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Chen, AJ-W, Novakovic-Agopian T, Nycum TJ, Song S, Turner GR, Hills N, Rome S, Abrams GM, D’Esposito.  2011.  Training of goal-directed attention regulation enhances control over neural processing for individuals with brain injury., 2011 May. Brain : a journal of neurology. 134:1541-54. Abstract2011_chen.pdf

Deficits in attention and executive control are some of the most common, debilitating and persistent consequences of brain injuries. Understanding neural mechanisms that support clinically significant improvements, when they do occur, may help advance treatment development. Intervening via rehabilitation provides an opportunity to probe such mechanisms. Our objective was to identify neural mechanisms that underlie improvements in attention and executive control with rehabilitation training. We tested the hypothesis that intensive training enhances modulatory control of neural processing of perceptual information in patients with acquired brain injuries. Patients (n=12) participated either in standardized training designed to target goal-directed attention regulation, or a comparison condition (brief education). Training resulted in significant improvements on behavioural measures of attention and executive control. Functional magnetic resonance imaging methods adapted for testing the effects of intervention for patients with varied injury pathology were used to index modulatory control of neural processing. Pattern classification was utilized to decode individual functional magnetic resonance imaging data acquired during a visual selective attention task. Results showed that modulation of neural processing in extrastriate cortex was significantly enhanced by attention regulation training. Neural changes in prefrontal cortex, a candidate mediator for attention regulation, appeared to depend on individual baseline state. These behavioural and neural effects did not occur with the comparison condition. These results suggest that enhanced modulatory control over visual processing and a rebalancing of prefrontal functioning may underlie improvements in attention and executive control.

Cools, R, D’Esposito.  2011.  Inverted-U-shaped dopamine actions on human working memory and cognitive control., 2011 Jun 15. Biological psychiatry. 69:e113-25. Abstract2011_cools.pdf

Brain dopamine (DA) has long been implicated in cognitive control processes, including working memory. However, the precise role of DA in cognition is not well-understood, partly because there is large variability in the response to dopaminergic drugs both across different behaviors and across different individuals. We review evidence from a series of studies with experimental animals, healthy humans, and patients with Parkinson’s disease, which highlight two important factors that contribute to this large variability. First, the existence of an optimum DA level for cognitive function implicates the need to take into account baseline levels of DA when isolating the effects of DA. Second, cognitive control is a multifactorial phenomenon, requiring a dynamic balance between cognitive stability and cognitive flexibility. These distinct components might implicate the prefrontal cortex and the striatum, respectively. Manipulating DA will thus have paradoxical consequences for distinct cognitive control processes, depending on distinct basal or optimal levels of DA in different brain regions.

Rokem, A, Landau AN, Prinzmetal W, Wallace DL, Silver MA, D’Esposito.  2011.  Modulation of Inhibition of Return by the Dopamine D2 Receptor Agonist Bromocriptine Depends on Individual DAT1 Genotype., 2011 Jul 28. Cerebral cortex (New York, N.Y. : 1991). Abstract2011_rokem.pdf

Involuntary visual spatial attention is captured when a salient cue appears in the visual field. If a target appears soon after the cue, response times to targets at the cue location are faster relative to other locations. However, after longer cue-target intervals, responses to targets at the cue location are slower, due to inhibition of return (IOR). IOR depends on striatal dopamine (DA) levels: It varies with different alleles of the DA transporter gene DAT1 and is reduced in patients with Parkinson’s disease, a disease characterized by reduced striatal dopaminergic transmission. We examined the role of DA in involuntary attention and IOR by administering the DA D2 receptor-specific agonist bromocriptine to healthy human subjects. There was no effect of either DAT1 genotype or bromocriptine on involuntary attention, but participants with DAT1 alleles predicting higher striatal DA had a larger IOR. Furthermore, bromocriptine increased the magnitude of IOR in participants with low striatal DA but abolished the IOR in subjects with high striatal DA. This inverted U-shaped pattern resembles previously described relationships between DA levels and performance on cognitive tasks and suggests an involvement of striatal DA in IOR that does not include a role in involuntary attention.

Willems, RM, Labruna L, D’Esposito, Ivry R, Casasanto D.  2011.  A functional role for the motor system in language understanding: evidence from theta-burst transcranial magnetic stimulation., 2011 Jul 1. Psychological science. 22:849-54. Abstract2011_willems.pdf

Does language comprehension depend, in part, on neural systems for action? In previous studies, motor areas of the brain were activated when people read or listened to action verbs, but it remains unclear whether such activation is functionally relevant for comprehension. In the experiments reported here, we used off-line theta-burst transcranial magnetic stimulation to investigate whether a causal relationship exists between activity in premotor cortex and action-language understanding. Right-handed participants completed a lexical decision task, in which they read verbs describing manual actions typically performed with the dominant hand (e.g., "to throw," "to write") and verbs describing nonmanual actions (e.g., "to earn," "to wander"). Responses to manual-action verbs (but not to nonmanual-action verbs) were faster after stimulation of the hand area in left premotor cortex than after stimulation of the hand area in right premotor cortex. These results suggest that premotor cortex has a functional role in action-language understanding.

Buchsbaum, BR, Baldo J, Okada K, Berman KF, Dronkers N, D’Esposito, Hickok G.  2011.  Conduction aphasia, sensory-motor integration, and phonological short-term memory - An aggregate analysis of lesion and fMRI data., 2011 Jan 20. Brain and language. Abstract2011_buchsbaum.pdf

Conduction aphasia is a language disorder characterized by frequent speech errors, impaired verbatim repetition, a deficit in phonological short-term memory, and naming difficulties in the presence of otherwise fluent and grammatical speech output. While traditional models of conduction aphasia have typically implicated white matter pathways, recent advances in lesions reconstruction methodology applied to groups of patients have implicated left temporoparietal zones. Parallel work using functional magnetic resonance imaging (fMRI) has pinpointed a region in the posterior most portion of the left planum temporale, area Spt, which is critical for phonological working memory. Here we show that the region of maximal lesion overlap in a sample of 14 patients with conduction aphasia perfectly circumscribes area Spt, as defined in an aggregate fMRI analysis of 105 subjects performing a phonological working memory task. We provide a review of the evidence supporting the idea that Spt is an interface site for the integration of sensory and vocal tract-related motor representations of complex sound sequences, such as speech and music and show how the symptoms of conduction aphasia can be explained by damage to this system.

Miller, BT, Vytlacil J, Fegen D, Pradhan S, D’Esposito.  2011.  The prefrontal cortex modulates category selectivity in human extrastriate cortex., 2011 Jan. Journal of cognitive neuroscience. 23:1-10. Abstract2011_miller.pdf

Different categories of visual objects evoke distinct stimulus-evoked sensory responses in extrastriate visual cortex. Although numerous lines of evidence support a distinct representational neural architecture, the mechanisms underlying the modulation of the category selectivity by top-down influences remains uncertain. In this study, we investigate the causal role of the PFC in the modulation of evoked activity to face and scene stimuli in the extrastriate cortex. We used two experimental approaches to disrupt prefrontal cortical function-repetitive TMS to PFC in healthy participants (Experiment 1) and focal PFC lesions in stroke patients (Experiment 2). After these perturbations to normal PFC function (pre- vs. post-TMS and lesion vs. intact hemisphere), stimulus-evoked activity in extrastriate cortex exhibited less distinct category selectivity to faces and scenes. These two experiments provide convergent evidence highlighting a direct role of PFC in the top-down modulation of bottom-up visual signals.

Jacobs, E, D’Esposito.  2011.  Estrogen shapes dopamine-dependent cognitive processes: implications for women’s health., 2011 Apr 6. The Journal of neuroscience : the official journal of the Society for Neuroscience. 31:5286-93. Abstract2011_jacobs.pdf

The prefrontal cortex (PFC) is exquisitely sensitive to its neurochemical environment. Minor fluctuations in cortical dopamine (DA) can profoundly alter working memory, a PFC-dependent cognitive function that supports an array of essential human behaviors. Dopamine’s action in the PFC follows an inverted U-shaped curve, where an optimal DA level results in maximal function and insufficient or excessive DA impairs PFC function. In animals, 17β-estradiol (the major estrogen in most mammals, referred to henceforth as estradiol) has been shown to enhance DA activity, yet no human study has adequately addressed whether estradiol’s impact on cognition occurs by way of modulating specific neurochemical systems. Here we examined the effects of endogenous fluctuations in estradiol on working memory in healthy young women as a function of baseline PFC DA [indexed by catechol-O-methyltransferase (COMT) Val(158)Met genotype and, at a finer scale, COMT enzyme activity]. The results demonstrate that estradiol status impacts working memory function and, crucially, the direction of the effect depends on indices of baseline DA. Moreover, consistent with a DA cortical efficiency hypothesis, functional MRI revealed that inferred optimal DA was associated with reduced PFC activity sustained across task blocks and selectively enhanced PFC activity on trials with the greatest demand for cognitive control. The magnitude of PFC activity during high control trials was predictive of an individual’s performance. These findings show that although estrogen, considered in isolation, may have unpredictable effects on cognitive performance, its influence is clarified when considered within a larger neuromodulatory framework. Given the clinical prevalence of dopaminergic drugs, understanding the relationship between estrogen and DA is essential for advancing women’s health.

Wallace, DL, Vytlacil JJ, Nomura EM, Gibbs SE, D’Esposito.  2011.  The dopamine agonist bromocriptine differentially affects fronto-striatal functional connectivity during working memory., 2011. Frontiers in human neuroscience. 5:32. Abstract2011_wallace.pdf

We investigated the effect of bromocriptine, a dopamine agonist, on individual differences in behavior as well as frontal-striatal connectivity during a working memory task. After dopaminergic augmentation, frontal-striatal connectivity in low working memory capacity individuals increases, corresponding with behavioral improvement whereas decreases in connectivity in high working memory capacity individuals are associated with poorer behavioral performance. These findings corroborate an inverted U-shape response of dopamine function in behavioral performance and provide insight on the corresponding neural mechanisms.

Buchsbaum, BR, Ye D, D’Esposito.  2011.  Recency Effects in the Inferior Parietal Lobe during Verbal Recognition Memory., 2011. Frontiers in human neuroscience. 5:59. Abstract2011_buchsbaum_fihn.pdf

The most recently encountered information is often most easily remembered in psychological tests of memory. Recent investigations of the neural basis of such "recency effects" have shown that activation in the lateral inferior parietal cortex (LIPC) tracks the recency of a probe item when subjects make recognition memory judgments. A key question regarding recency effects in the LIPC is whether they fundamentally reflect the storage (and strength) of information in memory, or whether such effects are a consequence of task difficulty or an upswing in resting state network activity. Using functional magnetic resonance imaging we show that recency effects in the LIPC are independent of the difficulty of recognition memory decisions, that they are not a by-product of an increase in resting state network activity, and that they appear to dissociate from regions known to be involved in verbal working memory maintenance. We conclude with a discussion of two alternative explanations - the memory strength and "expectancy" hypotheses, respectively - of the parietal lobe recency effect.

