task-related regions including the prefrontal and parietal cortices.

Cools, R, Sheridan M, Jacobs E, D’Esposito.  2007.  Impulsive personality predicts dopamine-dependent changes in frontostriatal activity during component processes of working memory., 2007 May 16. The Journal of neuroscience : the official journal of the Society for Neuroscience. 27:5506-14. Abstract2007cools.pdf

Dopaminergic drugs affect a variety of cognitive processes, but the direction and extent of effects vary across individuals and tasks. Paradoxical effects are observed, by which the same drug causes cognitive enhancing as well as adverse effects. Here, we demonstrate that individual differences in impulsive personality account for the contrasting effects of dopaminergic drugs on working memory and associated frontostriatal activity. We observed that the dopamine D2 receptor agonist bromocriptine improved the flexible updating (switching) of relevant information in working memory in high-impulsive subjects, but not in low-impulsive subjects. These behavioral effects in high-impulsive subjects accompanied dissociable effects on frontostriatal activity. Bromocriptine modulated the striatum during switching but not during distraction from relevant information in working memory. Conversely, the lateral frontal cortex was modulated by bromocriptine during distraction but not during switching. The present results provide a key link between dopamine D2 receptor function, impulsivity, and frontostriatal activity during component processes of working memory.