D'Esposito, M, Badre D.  2011.  Combining the insights derived from lesion and fMRI studies to understand the function of prefrontal cortex. Mind and the Frontal Lobes: Cognition, Behavior, and Brain Imaging. , New York: Oxford University Press
D'Esposito, M, Kayser A, Chen A.  2011.  Functional MRI: cognitive neuroscience applications. Functional Neuroradiology: Principles and Clinical Applications. , Berlin: Springer-Verlag
Turner, G, D'Esposito M.  2011.  Functional neuroimaging of aging. Clinical Neurology of Aging, 3rd Edition. , Oxford: Oxford University Press
Kayser, A, Erickson DT, Buchsbaum BR, D’Esposito.  2010.  Neural representations of relevant and irrelevant features in perceptual decision making., 2010 Nov 24. The Journal of neuroscience : the official journal of the Society for Neuroscience. 30:15778-89. Abstract2010_kayser.pdf

Although perceptual decision making activates a network of brain areas involved in sensory, integrative, and motor functions, circuit activity can clearly be modulated by factors beyond the stimulus. Of particular interest is to understand how the network is modulated by top-down factors such as attention. Here, we demonstrate in a motion coherence task that selective attention produces marked changes in the blood oxygen level-dependent (BOLD) response in a subset of regions within a human perceptual decision-making circuit. Specifically, when motion is attended, the BOLD response decreases with increasing motion coherence in many regions, including the motion-sensitive area MT+, the intraparietal sulcus, and the inferior frontal sulcus. However, when motion is ignored, the negative parametric response in a subset of this circuit becomes positive. Through both modeling and connectivity analyses, we demonstrate that this inversion both reflects a top-down influence and segregates attentional from accumulation regions, thereby permitting us to further delineate the contributions of different regions to the perceptual decision.

Kayser, A, Buchsbaum BR, Erickson DT, D’Esposito.  2010.  The functional anatomy of a perceptual decision in the human brain., 2010 Mar. Journal of neurophysiology. 103:1179-94. Abstract2010_kayser_neurophysiology.pdf

Our ability to make rapid decisions based on sensory information belies the complexity of the underlying computations. Recently, "accumulator" models of decision making have been shown to explain the activity of parietal neurons as macaques make judgments concerning visual motion. Unraveling the operation of a decision-making circuit, however, involves understanding both the responses of individual components in the neural circuitry and the relationships between them. In this functional magnetic resonance imaging study of the decision process in humans, we demonstrate that an accumulator model predicts responses to visual motion in the intraparietal sulcus (IPS). Significantly, the metrics used to define responses within the IPS also reveal distinct but interacting nodes in a circuit, including early sensory detectors in visual cortex, the visuomotor integration system of the IPS, and centers of cognitive control in the prefrontal cortex, all of which collectively define a perceptual decision-making network.

Nomura, EM, Gratton C, Visser RM, Kayser A, Perez F, D’Esposito.  2010.  Double dissociation of two cognitive control networks in patients with focal brain lesions., 2010 Jun 29. Proceedings of the National Academy of Sciences of the United States of America. 107:12017-22. Abstract2010_nomura.pdf

Neuroimaging studies of cognitive control have identified two distinct networks with dissociable resting state connectivity patterns. This study, in patients with heterogeneous damage to these networks, demonstrates network independence through a double dissociation of lesion location on two different measures of network integrity: functional correlations among network nodes and within-node graph theory network properties. The degree of network damage correlates with a decrease in functional connectivity within that network while sparing the nonlesioned network. Graph theory properties of intact nodes within the damaged network show evidence of dysfunction compared with the undamaged network. The effect of anatomical damage thus extends beyond the lesioned area, but remains within the bounds of the existing network connections. Together this evidence suggests that networks defined by their role in cognitive control processes exhibit independence in resting data.

Sheridan, MA, Hinshaw S, D’Esposito.  2010.  Stimulant medication and prefrontal functional connectivity during working memory in ADHD: a preliminary report., 2010 Jul. Journal of attention disorders. 14:69-78. Abstract2010_sheridan.pdf

OBJECTIVE: Recent theoretical and empirical work suggests that while unmedicated, children with ADHD have a deficit in subcortical processing that leads to greater and more varied prefrontal cortical (PFC) activation, compared to (a) age-matched control participants and (b) their own brain activity while on stimulant medication. This pattern has been described elsewhere as inefficient. METHOD: Functional magnetic resonance imaging (fMRI) and functional connectivity analyses were used during a working memory task for five female adolescents with ADHD, aged 11 to 17 years, both on and off their usual dose of stimulant medication. RESULTS: On medication, adolescents with ADHD demonstrated less PFC activation and less functional connectivity between frontal and subcortical regions compared to off medication. CONCLUSIONS: Because of the small sample size, results are presented as preliminary findings which await replication in a larger sample. However, these findings lend support to the idea that remediation of inefficiencies in PFC function for individuals with ADHD by stimulant medication may be related, in part, to frontal-subcortical connectivity.

Hooker, CI, Verosky SC, Germine LT, Knight RT, D’Esposito.  2010.  Neural activity during social signal perception correlates with self-reported empathy., 2010 Jan 13. Brain research. 1308:100-13. Abstract2010_hooker.pdf

Empathy is an important component of human relationships, yet the neural mechanisms that facilitate empathy are unclear. The broad construct of empathy incorporates both cognitive and affective components. Cognitive empathy includes mentalizing skills such as perspective-taking. Affective empathy consists of the affect produced in response to someone else’s emotional state, a process which is facilitated by simulation or "mirroring." Prior evidence shows that mentalizing tasks engage a neural network which includes the temporoparietal junction, superior temporal sulcus, and medial prefrontal cortex. On the other hand, simulation tasks engage the fronto-parietal mirror neuron system (MNS) which includes the inferior frontal gyrus (IFG) and the somotosensory related cortex (SRC). Here, we tested whether neural activity in these two neural networks was related to self-reports of cognitive and affective empathy in daily life. Participants viewed social scenes in which the shift of direction of attention of a character did or did not change the character’s mental and emotional state. As expected, the task robustly activated both mentalizing and MNS networks. We found that when detecting the character’s change in mental and emotional state, neural activity in both networks is strongly related to cognitive empathy. Specifically, neural activity in the IFG, SRC, and STS were related to cognitive empathy. Activity in the precentral gyrus was related to affective empathy. The findings suggest that both simulation and mentalizing networks contribute to multiple components of empathy.

Cools, R, Miyakawa A, Sheridan M, D’Esposito.  2010.  Enhanced frontal function in Parkinson’s disease., 2010 Jan. Brain : a journal of neurology. 133:225-33. Abstract2010_cools.pdf

We investigated the role of dopamine in working memory by examining effects of withdrawing dopaminergic medication in patients with Parkinson’s disease. Resistance to distraction during a delayed response task was abnormally enhanced in Parkinson’s disease patients OFF medication relative to controls. Conversely, performance on a backward digit span test was impaired in these same Parkinson’s disease patients OFF medication. Dopaminergic medication reinstated susceptibility to distraction and backward digit span performance, so that performance of Parkinson’s disease patients ON medication did not differ from that of controls. We hypothesize that the enhanced distractor resistance and impaired backward digit span in Parkinson’s disease reflects low dopamine levels in the striatum, and perhaps upregulated frontal dopamine levels. Dopaminergic medication may reinstate distractibility by normalizing the balance between striatal and prefrontal dopamine transmission.

Finn, AS, Sheridan MA, Kam CHL, Hinshaw S, D’Esposito.  2010.  Longitudinal evidence for functional specialization of the neural circuit supporting working memory in the human brain., 2010 Aug 18. The Journal of neuroscience : the official journal of the Society for Neuroscience. 30:11062-7. Abstract2010_finn.pdf

Although children perform more poorly than adults on many cognitive measures, they are better able to learn things such as language and music. These differences could result from the delayed specialization of neural circuits and asynchronies in the maturation of neural substrates required for learning. Working memory–the ability to hold information in mind that is no longer present in the environment–comprises a set of cognitive processes required for many, if not all, forms of learning. A critical neural substrate for working memory (the prefrontal cortex) continues to mature through early adulthood. What are the functional consequences of this late maturation for working memory? Using a longitudinal design, we show that although individuals recruit prefrontal cortex as expected during both early and late adolescence during a working memory task, this recruitment is correlated with behavior only in late adolescence. The hippocampus is also recruited, but only during early, and not late, adolescence. Moreover, the hippocampus and prefrontal cortex are coactive in early adolescence regardless of task demands or performance, in contrast to the pattern seen in late adolescents and adults, when these regions are coactive only under high task demands. Together, these data demonstrate that neural circuitry underlying working memory changes during adolescent development. The diminishing contribution of the hippocampus in working memory function with age is an important observation that informs questions about how children and adults learn differently.

Badre, D, Kayser A, D’Esposito.  2010.  Frontal cortex and the discovery of abstract action rules., 2010 Apr 29. Neuron. 66:315-26. Abstract2010_badre.pdf

Although we often encounter circumstances with which we have no prior experience, we rapidly learn how to behave in these novel situations. Such adaptive behavior relies on abstract behavioral rules that are generalizable, rather than concrete rules mapping specific cues to specific responses. Although the frontal cortex is known to support concrete rule learning, less well understood are the neural mechanisms supporting the acquisition of abstract rules. Here, we use a reinforcement learning paradigm to demonstrate that more anterior regions along the rostro-caudal axis of frontal cortex support rule learning at higher levels of abstraction. Moreover, these results indicate that when humans confront new rule learning problems, this rostro-caudal division of labor supports the search for relationships between context and action at multiple levels of abstraction simultaneously.

Chen, AJ-W, D’Esposito.  2010.  Traumatic brain injury: from bench to bedside [corrected] to society., 2010 Apr 15. Neuron. 66:11-4. Abstract2010_chen.pdf

Traumatic injury to the brain is a problem as old as humanity, but advances in cognitive neuroscience and a long-term view of the dynamic nature of the brain across the lifespan may change how the disorder is understood and treated.

D'Esposito, M.  2010.  Why Methods Matter in the Study of the Biological Basis of the Mind: A Behavioral Neurologist’s Perspective. The Cognitive Neuroscience of Mind: A Tribute to Michael S. Gazzaniga. , Cambridge: MIT Press Abstract2010despo01.pdf


Badre, D, D’Esposito.  2009.  Is the rostro-caudal axis of the frontal lobe hierarchical?, 2009 Sep Nature reviews. Neuroscience. 10:659-69. Abstract2009badrenature.pdf

The frontal lobes in the brain are a component of the cerebral system that supports goal-directed behaviour. However, their functional organization remains controversial. Recent studies have reported rostro-caudal distinctions in frontal cortex activity based on the abstractness of action representations. In addition, some have proposed that these differences reflect a hierarchical organization, whereby anterior frontal regions influence processing by posterior frontal regions during the realization of abstract action goals as motor acts. However, few have considered whether the anatomy and physiology of the frontal lobes support such a scheme. To address this gap, this Review surveys anatomical, neuroimaging, electrophysiological and developmental findings, and considers the question: could the organization of the frontal cortex be hierarchical?

Boettiger, CA, Kelley EA, Mitchell JM, D’Esposito, Fields HL.  2009.  Now or Later? An fMRI study of the effects of endogenous opioid blockade on a decision-making network., 2009 Sep Pharmacology, biochemistry, and behavior. 93:291-9. Abstractpbb70653.pdf

Previously, we found that distinct brain areas predict individual selection bias in decisions between small immediate ("Now") and larger delayed rewards ("Later"). Furthermore, such selection bias can be manipulated by endogenous opioid blockade. To test whether blocking endogenous opioids with naltrexone (NTX) alters brain activity during decision-making in areas predicting individual bias, we compared fMRI BOLD signal correlated with Now versus Later decision-making after acute administration of NTX (50 mg) or placebo. We tested abstinent alcoholics and control subjects in a double-blind two-session design. We defined regions of interest (ROIs) centered on activation peaks predicting Now versus Later selection bias. NTX administration significantly increased BOLD signal during decision-making in the right lateral orbital gyrus ROI, an area where enhanced activity during decision-making predicts Later bias. Exploratory analyses identified additional loci where BOLD signal during decision-making was enhanced (left orbitofrontal cortex, left inferior temporal gyrus, and cerebellum) or reduced (right superior temporal pole) by NTX. Additional analyses identified sites, including the right lateral orbital gyrus, in which NTX effects on BOLD signal predicted NTX effects on selection bias. These data agree with opioid receptor expression in human frontal and temporal cortices, and suggest possible mechanisms of NTX’s therapeutic effects.

Kayser, A, Sun FT, D’Esposito.  2009.  A comparison of Granger causality and coherency in fMRI-based analysis of the motor system., 2009 Nov. Human brain mapping. 30:3475-94. Abstract2009kayserhbm.pdf

The ability of functional MRI to acquire data from multiple brain areas has spurred developments not only in voxel-by-voxel analyses, but also in multivariate techniques critical to quantifying the interactions between brain areas. As the number of multivariate techniques multiplies, however, few studies in any modality have directly compared different connectivity measures, and fewer still have done so in the context of well-characterized neural systems. To focus specifically on the temporal dimension of interactions between brain regions, we compared Granger causality and coherency (Sun et al., 2004, 2005: Neuroimage 21:647-658, Neuroimage 28:227-237) in a well-studied motor system (1) to gain further insight into the convergent and divergent results expected from each technique, and (2) to investigate the leading and lagging influences between motor areas as subjects performed a motor task in which they produced different learned series of eight button presses. We found that these analyses gave convergent but not identical results: both techniques, for example, suggested an anterior-to-posterior temporal gradient of activity from supplemental motor area through premotor and motor cortices to the posterior parietal cortex, but the techniques were differentially sensitive to the coupling strength between areas. We also found practical reasons that might argue for the use of one technique over another in different experimental situations. Ultimately, the ideal approach to fMRI data analysis is likely to involve a complementary combination of methods, possibly including both Granger causality and coherency.

Rissman, J, Gazzaley A, D’Esposito.  2009.  The effect of non-visual working memory load on top-down modulation of visual processing., 2009 Jun. Neuropsychologia. 47:1637-46. Abstract2009rissmanneuropsychologia.pdf

While a core function of the working memory (WM) system is the active maintenance of behaviorally relevant sensory representations, it is also critical that distracting stimuli are appropriately ignored. We used functional magnetic resonance imaging to examine the role of domain-general WM resources in the top-down attentional modulation of task-relevant and irrelevant visual representations. In our dual-task paradigm, each trial began with the auditory presentation of six random (high load) or sequentially ordered (low load) digits. Next, two relevant visual stimuli (e.g., faces), presented amongst two temporally interspersed visual distractors (e.g., scenes), were to be encoded and maintained across a 7-s delay interval, after which memory for the relevant images and digits was probed. When taxed by high load digit maintenance, participants exhibited impaired performance on the visual WM task and a selective failure to attenuate the neural processing of task-irrelevant scene stimuli. The over-processing of distractor scenes under high load was indexed by elevated encoding activity in a scene-selective region-of-interest relative to low load and passive viewing control conditions, as well as by improved long-term recognition memory for these items. In contrast, the load manipulation did not affect participants’ ability to upregulate activity in this region when scenes were task-relevant. These results highlight the critical role of domain-general WM resources in the goal-directed regulation of distractor processing. Moreover, the consequences of increased WM load in young adults closely resemble the effects of cognitive aging on distractor filtering [Gazzaley, A., Cooney, J. W., Rissman, J., & D’Esposito, M. (2005). Top-down suppression deficit underlies working memory impairment in normal aging. Nature Neuroscience 8, 1298-1300], suggesting the possibility of a common underlying mechanism.

Buchsbaum, BR, D’Esposito.  2009.  Repetition suppression and reactivation in auditory-verbal short-term recognition memory., 2009 Jun. Cerebral cortex (New York, N.Y. : 1991). 19:1474-85. Abstract2008buchsbaum2.pdf

The neural response to stimulus repetition is not uniform across brain regions, stimulus modalities, or task contexts. For instance, it has been observed in many functional magnetic resonance imaging (fMRI) studies that sometimes stimulus repetition leads to a relative reduction in neural activity (repetition suppression), whereas in other cases repetition results in a relative increase in activity (repetition enhancement). In the present study, we hypothesized that in the context of a verbal short-term recognition memory task, repetition-related "increases" should be observed in the same posterior temporal regions that have been previously associated with "persistent activity" in working memory rehearsal paradigms. We used fMRI and a continuous recognition memory paradigm with short lags to examine repetition effects in the posterior and anterior regions of the superior temporal cortex. Results showed that, consistent with our hypothesis, the 2 posterior temporal regions consistently associated with working memory maintenance, also show repetition increases during short-term recognition memory. In contrast, a region in the anterior superior temporal lobe showed repetition suppression effects, consistent with previous research work on perceptual adaptation in the auditory-verbal domain. We interpret these results in light of recent theories of the functional specialization along the anterior and posterior axes of the superior temporal lobe.

Cools, R, Frank MJ, Gibbs SE, Miyakawa A, Jagust W, D’Esposito.  2009.  Striatal dopamine predicts outcome-specific reversal learning and its sensitivity to dopaminergic drug administration., 2009 Feb 4. The Journal of neuroscience : the official journal of the Society for Neuroscience. 29:1538-43. Abstract2009cools.pdf

Individual variability in reward-based learning has been ascribed to quantitative variation in baseline levels of striatal dopamine. However, direct evidence for this pervasive hypothesis has hitherto been unavailable. We demonstrate that individual differences in reward-based reversal learning reflect variation in baseline striatal dopamine synthesis capacity, as measured with neurochemical positron emission tomography. Subjects with high baseline dopamine synthesis in the striatum showed relatively better reversal learning from unexpected rewards than from unexpected punishments, whereas subjects with low baseline dopamine synthesis in the striatum showed the reverse pattern. In addition, baseline dopamine synthesis predicted the direction of dopaminergic drug effects. The D(2) receptor agonist bromocriptine improved reward-based relative to punishment-based reversal learning in subjects with low baseline dopamine synthesis capacity, while impairing it in subjects with high baseline dopamine synthesis capacity in the striatum. Finally, this pattern of drug effects was outcome-specific, and driven primarily by drug effects on punishment-, but not reward-based reversal learning. These data demonstrate that the effects of D(2) receptor stimulation on reversal learning in humans depend on task demands and baseline striatal dopamine synthesis capacity.

Rajah, MN, Bastianetto S, Bromley-Brits K, Cools R, D’Esposito, Grady CL, Poirier J, Quirion R, Raz N, Rogaeva E, Song W, Pruessner J.  2009.  Biological changes associated with healthy versus pathological aging: a symposium review., 2009 Apr. Ageing research reviews. 8:140-6. Abstractrajah_2009_ageing-research-reviews.pdf

The Douglas Mental Health University Institute, in collaboration with the McGill Centre for Studies in Aging, organized a 2-day symposium entitled "Biological Changes Associated with Healthy Versus Pathological Aging" that was held in 13 and 14 December 2007 on the Douglas campus. The symposium involved presentations on current trends in aging and dementia research across several sub-disciplines: genetics, neurochemistry, structural and functional neuroimaging and clinical treatment and rehabilitation. The goal of this symposium was to provide a forum for knowledge-transfer between scientists and clinicians with different specializations in order to promote cross-fertilization of research ideas that would lead to future collaborative neuroscience research in aging and dementia. In this review article, we summarize the presentations made by the 13 international scientists at the symposium and highlight: (i) past research, and future research trends in neuroscience of aging and dementia and (ii) links across levels of analysis that can lead to fruitful transdisciplinary research programs that will advance knowledge about the neurobiological changes associated with healthy aging and dementia.

Badre, D, Hoffman J, Cooney JW, D’Esposito.  2009.  Hierarchical cognitive control deficits following damage to the human frontal lobe., 2009 Apr. Nature neuroscience. 12:515-22. Abstract2009badrenatureneuroscience.pdf

Cognitive control permits us to make decisions about abstract actions, such as whether to e-mail versus call a friend, and to select the concrete motor programs required to produce those actions, based on our goals and knowledge. The frontal lobes are necessary for cognitive control at all levels of abstraction. Recent neuroimaging data have motivated the hypothesis that the frontal lobes are organized hierarchically, such that control is supported in progressively caudal regions as decisions are made at more concrete levels of action. We found that frontal damage impaired action decisions at a level of abstraction that was dependent on lesion location (rostral lesions affected more abstract tasks, whereas caudal lesions affected more concrete tasks), in addition to impairing tasks requiring more, but not less, abstract action control. Moreover, two adjacent regions were distinguished on the basis of the level of control, consistent with previous functional magnetic resonance imaging results. These results provide direct evidence for a rostro-caudal hierarchical organization of the frontal lobes.

Van Boven, RW, Harrington GS, Hackney DB, Ebel A, Gauger G, Bremner DJ, D’Esposito, Detre JA, Haacke ME, Jack CR, Jagust W, Le Bihan D, Mathis CA, Mueller S, Mukherjee P, Schuff N, Chen AJ-W, Weiner MW.  2009.  Advances in neuroimaging of traumatic brain injury and posttraumatic stress disorder., 2009. Journal of rehabilitation research and development. 46:717-57. Abstract2009vanboven.pdf

Improved diagnosis and treatment of traumatic brain injury (TBI) and posttraumatic stress disorder (PTSD) are needed for our military and veterans, their families, and society at large. Advances in brain imaging offer important biomarkers of structural, functional, and metabolic information concerning the brain. This article reviews the application of various imaging techniques to the clinical problems of TBI and PTSD. For TBI, we focus on findings and advances in neuroimaging that hold promise for better detection, characterization, and monitoring of objective brain changes in symptomatic patients with combat-related, closed-head brain injuries not readily apparent by standard computed tomography or conventional magnetic resonance imaging techniques.

DeGutis, J, D’Esposito.  2009.  Network changes in the transition from initial learning to well-practiced visual categorization., 2009. Frontiers in human neuroscience. 3:44. Abstract2009degutis.pdf

Visual categorization is a remarkable ability that allows us to effortlessly identify objects and efficiently respond to our environment. The neural mechanisms of how visual categories become well-established are largely unknown. Studies of initial category learning implicate a network of regions that include inferior temporal cortex (ITC), medial temporal lobe (MTL), basal ganglia (BG), premotor cortex (PMC) and prefrontal cortex (PFC). However, how these regions change with extended learning is poorly characterized. To understand the neural changes in the transition from initially learned to well-practiced categorization, we used functional MRI and compared brain activity and functional connectivity when subjects performed an initially learned categorization task (100 trials of training) and a well-practiced task (4250 trials of training). We demonstrate that a similar network is implicated for initially learned and well-practiced categorization. Additionally, connectivity analyses reveal an increased coordination between ITC, MTL, and PMC when making category judgments during the well-practiced task. These results suggest that category learning involves an increased coordination between a distributed network of regions supporting retrieval and representation of categories.

Lauritzen, TZ, D’Esposito, Heeger DJ, Silver MA.  2009.  Top-down flow of visual spatial attention signals from parietal to occipital cortex., 2009. Journal of vision. 9:18.1-14. Abstract2009lauritzen.pdf

Given the complexity of our visual environment, the ability to selectively attend to certain locations, while ignoring others, is crucial for reducing the amount of visual information to manageable levels and for optimizing behavioral performance. Sustained allocation of spatial attention causes persistent increases in functional magnetic resonance imaging (fMRI) signals in portions of early visual cortex that retinotopically represent the attended location, even in the absence of a visual stimulus. Here we test the hypothesis that topographically organized posterior parietal cortical areas IPS1 and IPS2 transmit top-down spatial attention signals to early visual cortex. We employed fMRI and coherency analysis to measure functional connectivity among cortical areas V1, V2, V3, V3A, V3B, V7, IPS1, and IPS2 during sustained visual spatial attention. Attention increased the magnitude of coherency for many pairs of areas in occipital and parietal cortex. Additionally, attention-related activity in IPS1 and IPS2 led activity in several visual cortical areas by a few hundred milliseconds. These results are consistent with transmission of top-down spatial attention signals from IPS1 and IPS2 to early visual cortex.

Cools, R, D'Esposito M.  2009.  Dopaminergic modulation of flexible cognitive control in humans. Dopamine Handbook. , Oxford, UK: Oxford University Press
D'Esposito, M, Kayser A, Chen A.  2009.  Functional MRI: applications in cognitive neuroscience. Functional MRI Techniques and Protocols. : Humana Press
Buchsbaum, BR, D'Esposito M.  2009.  Is there anything special about working memory? Neuroimaging of Human Memory: Linking Cognitive Process to Neural Systems. , Oxford: Oxford University Press Abstract2009buchsbaum.pdf


Gazzaley, A, Clapp W, Kelley J, McEvoy K, Knight RT, D’Esposito.  2008.  Age-related top-down suppression deficit in the early stages of cortical visual memory processing., 2008 Sep 2. Proceedings of the National Academy of Sciences of the United States of America. 105:13122-6. Abstractpnas-2008-gazzaley-13122-6.pdf

In this study, electroencephalography (EEG) was used to examine the relationship between two leading hypotheses of cognitive aging, the inhibitory deficit and the processing speed hypothesis. We show that older adults exhibit a selective deficit in suppressing task-irrelevant information during visual working memory encoding, but only in the early stages of visual processing. Thus, the employment of suppressive mechanisms are not abolished with aging but rather delayed in time, revealing a decline in processing speed that is selective for the inhibition of irrelevant information. EEG spectral analysis of signals from frontal regions suggests that this results from excessive attention to distracting information early in the time course of viewing irrelevant stimuli. Subdividing the older population based on working memory performance revealed that impaired suppression of distracting information early in the visual processing stream is associated with poorer memory of task-relevant information. Thus, these data reconcile two cognitive aging hypotheses by revealing that an interaction of deficits in inhibition and processing speed contributes to age-related cognitive impairment.

Samanez-Larkin, GR, D’Esposito.  2008.  Group comparisons: imaging the aging brain., 2008 Sep. Social cognitive and affective neuroscience. 3:290-7. Abstract2008samanezlarkin.pdf

With the recent growth of functional magnetic resonance imaging (fMRI), scientists across a range of disciplines are comparing neural activity between groups of interest, such as healthy controls and clinical patients, children and young adults and younger and older adults. In this edition of Tools of the Trade, we will discuss why great caution must be taken when making group comparisons in studies using fMRI. Although many methodological contributions have been made in recent years, the suggestions for overcoming common issues are too often overlooked. This review focuses primarily on neuroimaging studies of healthy aging, but many of the issues raised apply to other group designs as well.

Hooker, CI, Verosky SC, Miyakawa A, Knight RT, D’Esposito.  2008.  The influence of personality on neural mechanisms of observational fear and reward learning., 2008 Sep. Neuropsychologia. 46:2709-24. Abstract2008hooker.pdf

Fear and reward learning can occur through direct experience or observation. Both channels can enhance survival or create maladaptive behavior. We used fMRI to isolate neural mechanisms of observational fear and reward learning and investigate whether neural response varied according to individual differences in neuroticism and extraversion. Participants learned object-emotion associations by observing a woman respond with fearful (or neutral) and happy (or neutral) facial expressions to novel objects. The amygdala-hippocampal complex was active when learning the object-fear association, and the hippocampus was active when learning the object-happy association. After learning, objects were presented alone; amygdala activity was greater for the fear (vs. neutral) and happy (vs. neutral) associated object. Importantly, greater amygdala-hippocampal activity during fear (vs. neutral) learning predicted better recognition of learned objects on a subsequent memory test. Furthermore, personality modulated neural mechanisms of learning. Neuroticism positively correlated with neural activity in the amygdala and hippocampus during fear (vs. neutral) learning. Low extraversion/high introversion was related to faster behavioral predictions of the fearful and neutral expressions during fear learning. In addition, low extraversion/high introversion was related to greater amygdala activity during happy (vs. neutral) learning, happy (vs. neutral) object recognition, and faster reaction times for predicting happy and neutral expressions during reward learning. These findings suggest that neuroticism is associated with an increased sensitivity in the neural mechanism for fear learning which leads to enhanced encoding of fear associations, and that low extraversion/high introversion is related to enhanced conditionability for both fear and reward learning.

Hooker, CI, Verosky SC, Germine LT, Knight RT, D’Esposito.  2008.  Mentalizing about emotion and its relationship to empathy., 2008 Sep. Social cognitive and affective neuroscience. 3:204-17. Abstract2008hooker1.pdf

Mentalizing involves the ability to predict someone else’s behavior based on their belief state. More advanced mentalizing skills involve integrating knowledge about beliefs with knowledge about the emotional impact of those beliefs. Recent research indicates that advanced mentalizing skills may be related to the capacity to empathize with others. However, it is not clear what aspect of mentalizing is most related to empathy. In this study, we used a novel, advanced mentalizing task to identify neural mechanisms involved in predicting a future emotional response based on a belief state. Subjects viewed social scenes in which one character had a False Belief and one character had a True Belief. In the primary condition, subjects were asked to predict what emotion the False Belief Character would feel if they had a full understanding about the situation. We found that neural regions related to both mentalizing and emotion were involved when predicting a future emotional response, including the superior temporal sulcus, medial prefrontal cortex, temporal poles, somatosensory related cortices (SRC), inferior frontal gyrus and thalamus. In addition, greater neural activity in primarily emotion-related regions, including right SRC and bilateral thalamus, when predicting emotional response was significantly correlated with more self-reported empathy. The findings suggest that predicting emotional response involves generating and using internal affective representations and that greater use of these affective representations when trying to understand the emotional experience of others is related to more empathy.

Bartrés-Faz, D, Serra-Grabulosa JM, Sun FT, Solé-Padullés C, Rami L, Molinuevo JL, Bosch B, Mercader JM, Bargalló N, Falcón C, Vendrell P, Junqué C, D’Esposito.  2008.  Functional connectivity of the hippocampus in elderly with mild memory dysfunction carrying the APOE epsilon4 allele., 2008 Nov. Neurobiology of aging. 29:1644-53. Abstract2007bartres.pdf

The purpose of the present study was to evaluate functional connectivity of the hippocampus during a fMRI face-name learning task in a group of elders with mild memory impairment on the basis of the presence or absence of the APOE epsilon4 allele. Twelve epsilon4 carriers and 20 non-carriers with mild memory dysfunction and exhibiting equivalent performance in clinical evaluations of global cognitive function and memory were studied. Subjects underwent a fMRI session consisting of a face-name encoding memory task. Following scanning, subjects were asked to pair faces with their corresponding proper name. Functional connectivity of the hippocampus was measured by using coherence analysis to evaluate the activity of brain circuits related to memory encoding processes. In contrast to non-APOE epsilon4 allele bearers, APOE epsilon4 carriers showed enhanced connectivity with the anterior cingulate, inferior parietal/postcentral gyrus region and the caudate nucleus. Enhanced hippocampal connectivity with additional brain regions in APOE epsilon4 allele carriers during the performance of an associative memory task may reveal the existence of additional activity in the cortico-subcortical network engaged during memory encoding in subjects carrying this genetic variant.

Buchsbaum, BR, D’Esposito.  2008.  The search for the phonological store: from loop to convolution., 2008 May. Journal of cognitive neuroscience. 20:762-78. Abstract2008buchsbaum.pdf

The phonological loop system of Baddeley and colleagues’ Working Memory model is a major accomplishment of the modern era of cognitive psychology. It was one of the first information processing models to make an explicit attempt to accommodate both traditional behavioral data and the results of neuropsychological case studies in an integrated theoretical framework. In the early and middle 1990s, the purview of the phonological loop was expanded to include the emerging field of functional brain imaging. The modular and componential structure of the phonological loop seemed to disclose a structure that might well be transcribed, intact, onto the convolutions of the brain. It was the phonological store component, however, with its simple and modular quality, that most appealed to the neuroimaging field as the psychological "box" that might most plausibly be located in the brain. Functional neuroimaging studies initially designated regions in the parietal cortex as constituting the "neural correlate" of the phonological store, whereas later studies pointed to regions in the posterior temporal cortex. In this review, however, we argue the phonological store as a theoretical construct does not precisely correspond to a single, functionally discrete, brain region. Rather, converging evidence from neurology, cognitive psychology, and functional neuroimaging argue for a reconceptualization of phonological short-term memory as emerging from the integrated action of the neural processes that underlie the perception and production of speech.

Rajah, NM, Ames B, D’Esposito.  2008.  Prefrontal contributions to domain-general executive control processes during temporal context retrieval., 2008 Mar 7. Neuropsychologia. 46:1088-103. Abstract2008rajah.pdf

Neuroimaging studies have reported increased prefrontal cortex (PFC) activity during temporal context retrieval versus recognition memory. However, it remains unclear if these activations reflect PFC contributions to domain-general executive control processes or domain-specific retrieval processes. To gain a better understanding of the functional roles of these various PFC regions during temporal context retrieval we propose it is necessary to examine PFC activity across tasks from different domains, in which parallel manipulations are included targeting specific cognitive processes. In the current fMRI study, we examined domain-general and domain-specific PFC contributions to temporal context retrieval by increasing stimulus (but maintaining response number) and increasing response number (but maintaining stimulus number) across temporal context memory and ordering control tasks, for faces. The control task required subjects to order faces from youngest to oldest. Our behavioral results indicate that the combination of increased stimulus and response numbers significantly increased task difficulty for temporal context retrieval and ordering tasks. Across domains, increasing stimulus number, while maintaining response numbers, caused greater right lateral premotor cortex (BA 6/8) activity; whereas increasing response number, while maintaining stimulus number, caused greater domain-general left DLPFC (BA 9) and VLPFC (BA 44/45) activity. In addition, we found domain-specific right DLPFC (BA 9) activity only during retrieval events. These results highlight the functional heterogeneity of frontal cortex, and suggest its involvement in temporal context retrieval is related to its role in various cognitive control processes.

Rissman, J, Gazzaley A, D’Esposito.  2008.  Dynamic adjustments in prefrontal, hippocampal, and inferior temporal interactions with increasing visual working memory load., 2008 Jul. Cerebral cortex (New York, N.Y. : 1991). 18:1618-29. Abstract2008_rissman.pdf

The maintenance of visual stimuli across a delay interval in working memory tasks is thought to involve reverberant neural communication between the prefrontal cortex and posterior visual association areas. Recent studies suggest that the hippocampus might also contribute to this retention process, presumably via reciprocal interactions with visual regions. To characterize the nature of these interactions, we performed functional connectivity analysis on an event-related functional magnetic resonance imaging data set in which participants performed a delayed face recognition task. As the number of faces that participants were required to remember was parametrically increased, the right inferior frontal gyrus (IFG) showed a linearly decreasing degree of functional connectivity with the fusiform face area (FFA) during the delay period. In contrast, the hippocampus linearly increased its delay period connectivity with both the FFA and the IFG as the mnemonic load increased. Moreover, the degree to which participants’ FFA showed a load-dependent increase in its connectivity with the hippocampus predicted the degree to which its connectivity with the IFG decreased with load. Thus, these neural circuits may dynamically trade off to accommodate the particular mnemonic demands of the task, with IFG-FFA interactions mediating maintenance at lower loads and hippocampal interactions supporting retention at higher loads.

Cools, R, Gibbs SE, Miyakawa A, Jagust W, D’Esposito.  2008.  Working memory capacity predicts dopamine synthesis capacity in the human striatum., 2008 Jan 30. The Journal of neuroscience : the official journal of the Society for Neuroscience. 28:1208-12. Abstract2008_cools_j_neuro.pdf

Evidence from psychopharmacological research has revealed that dopamine receptor agents have opposite effects on cognitive function depending on baseline levels of working memory capacity. These contrasting effects have been interpreted to reflect differential baseline levels of dopamine. Here we demonstrate for the first time that working memory capacity as measured by listening span predicts dopamine synthesis capacity in the striatum, indicating that subjects with low working memory capacity have low DA synthesis capacity in the striatum, whereas subjects with high working memory capacity have high DA synthesis capacity in the striatum.

Miller, BT, Verstynen T, Johnson MK, D’Esposito.  2008.  Prefrontal and parietal contributions to refreshing: an rTMS study., 2008 Jan 1. NeuroImage. 39:436-40. Abstract2007miller.pdf

Refreshing is a basic reflective component process that can serve to prolong activation of task-relevant information. Neuroimaging work has shown that left middle frontal gyrus (MFG) and supramarginal gyrus (SMG) are selectively engaged during refreshing. Functional MRI (fMRI), however, is not able to determine if these regions are necessary for refreshing. In this experiment, we utilize repetitive transcranial magnetic stimulation (rTMS) to assess the behavioral effect of functionally deactivating these regions. We report a selective slowing of response times (RTs) to refresh words following MFG stimulation, consistent with a role of lateral prefrontal cortex (PFC) in top-down control mechanisms necessary for refreshing. In contrast, SMG stimulation slowed participants in both refreshing and repeating words, indicating a more general role of SMG in verbal processing.

Silver, MA, Shenhav A, D’Esposito.  2008.  Cholinergic enhancement reduces spatial spread of visual responses in human early visual cortex., 2008 Dec 10. Neuron. 60:904-14. Abstract2008silver.pdf

Animal studies have shown that acetylcholine decreases excitatory receptive field size and spread of excitation in early visual cortex. These effects are thought to be due to facilitation of thalamocortical synaptic transmission and/or suppression of intracortical connections. We have used functional magnetic resonance imaging (fMRI) to measure the spatial spread of responses to visual stimulation in human early visual cortex. The cholinesterase inhibitor donepezil was administered to normal healthy human subjects to increase synaptic levels of acetylcholine in the brain. Cholinergic enhancement with donepezil decreased the spatial spread of excitatory fMRI responses in visual cortex, consistent with a role of acetylcholine in reducing excitatory receptive field size of cortical neurons. Donepezil also reduced response amplitude in visual cortex, but the cholinergic effects on spatial spread were not a direct result of reduced amplitude. These findings demonstrate that acetylcholine regulates spatial integration in human visual cortex.

Nagel, IE, Schumacher EH, Goebel R, D’Esposito.  2008.  Functional MRI investigation of verbal selection mechanisms in lateral prefrontal cortex., 2008 Dec. NeuroImage. 43:801-7. Abstract2008nagel.pdf

Response selection activates appropriate response representations to task-relevant environmental stimuli. Research implicates dorsolateral prefrontal cortex (dlPFC) for this process. On the other hand, studies of semantic selection, which activates verbal responses based on the semantic requirements of a task, implicate ventrolateral PFC (vlPFC). Despite this apparent dissociation, the neurocognitive distinction between response and semantic selection is controversial. The current functional MRI study attempts to resolve this controversy by investigating verbal response and semantic selection in the same participants. Participants responded vocally with a word to a visually presented noun, either from a memorized list of paired associates (response selection task), or by generating a semantically related verb (semantic selection task). We found a dissociation in left lateral PFC. Activation increased significantly in dlPFC with response selection difficulty, but not semantic selection difficulty. Conversely, semantic, but not response, selection difficulty increased activity significantly in vlPFC. Activity in left parietal cortex, on the other hand, was affected by difficulty increases in both selection tasks. These results suggest that response and semantic selection may be distinct cognitive processes mediated by different regions of lateral PFC; but both of these selection processes rely on cognitive mechanisms mediated by parietal cortex.

Miller, BT, Deouell LY, Dam C, Knight RT, D’Esposito.  2008.  Spatio-temporal dynamics of neural mechanisms underlying component operations in working memory., 2008 Apr 24. Brain research. 1206:61-75. Abstract2008miller2.pdf

Neuroimaging and neurophysiology evidence suggests that component operations in working memory (WM) emerge from the coordinated interaction of posterior perceptual cortices with heteromodal regions in the prefrontal and parietal cortices. Still, little is known about bottom-up and top-down signaling during the formation and retrieval of WM representations. In the current set of experiments, we combine complementary fMRI and EEG measures to obtain high-resolution spatial and temporal measures of neural activity during WM encoding and retrieval processes. Across both experiments, participants performed a face delayed recognition WM task in which the nature of sensory input across stages was held constant. In experiment 1, we utilized a latency-resolved fMRI approach to assess temporal parameters of the BOLD response during stage-specific encoding and retrieval waveforms. Relative to the latency at encoding, the PFC exhibited an earlier peak of fMRI activity at retrieval showing stage-specific differences in the temporal dynamics of PFC engagement across WM operations. In experiment 2, we analyzed the first 200 ms of the ERP response during this WM task providing a more sensitive temporal measure of these differences. Divergence of the ERP pattern during encoding and retrieval began as early as 60 ms post-stimulus. The parallel fMRI and ERP results during memory-guided decisions support a key role of the PFC in top-down biasing of perceptual processing and reveal rapid differences across WM component operations in the presence of identical bottom-up sensory input.

D’Esposito.  2008.  Working memory., 2008. Handbook of clinical neurology / edited by P.J. Vinken and G.W. Bruyn. 88:237-47. Abstractdespositowm.pdf


D'Esposito, M.  2008.  From cognitive to neural models of working memory. Mental Processes in the Human Brain. , Oxford, UK: Oxford University Press
Curtis, CE, D'Esposito M.  2008.  The inhibition of unwanted actions. Psychology of Action, Vol. 2. , Oxford: Oxford University Press2008curtis.pdf
Buchsbaum, BR, D'Esposito M.  2008.  Short term and working memory systems. Learning and Memory: A Comprehensive Reference. , Oxford: Elsevier2008buchsbaum1.pdf
Deouell, LY, Heller AS, Malach R, D’Esposito, Knight RT.  2007.  Cerebral responses to change in spatial location of unattended sounds., 2007 Sep 20. Neuron. 55:985-96. Abstract2007deouell.pdf

The neural basis of spatial processing in the auditory cortex has been controversial. Human fMRI studies suggest that a part of the planum temporale (PT) is involved in auditory spatial processing, but it was recently argued that this region is active only when the task requires voluntary spatial localization. If this is the case, then this region cannot harbor an ongoing spatial representation of the acoustic environment. In contrast, we show in three fMRI experiments that a region in the human medial PT is sensitive to background auditory spatial changes, even when subjects are not engaged in a spatial localization task, and in fact attend the visual modality. During such times, this area responded to rare location shifts, and even more so when spatial variation increased, consistent with spatially selective adaptation. Thus, acoustic space is represented in the human PT even when sound processing is not required by the ongoing task.

Gazzaley, A, Sheridan MA, Cooney JW, D’Esposito.  2007.  Age-related deficits in component processes of working memory., 2007 Sep. Neuropsychology. 21:532-9. Abstract

Working memory deficits in normal aging have been well documented, and studies suggest that high memory load plus the presence of distraction negatively impacts successful memory performance to a greater degree in older individuals. However, characterization of the component processes that are impaired by these task manipulations is not clear. In this behavioral study, younger and older subjects were tested with a delayed-recognition and recall task in which the encoding and delay period were both manipulated. During the encoding period, the subjects were presented with either a single letter or multiple letters at their predetermined forward letter span, and the delay period was either uninterrupted or interrupted with a visual distraction. There was an age-related impairment of working memory recognition accuracy only in the combination of high memory load and distraction. These results suggest that when working memory maintenance systems are taxed, faulty recognition processes may underlie cognitive aging deficits in healthy older individuals.

DeGutis, J, D’Esposito.  2007.  Distinct mechanisms in visual category learning., 2007 Sep. Cognitive, affective & behavioral neuroscience. 7:251-9. Abstract2007degutis2.pdf

The ways in which visual categories are learned, and in which well-established categories are represented and retrieved, are fundamental issues of cognitive neuroscience. Researchers have typically studied these issues separately, and the transition from the initial phase of category learning to expertise is poorly characterized. The acquisition of novel categories has been shown to depend on the striatum, hippocampus, and prefrontal cortex, whereas visual category expertise has been shown to involve changes in inferior temporal cortex. The goal of the present experiment is to understand the respective roles of these brain regions in the transition from initial learning to expertise when category judgments are being made. Subjects were explicitly trained, over 2 days, to classify realistic faces. Subjects then performed the categorization task during fMRI scanning, as well as a perceptual matching task, in order to characterize how brain regions respond to these faces when not explicitly categorizing them. We found that, during face categorization, face-selective inferotemporal cortex, lateral prefrontal cortex, and dorsal striatum are more responsive to faces near the category boundary, which are most difficult to categorize. In contrast, the hippocampus and left superior frontal sulcus responded most to faces farthest from the category boundary. These dissociable effects suggest that there are several distinct neural mechanisms involved in categorization, and provide a framework for understanding the contribution of each of these brain regions in categorization.

Gazzaley, A, Rissman J, Cooney JW, Rutman A, Seibert T, Clapp W, D’Esposito.  2007.  Functional interactions between prefrontal and visual association cortex contribute to top-down modulation of visual processing., 2007 Sep. Cerebral cortex (New York, N.Y. : 1991). 17 Suppl 1:i125-35. Abstract2007gazzaley2.pdf

Attention-dependent modulation of neural activity in visual association cortex (VAC) is thought to depend on top-down modulatory control signals emanating from the prefrontal cortex (PFC). In a previous functional magnetic resonance imaging study utilizing a working memory task, we demonstrated that activity levels in scene-selective VAC (ssVAC) regions can be enhanced above or suppressed below a passive viewing baseline level depending on whether scene stimuli were attended or ignored (Gazzaley, Cooney, McEvoy, et al. 2005). Here, we use functional connectivity analysis to identify possible sources of these modulatory influences by examining how network interactions with VAC are influenced by attentional goals at the time of encoding. Our findings reveal a network of regions that exhibit strong positive correlations with a ssVAC seed during all task conditions, including foci in the left middle frontal gyrus (MFG). This PFC region is more correlated with the VAC seed when scenes were remembered and less correlated when scenes were ignored, relative to passive viewing. Moreover, the strength of MFG-VAC coupling correlates with the magnitude of attentional enhancement and suppression of VAC activity. Although our correlation analyses do not permit assessment of directionality, these findings suggest that PFC biases activity levels in VAC by adjusting the strength of functional coupling in accordance with stimulus relevance.

Handwerker, DA, Gazzaley A, Inglis BA, D’Esposito.  2007.  Reducing vascular variability of fMRI data across aging populations using a breathholding task., 2007 Sep. Human brain mapping. 28:846-59. Abstract2007handwerker.pdf

The magnitude and shape of blood oxygen level-dependent (BOLD) responses in functional MRI (fMRI) studies vary across brain regions, subjects, and populations. This variability may be secondary to neural activity or vasculature differences, thus complicating interpretations of BOLD signal changes in fMRI experiments. We compare the BOLD responses to neural activity and a vascular challenge and test a method to dissociate these influences in 26 younger subjects (ages 18-36) and 24 older subjects (ages 51-78). Each subject performed a visuomotor saccade task (a vascular response to neural activity) and a breathholding task (vascular dilation induced by hypercapnia) during separate runs in the same scanning session. For the saccade task, signal magnitude showed a significant decrease with aging in FEF, SEF, and V1, and a delayed time-to-peak with aging in V1. The signal magnitudes from the saccade and hypercapnia tasks showed significant linear regressions within subjects and across individuals and populations. These two tasks had weaker, but sometimes significant linear regressions for time-to-peak and coherence phase measures. The significant magnitude decrease with aging in V1 remained after dividing the saccade task magnitude by the hypercapnia task magnitude, implying that the signal decrease is neural in origin. These findings may lead to a method to identify vascular reactivity-induced differences in the BOLD response across populations and the development of methods to account for the influence of these vasculature differences in a simple, noninvasive manner.

Sheridan, MA, Hinshaw S, D’Esposito.  2007.  Efficiency of the prefrontal cortex during working memory in attention-deficit/hyperactivity disorder., 2007 Oct. Journal of the American Academy of Child and Adolescent Psychiatry. 46:1357-66. Abstract2007sheridan.pdf

OBJECTIVE: Previous research has demonstrated that during task conditions requiring an increase in inhibitory function or working memory, children and adults with attention-deficit/hyperactivity disorder (ADHD) exhibit greater and more varied prefrontal cortical (PFC) activation compared to age-matched control participants. This pattern may reflect cortical inefficiency. We examined this hypothesis using a working memory task in a group of adolescent girls with and without ADHD. METHOD: Functional magnetic resonance imaging was used to investigate blood oxygenated level-dependent signal during a working memory task for 10 adolescents from each group, ages 11 to 17 years. We analyzed brain-behavior relationships with anatomically defined regions of interest in the PFC and primary motor cortex. RESULTS: The relationship between brain activity in the dorsolateral PFC and ventrolateral PFC and memory retrieval speed differed by group membership, whereby comparison girls had a more efficient brain-behavior relationship than girls with ADHD. There were no such group differences in brain-behavior relationships for primary motor cortex. CONCLUSIONS: These findings lend support to the idea that cognitive and behavioral deficits experienced by children and adolescents with ADHD may in part be related to relatively low efficiency of PFC function.

Landau, SM, Garavan H, Schumacher EH, D’Esposito.  2007.  Regional specificity and practice: dynamic changes in object and spatial working memory., 2007 Nov 14. Brain research. 1180:78-89. Abstract2007landau.pdf

Working memory (WM) tasks engage a network of brain regions that includes primary, unimodal, and multimodal associative cortices. Little is known, however, about whether task practice influences these types of regions differently. In this experiment, we used event-related fMRI to examine practice-related activation changes in different region types over the course of a scanning session while participants performed a delayed-recognition task. The task contained separate WM processing stages (encoding, maintenance, retrieval) and different materials (object, spatial), which allowed us to investigate the influence of practice on different component processes. We observed significant monotonic decreases, and not increases, in fMRI signal primarily in unimodal and multimodal regions. These decreases occurred during WM encoding and retrieval, but not during maintenance. Finally, regions specific to the type of memoranda (e.g., spatial or object) showed a lesser degree of sensitivity to practice as compared to regions activated by both types of memoranda, suggesting that these regions may be specialized more for carrying out processing within a particular modality than for experience-related flexibility. Overall, these findings indicate that task practice does not have a uniform effect on stages of WM processing, the type of WM memoranda being processed or on different types of brain regions. Instead, regions engaged during WM encoding and retrieval may have greater capacity for functional plasticity than WM maintenance. Additionally, the degree of specialization within brain regions may determine processing efficiency. Unimodal and multimodal regions that participate in both object and spatial processing may be specialized for flexible experience-related change, while those supporting primary sensorimotor processing may operate at optimal efficiency and are less susceptible to practice.

DeGutis, J, Bentin S, Robertson LC, D’Esposito.  2007.  Functional plasticity in ventral temporal cortex following cognitive rehabilitation of a congenital prosopagnosic., 2007 Nov. Journal of cognitive neuroscience. 19:1790-802. Abstract2007degutis.pdf

We used functional magnetic resonance imaging (fMRI) and electroencephalography (EEG) to measure neural changes associated with training configural processing in congenital prosopagnosia, a condition in which face identification abilities are not properly developed in the absence of brain injury or visual problems. We designed a task that required discriminating faces by their spatial configuration and, after extensive training, prosopagnosic MZ significantly improved at face identification. Event-related potential results revealed that although the N170 was not selective for faces before training, its selectivity after training was normal. fMRI demonstrated increased functional connectivity between ventral occipital temporal face-selective regions (right occipital face area and right fusiform face area) that accompanied improvement in face recognition. Several other regions showed fMRI activity changes with training; the majority of these regions increased connectivity with face-selective regions. Together, the neural mechanisms associated with face recognition improvements involved strengthening early face-selective mechanisms and increased coordination between face-selective and nonselective regions, particularly in the right hemisphere.

Klein, HE, D’Esposito.  2007.  Neurocognitive inefficacy of the strategy process., 2007 Nov. Annals of the New York Academy of Sciences. 1118:163-85. Abstract

The most widely used (and taught) protocols for strategic analysis-Strengths, Weaknesses, Opportunities, and Threats (SWOT) and Porter’s (1980) Five Force Framework for industry analysis-have been found to be insufficient as stimuli for strategy creation or even as a basis for further strategy development. We approach this problem from a neurocognitive perspective. We see profound incompatibilities between the cognitive process-deductive reasoning-channeled into the collective mind of strategists within the formal planning process through its tools of strategic analysis (i.e., rational technologies) and the essentially inductive reasoning process actually needed to address ill-defined, complex strategic situations. Thus, strategic analysis protocols that may appear to be and, indeed, are entirely rational and logical are not interpretable as such at the neuronal substrate level where thinking takes place. The analytical structure (or propositional representation) of these tools results in a mental dead end, the phenomenon known in cognitive psychology as functional fixedness. The difficulty lies with the inability of the brain to make out meaningful (i.e., strategy-provoking) stimuli from the mental images (or depictive representations) generated by strategic analysis tools. We propose decreasing dependence on these tools and conducting further research employing brain imaging technology to explore complex data handling protocols with richer mental representation and greater potential for strategy creation.

D’Esposito.  2007.  From cognitive to neural models of working memory., 2007 May 29. Philosophical transactions of the Royal Society of London. Series B, Biological sciences. 362:761-72. Abstract2007despo.pdf

Working memory refers to the temporary retention of information that was just experienced or just retrieved from long-term memory but no longer exists in the external environment. These internal representations are short-lived, but can be stored for longer periods of time through active maintenance or rehearsal strategies, and can be subjected to various operations that manipulate the information in such a way that makes it useful for goal-directed behaviour. Empirical studies of working memory using neuroscientific techniques, such as neuronal recordings in monkeys or functional neuroimaging in humans, have advanced our knowledge of the underlying neural mechanisms of working memory. This rich dataset can be reconciled with behavioural findings derived from investigating the cognitive mechanisms underlying working memory. In this paper, I review the progress that has been made towards this effort by illustrating how investigations of the neural mechanisms underlying working memory can be influenced by cognitive models and, in turn, how cognitive models can be shaped and modified by neuroscientific data. One conclusion that arises from this research is that working memory can be viewed as neither a unitary nor a dedicated system. A network of brain regions, including the prefrontal cortex (PFC), is critical for the active maintenance of internal representations that are necessary for goal-directed behaviour. Thus, working memory is not localized to a single brain region but probably is an emergent property of the functional interactions between the PFC and the rest of the brain.

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.

Sun, FT, Miller LM, Rao AA, D’Esposito.  2007.  Functional connectivity of cortical networks involved in bimanual motor sequence learning., 2007 May. Cerebral cortex (New York, N.Y. : 1991). 17:1227-34. Abstract2007sun.pdf

Motor skill learning requires the involvement and integration of several cortical and subcortical regions. In this study, we focus on how the functional connectivity of cortical networks changes with the acquisition of a novel motor skill. Using functional magnetic resonance imaging, we measured the localized blood oxygenation level-dependent (BOLD) signal in cortical regions while subjects performed a bimanual serial reaction time task under 2 conditions: 1) explicitly learning a novel sequence (NOVEL) and 2) playing a previously learned sequence (LEARNED). To investigate stages of learning, each condition was further divided into nonoverlapping early and late conditions. Functional connectivity was measured using a task-specific low-frequency coherence analysis of the data. We show that within the cortical motor network, the sensorimotor cortex, premotor cortex, and supplementary motor area have significantly greater inter- and intrahemispheric coupling during the early NOVEL condition compared with the late NOVEL condition. Additionally, we observed greater connectivity between frontal regions and cortical motor regions in the early versus late NOVEL contrast. No changes in functional connectivity were observed in the LEARNED condition. These results demonstrate that the functional connectivity of the cortical motor network is modulated with practice and suggest that early skill learning is mediated by enhanced interregional coupling.

Schumacher, EH, Cole MW, D’Esposito.  2007.  Selection and maintenance of stimulus-response rules during preparation and performance of a spatial choice-reaction task., 2007 Mar 9. Brain research. 1136:77-87. Abstract2007schumacher.pdf

The ability to select an appropriate response among competing alternatives is a fundamental requirement for successful performance of a variety of everyday tasks. Recent research suggests that a frontal-parietal network of brain regions (including dorsal prefrontal, dorsal premotor and superior parietal cortices) mediate response selection for spatial material. Most of this research has used blocked experimental designs. Thus, the frontal-parietal activity reported may be due either to tonic activity across a block or to processing occurring at the trial level. Our current event-related fMRI study investigated response selection at the level of the trial in order to identify possible response selection sub-processes. In the study, participants responded to a visually presented stimulus with either a spatially compatible or incompatible manual response. On some trials, several seconds prior to stimulus onset, a cue indicated which task was to be performed. In this way we could identify separate brain regions for task preparation and task performance, if they exist. Our results showed that the frontal-parietal network for spatial response selection activated both during task preparation as well as during task performance. We found no evidence for preparation specific brain mechanisms in this task. These data suggest that spatial response selection and response preparation processes rely on the same neurocognitive mechanisms.

Hester, R, D’Esposito, Cole MW, Garavan H.  2007.  Neural mechanisms for response selection: comparing selection of responses and items from working memory., 2007 Jan 1. NeuroImage. 34:446-54. Abstract2007hester.pdf

Recent functional imaging studies of working memory (WM) have suggested a relationship between the requirement for response selection and activity in dorsolateral prefrontal (DLPFC) and parietal regions. Although a number of WM operations are likely to occur during response selection, the current study was particularly interested in the contribution of this neural network to WM-based response selection when compared to the selection of an item from a list being maintained in memory, during a verbal learning task. The design manipulated stimulus-response mappings so that selecting an item from memory was not always accompanied with selecting a motor response. Functional activation during selection supported previous findings of fronto-parietal involvement, although in contrast to previous findings left, rather than right, DLPFC activity was significantly more active for selecting a memory-guided motor response, when compared to selecting an item currently maintained in memory or executing a memory-guided response. Our results contribute to the debate over the role of fronto-parietal activity during WM tasks, suggesting that this activity appears particularly related to response selection, potentially supporting the hypothesized role of prefrontal activity in biasing attention toward task-relevant material in more posterior regions.

Bentin, S, DeGutis J, D’Esposito, Robertson LC.  2007.  Too many trees to see the forest: performance, event-related potential, and functional magnetic resonance imaging manifestations of integrative congenital prosopagnosia., 2007 Jan. Journal of cognitive neuroscience. 19:132-46. Abstract2007bentin.pdf

Neuropsychological, event-related potential (ERP), and functional magnetic resonance imaging (fMRI) methods were combined to provide a comprehensive description of performance and neurobiological profiles for K.W., a case of congenital prosopagnosia. We demonstrate that K.W.’s visual perception is characterized by almost unprecedented inability to identify faces, a large bias toward local features, and an extreme deficit in global/configural processing that is not confined to faces. This pattern could be appropriately labeled congenital integrative prosopagnosia, and accounts for some, albeit not all, cases of face recognition impairments without identifiable brain lesions. Absence of face selectivity is evident in both biological markers of face processing, fMRI (the fusiform face area [FFA]), and ERPs (N170). Nevertheless, these two neural signatures probably manifest different perceptual mechanisms. Whereas the N170 is triggered by the occurrence of physiognomic stimuli in the visual field, the deficient face-selective fMRI activation in the caudal brain correlates with the severity of global processing deficits. This correlation suggests that the FFA might be associated with global/configural computation, a crucial part of face identification.

Logie, RH, D’Esposito.  2007.  Working memory in the brain., 2007 Jan. Cortex; a journal devoted to the study of the nervous system and behavior. 43:1-4. Abstract2007logie.pdf


Fuhrmann Alpert, G, Sun FT, Handwerker DA, D’Esposito, Knight RT.  2007.  Spatio-temporal information analysis of event-related BOLD responses., 2007 Feb 15. NeuroImage. 34:1545-61. Abstract2007fuhrmann.pdf

A new approach for analysis of event-related fMRI (BOLD) signals is proposed. The technique is based on measures from information theory and is used both for spatial localization of task-related activity, as well as for extracting temporal information regarding the task-dependent propagation of activation across different brain regions. This approach enables whole brain visualization of voxels (areas) most involved in coding of a specific task condition, the time at which they are most informative about the condition, as well as their average amplitude at that preferred time. The approach does not require prior assumptions about the shape of the hemodynamic response function (HRF) nor about linear relations between BOLD response and presented stimuli (or task conditions). We show that relative delays between different brain regions can also be computed without prior knowledge of the experimental design, suggesting a general method that could be applied for analysis of differential time delays that occur during natural, uncontrolled conditions. Here we analyze BOLD signals recorded during performance of a motor learning task. We show that, during motor learning, the BOLD response of unimodal motor cortical areas precedes the response in higher-order multimodal association areas, including posterior parietal cortex. Brain areas found to be associated with reduced activity during motor learning, predominantly in prefrontal brain regions, are informative about the task typically at significantly later times.

Mitchell, JM, Tavares VC, Fields HL, D’Esposito, Boettiger CA.  2007.  Endogenous opioid blockade and impulsive responding in alcoholics and healthy controls., 2007 Feb. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology. 32:439-49. Abstract2007mitchell.pdf

The opioid receptor antagonist naltrexone (NTX) is one of few approved treatments for alcoholism, yet the mechanism by which it reduces drinking remains unclear. In rats, NTX reduces morphine-induced impulsive choice bias; however, nothing is known about the drug’s effect on discrete aspects of impulsive behavior in humans, such as decision-making and inhibitory control. Here, we used a modified delay discounting procedure to investigate whether NTX improves decision-making or inhibitory control in humans. We measured the effect of acute NTX (50 mg) on choice between smaller sooner (SS) and larger later monetary rewards and on response errors (motor mismatch) in a high conflict condition in a group of abstinent alcoholics (AA) and healthy control subjects (CS). We previously reported that AA selected the SS option significantly more often than did CS in this paradigm. If the choice bias of AA is due to enhanced endogenous opioid signaling in response to potential reward, NTX should reduce such bias in the AA group. We found that NTX did not reliably reduce impulsive choice in the AA group; however, NTX’s effect on choice bias across individuals was robustly predictable. NTX’s effect on choice bias was significantly correlated with scores on Rotter’s Locus of Control (LOC) scale; increasingly internal LOC scores predicted increasing likelihood of impulsive choices on NTX. In addition, we found that NTX significantly enhanced control of motor responses, particularly within the CS group. These results suggest that endogenous opioids may impair response selection during decision-making under conflict, and that NTX’s effects on explicit decision-making are personality-dependent. Determining the biological basis of this dependence could have important implications for effective alcoholism treatment.

Gazzaley, A, D’Esposito.  2007.  Top-down modulation and normal aging., 2007 Feb. Annals of the New York Academy of Sciences. 1097:67-83. Abstract2007gazzaley.pdf

Normal aging is characterized by cognitive deficits that cross multiple domains and impair the ability of some older individuals to lead productive, high-quality lives. One of the primary goals of research in our laboratories is to study age-related alterations in neural mechanisms that underlie a wide range of cognitive processes so that we may generate a unifying principle of cognitive aging. Top-down modulation is the mechanism by which we enhance neural activity associated with relevant information and suppress activity for irrelevant information, thus establishing a foundation for both attention and memory processes. We use three converging technologies of human neurophysiology to study top-down modulation in aging: functional magnetic resonance imaging (fMRI), electroencephalography (EEG), and transcranial magnetic stimulation (TMS). Using these tools we have discovered that healthy older adults exhibit a selective inability to effectively suppress neural activity associated with distracting information and that this top-down suppression deficit is correlated with their memory impairment. We are now further characterizing the basis of these age-related alterations in top-down modulation and investigating interventions to remedy them.

Boettiger, CA, Mitchell JM, Tavares VC, Robertson M, Joslyn G, D’Esposito, Fields HL.  2007.  Immediate reward bias in humans: fronto-parietal networks and a role for the catechol-O-methyltransferase 158(Val/Val) genotype., 2007 Dec 26. The Journal of neuroscience : the official journal of the Society for Neuroscience. 27:14383-91. Abstract2007boettiger.pdf

The tendency to choose lesser immediate benefits over greater long-term benefits characterizes alcoholism and other addictive disorders. However, despite its medical and socioeconomic importance, little is known about its neurobiological mechanisms. Brain regions that are activated when deciding between immediate or delayed rewards have been identified (McClure et al., 2004, 2007), as have areas in which responses to reward stimuli predict a paper-and-pencil measure of temporal discounting (Hariri et al., 2006). These studies assume "hot" and "cool" response selection systems, with the hot system proposed to generate impulsive choices in the presence of a proximate reward. However, to date, brain regions in which the magnitude of activity during decision making reliably predicts intertemporal choice behavior have not been identified. Here we address this question in sober alcoholics and non-substance-abusing control subjects and show that immediate reward bias directly scales with the magnitude of functional magnetic resonance imaging bold oxygen level-dependent (BOLD) signal during decision making at sites within the posterior parietal cortex (PPC), dorsal prefrontal cortex (dPFC), and rostral parahippocampal gyrus regions. Conversely, the tendency of an individual to wait for a larger, delayed reward correlates directly with BOLD signal in the lateral orbitofrontal cortex. In addition, genotype at the Val158Met polymorphism of the catechol-O-methyltransferase gene predicts both impulsive choice behavior and activity levels in the dPFC and PPC during decision making. These genotype effects remained significant after controlling for alcohol abuse history. These results shed new light on the neurobiological underpinnings of temporal discounting behavior and identify novel behavioral and neural consequences of genetic variation in dopamine metabolism.

Yoon, JH, Hoffman J, D’Esposito.  2007.  Segregation of function in the lateral prefrontal cortex during visual object working memory., 2007 Dec 12. Brain research. 1184:217-25. Abstractyoonbr2007.pdf

Working memory is a set of cognitive operations facilitating higher order cognition and complex behavior. A particularly important aspect of working memory is the linkage of past sensory events to planned actions. While the lateral prefrontal cortex has been proposed to serve this temporal integrative function, the precise mapping of specific components of this process within the lateral prefrontal cortex has yet to be clarified. In this human fMRI experiment, we employed a paradigm that segregates retrospective sensory maintenance from prospective action planning processes. Our results suggest that the ventrolateral PFC supports retrospective sensory representations while the dorsolateral PFC supports prospective action representations.

Badre, D, D’Esposito.  2007.  Functional magnetic resonance imaging evidence for a hierarchical organization of the prefrontal cortex., 2007 Dec. Journal of cognitive neuroscience. 19:2082-99. Abstract2007badre.pdf

The prefrontal cortex (PFC) is central to flexible and organized action. Recent theoretical and empirical results suggest that the rostro-caudal axis of the frontal lobes may reflect a hierarchical organization of control. Here, we test whether the rostro-caudal axis of the PFC is organized hierarchically, based on the level of abstraction at which multiple representations compete to guide selection of action. Four functional magnetic resonance imaging (fMRI) experiments parametrically manipulated the set of task-relevant (a) responses, (b) features, (c) dimensions, and (d) overlapping cue-to-dimension mappings. A systematic posterior to anterior gradient was evident within the PFC depending on the manipulated level of representation. Furthermore, across four fMRI experiments, activation in PFC subregions was consistent with the sub- and superordinate relationships that define an abstract representational hierarchy. In addition to providing further support for a representational hierarchy account of the rostro-caudal gradient in the PFC, these data provide important empirical constraints on current theorizing about control hierarchies and the PFC.

Johnson, MR, Mitchell KJ, Raye CL, D’Esposito, Johnson MK.  2007.  A brief thought can modulate activity in extrastriate visual areas: Top-down effects of refreshing just-seen visual stimuli., 2007 Aug 1. NeuroImage. 37:290-9. Abstract2007johnson.pdf

Current models of executive function hold that the internal representations of stimuli used during reflective thought are maintained in the same posterior cortical regions initially activated during perception, and that activity in such regions is modulated by top-down signals originating in prefrontal cortex. In an event-related functional magnetic resonance imaging study, we presented participants with two pictures simultaneously, a face and a scene, immediately followed either by a repetition of one of the pictures (perception) or by a cue to think briefly of one of the just-seen, but no longer present, pictures (refreshing, a reflective act). Refreshing faces and scenes modulated activity in the fusiform face area (FFA) and parahippocampal place area (PPA), respectively, as well as other regions exhibiting relative perceptual selectivity for either faces or scenes. Four scene-selective regions (lateral precuneus, retrosplenial cortex, PPA, and middle occipital gyrus) showed an anatomical gradient of responsiveness to top-down reflective influences versus bottom-up perceptual influences. These results demonstrate that a brief reflective act can modulate posterior cortical activity in a stimulus-specific manner, suggesting that such modulatory mechanisms are engaged even during transient ongoing thought. Our findings are consistent with the hypothesis that refreshing is a component of more complex modulatory operations such as working memory and mental imagery, and that refresh-related activity may thus contribute to the common activation patterns seen across different cognitive tasks.

Krawczyk, DC, Gazzaley A, D’Esposito.  2007.  Reward modulation of prefrontal and visual association cortex during an incentive working memory task., 2007 Apr 13. Brain research. 1141:168-77. Abstract2007krawczyk.pdf

Cognitive performance differs with motivation, but little direct evidence exists regarding the neural mechanisms of the influence of reward motivation on working memory (WM). We tested the effects of motivation on the top-down control in visual WM. Encoding relevant stimuli for maintenance, while suppressing inappropriate inputs is considered a core process in cognition. Prior functional magnetic resonance imaging (fMRI) results demonstrated that stimulus-specific visual association cortex serves as a marker of activation differences for task-relevant and task-irrelevant inputs, such that enhanced activity occurs when attention is directed to relevant stimuli and suppressed activity occurs when attention is directed away from irrelevant stimuli [Gazzaley, A., Cooney, J., McEvoy, K., Knight, R.T., and D’Esposito, M. J. Cogn. Neurosci. 17, 507-517]. We used fMRI to test whether differential WM performance, indexed by lowered response times on a delayed-recognition task, was associated with amplification of enhancement and suppression effects during stimulus encoding within visual association cortex. Our results indicate that enhancement and suppression are amplified for trials with the highest reward level relative to non-rewarded trials for a scene-selective cortical region. In a face-selective region, similar modulation of enhancement for the highest reward level relative to non-rewarded trials was found. Prefrontal cortex also showed enhanced activity during high reward trials. Overall these results reveal that reward motivation can play a pivotal role in driving performance through top-down signaling in frontal regions involved in WM, as well as visual association regions selective to processing the perceptual inputs of the items to be remembered.

Gazzaley, A, D'Esposito M.  2007.  Considerations for the application of BOLD fMRI to neurological impaired populations. Functional Neuroimaging of Neurological Disorders. , New York: Guilford Publications Abstractesposito.pdf


Gazzaley, A, D'Esposito M.  2007.  Top-down modulation in visual working memory. Working Memory: Behavioral and Neural Correlates. : Oxford University Press Abstract12-osaka-chap123.pdf


Landau, SM, D’Esposito.  2006.  Sequence learning in pianists and nonpianists: an fMRI study of motor expertise., 2006 Sep. Cognitive, affective & behavioral neuroscience. 6:246-59. Abstractlandau2006sequence_learning_in_pianists_and_nonpianists-an_fmri_study_of_motor_expertise.pdf

Previous studies of motor learning have proposed a distinction betweenfast and slow learning, but these mechanisms have rarely been examined simultaneously. We examined the influence of long-term motor expertise (slow learning) while pianists and nonpianists performed alternating epochs of sequenced and random keypresses in response to visual cues (fast learning) during functional neuroimaging. All of the participants demonstrated learning of the sequence as demonstrated by decreasing reaction times (RTs) on sequence trials relative to random trials throughout the session. Pianists also demonstrated faster RTs and superior sequence acquisition in comparison with nonpianists. Within-session decreases in bilateral sensorimotor and parietal activation were observed for both groups. Additionally, there was more extensive activation throughout the session for pianists in comparison with nonpianists across a network of primarily right-lateralized prefrontal, sensorimotor, and parietal regions. These findings provide evidence that different neural systems subserve slow and fast phases of learning.

Rypma, B, Berger JS, Prabhakaran V, Bly BM, Kimberg DY, Biswal BB, D’Esposito.  2006.  Neural correlates of cognitive efficiency., 2006 Nov 15. NeuroImage. 33:969-79. Abstract2006rypma.pdf

Since its inception, experimental psychology has sought to account for individual differences in human performance. Some neuroimaging research, involving complex behavioral paradigms, has suggested that faster-performing individuals show greater neural activity than slower performers. Other research has suggested that faster-performing individuals show less neural activity than slower performers. To examine the neural basis of individual performance differences, we had participants perform a simple speeded-processing task during fMRI scanning. In some prefrontal cortical (PFC) brain regions, faster performers showed less cortical activity than slower performers while in other PFC and parietal regions they showed greater activity. Regional-causality analysis indicated that PFC exerted more influence over other brain regions for slower than for faster individuals. These results suggest that a critical determinant of individual performance differences is the efficiency of interactions between brain regions and that slower individuals may require more prefrontal executive control than faster individuals to perform successfully.

Stelzel, C, Schumacher EH, Schubert T, D’Esposito.  2006.  The neural effect of stimulus-response modality compatibility on dual-task performance: an fMRI study., 2006 Nov. Psychological research. 70:514-25. Abstractstelzel2005_the_neural_effect_of_stimulus-response_modality_compatibility_on_dual-task_performance_an_mri_study.pdf

Recent fMRI studies suggest that the inferior frontal sulcus (IFS) is involved in the coordination of interfering processes in dual-task situations. The present study aims to further specify this assumption by investigating whether the compatibility between stimulus and response modalities modulates dual-task-related activity along the IFS. It has been shown behaviorally that the degree of interference, as measured by dual-task costs, increases in modality-incompatible conditions (e.g. visual-vocal tasks combined with auditory-manual tasks) as compared to modality-compatible conditions (e.g. visual-manual tasks combined with auditory-vocal tasks). Using fMRI, we measured IFS activity when participants performed modality-compatible and modality-incompatible single and dual tasks. Behaviorally, we replicated the finding of higher dual-task costs for modality-incompatible tasks compared to modality-compatible tasks. The fMRI data revealed higher activity along the IFS in modality-incompatible dual tasks compared with modality-compatible dual tasks when inter-individual variability in functional brain organization is taken into account. We argue that in addition to temporal order coordination (Szameitat et al., 2002), the IFS is involved in the coordination of cognitive processes associated with the concurrent mapping of sensory information onto corresponding motor responses in dual-task situations.

Beer, JS, Knight RT, D’Esposito.  2006.  Controlling the integration of emotion and cognition: the role of frontal cortex in distinguishing helpful from hurtful emotional information., 2006 May. Psychological science. 17:448-53. Abstractbeer2006controlling_the_integration_of_emotion_and_cognition.pdf

Emotion has been both lauded and vilified for its role in decision making. How are people able to ensure that helpful emotions guide decision making and irrelevant emotions are kept out of decision making? The orbitofrontal cortex has been identified as a neural area involved in incorporating emotion into decision making. Is this area’s function specific to the integration of emotion and cognition, or does it more broadly govern whether emotional information should be integrated into cognition? The present research examined the role of orbitofrontal cortex when it was appropriate to control (i.e., prevent) the influence of emotion in decision making (Experiment 1) and to incorporate the influence of emotion in decision making (Experiment 2). Together, the two studies suggest that activity in lateral orbitofrontal cortex is associated with evaluating the contextual relevance of emotional information for decision making.

Chen, AJ-W, Abrams GM, D’Esposito.  2006.  Functional reintegration of prefrontal neural networks for enhancing recovery after brain injury., 2006 Mar-Apr. The Journal of head trauma rehabilitation. 21:107-18. Abstract2006chen.pdf

Functions of the prefrontal cortex (PFC) are fundamental to learning and rehabilitation after brain injuries, but the PFC is particularly vulnerable to trauma. We propose approaches to cognitive training that are hypothesized to specifically enhance PFC function. We present a theoretical framework that generates hypotheses regarding the effects of training on the functional integration of processes across distributed networks of brain regions. Specific outcome measurements that may be used to test these hypotheses in clinical trials are proposed. This neural network-level approach may guide cognitive rehabilitation and facilitate development of adjunctive biologic treatments to enhance the effects of training.

D’Esposito, Cooney JW, Gazzaley A, Gibbs SE, Postle BR.  2006.  Is the prefrontal cortex necessary for delay task performance? Evidence from lesion and FMRI data., 2006 Mar Journal of the International Neuropsychological Society : JINS. 12:248-60. Abstractdesposito2006_is_the_prefrontal_cortex_necessary_for_delay_task_performance.pdf

Although the prefrontal cortex (PFC) is consistently found to be associated with various working memory processes, the necessity of the PFC for such processes remains unclear. To elucidate PFC contributions to storage and rehearsal/maintenance processes engaged during verbal working memory function, we assessed behavior of patients with lesions to the left or right lateral PFC, and neural activity of healthy young subjects during fMRI scanning, during performance of working memory tasks. We found that PFC lesions did not affect storage processes–which is consistent with the notion that posterior cortical networks can support simple retention of information. We also found that PFC lesions did not affect rehearsal/maintenance processes, which was in contrast to our finding that healthy subjects performing a verbal delayed recognition task showed bilateral PFC activation. These combined imaging and behavioral data suggest that working memory rehearsal/maintenance processes may depend on both hemispheres, which may have implications for recovery of function and development of rehabilitation therapies after frontal injury.

Curtis, CE, D’Esposito.  2006.  Selection and maintenance of saccade goals in the human frontal eye fields., 2006 Jun. Journal of neurophysiology. 95:3923-7. Abstract2006curtis.pdf

In a delayed-response task, response selection marks an important transition from sensory to motor processing. Using event-related functional magnetic resonance imaging, we imaged the human brain during performance of a novel delayed-saccade task that isolated response selection from visual encoding and motor execution. The frontal eye fields (FEFs) and intraparietal sulcus (IPS) both showed robust contra-lateralized activity time-locked to response selection. Moreover, response selection affected delay-period activity differently in these regions; it persisted throughout the memory delay period following response selection in the FEF but not IPS. Our results indicate that the FEF and IPS both make important but distinct contributions to spatial working memory. The mechanism that the FEF uses to support spatial working memory is tied to the selection and prospective coding of saccade goals, whereas the role of the IPS may be more tied to retrospective coding of sensory representations.

Fiebach, CJ, Rissman J, D’Esposito.  2006.  Modulation of inferotemporal cortex activation during verbal working memory maintenance., 2006 Jul 20. Neuron. 51:251-61. Abstractfiebach_neuron_2006.pdf

Regions of the left inferotemporal cortex are involved in visual word recognition and semantics. We utilized functional magnetic resonance imaging to localize an inferotemporal language area and to demonstrate that this area is involved in the active maintenance of visually presented words in working memory. Maintenance activity in this inferotemporal area showed an effect of memory load for words, but not pseudowords. In the absence of visual input, the selective modulation of this language-related inferotemporal area for the maintenance of words is accompanied by an increased functional connectivity with left prefrontal cortex. These results demonstrate an involvement of inferotemporal cortex in verbal working memory and provide neurophysiological support for the notion that nonphonological language representations can be recruited in the service of verbal working memory. More generally, they suggest that verbal working memory should be conceptualized as the frontally guided, sustained activation of pre-existing cortical language representations.

Yoon, JH, Curtis CE, D’Esposito.  2006.  Differential effects of distraction during working memory on delay-period activity in the prefrontal cortex and the visual association cortex., 2006 Feb 15. NeuroImage. 29:1117-26. Abstractyoon2006differential_effects_of_distraction.pdf

Maintaining relevant information for later use is a critical aspect of working memory (WM). The lateral prefrontal cortex (PFC) and posterior sensory cortical areas appear to be important in supporting maintenance. However, the relative and unique contributions of these areas remain unclear. We have designed a WM paradigm with distraction to probe the contents of maintenance representations in these regions. During delayed recognition trials of faces, selective interference was evident behaviorally with face distraction leading to significantly worse performance than with scene distraction. Event-related fMRI of the human brain showed that maintenance activity in the lateral PFC, but not in visual association cortex (VAC), was selectively disrupted by face distraction. Additionally, the functional connectivity between the lateral PFC and the VAC was perturbed during these trials. We propose a hierarchical and distributed model of active maintenance in which the lateral PFC codes for abstracted mnemonic information, while sensory areas represent specific features of the memoranda. Furthermore, persistent coactivation between the PFC and sensory areas may be a mechanism by which information is actively maintained.

Yoon, JH, D’Esposito, Carter CS.  2006.  Preserved function of the fusiform face area in schizophrenia as revealed by fMRI., 2006 Dec 1. Psychiatry research. 148:205-16. Abstract2006yoon.pdf

Many lines of evidence suggest that individuals with schizophrenia suffer from face processing deficits. However, the specificity of these deficits and the neural dysfunction underlying them remain unclear. To address these questions, we evaluated the functional status of a critical region for face processing, the fusiform face area (FFA), in subjects with schizophrenia. Fourteen schizophrenia patients and 10 healthy control subjects participated in an fMRI experiment to determine the functional status of the FFA by viewing a series of faces and exemplars of other object categories, while completing a low-level task designed to verify their engagement with the stimuli. Behavioral performance and activation of the FFA were equivalent between groups. Thirteen of 14 patients and all control subjects displayed FFA activation. Furthermore, the degree of FFA activation, as measured by FFA volume and magnitude of activity, was similar between groups. The FFA, a critical region in the neural system subserving the perceptual processing of faces, appears to be intact in schizophrenia. These results call into question the presence of a specific face processing deficit in schizophrenia.

Cools, R, Ivry R, D’Esposito.  2006.  The human striatum is necessary for responding to changes in stimulus relevance., 2006 Dec. Journal of cognitive neuroscience. 18:1973-83. Abstract2006cools.pdf

Various lines of evidence suggest that the striatum is implicated in cognitive flexibility. The neuropsychological evidence has, for the most part, been based on research with patients with Parkinson’s disease, which is accompanied by chemical disruption of both the striatum and the prefrontal cortex. The present study examined this issue by testing patients with focal lesions of the striatum on a task measuring two forms of cognitive switching. Patients with striatal, but not frontal lobe lesions, were impaired in switching between concrete sensory stimuli. By contrast, both patient groups were unimpaired when switching between abstract task rules relative to baseline nonswitch trials. These results reveal a dissociation between two distinct forms of cognitive flexibility, providing converging evidence for a role of the striatum in flexible control functions associated with the selection of behaviorally relevant stimuli.

Hooker, CI, Germine LT, Knight RT, D’Esposito.  2006.  Amygdala response to facial expressions reflects emotional learning., 2006 Aug 30. The Journal of neuroscience : the official journal of the Society for Neuroscience. 26:8915-22. Abstract2006hooker.pdf

The functional role of the human amygdala in the evaluation of emotional facial expressions is unclear. Previous animal and human research shows that the amygdala participates in processing positive and negative reinforcement as well as in learning predictive associations between stimuli and subsequent reinforcement. Thus, amygdala response to facial expressions could reflect the processing of primary reinforcement or emotional learning. Here, using functional magnetic resonance imaging, we tested the hypothesis that amygdala response to facial expressions is driven by emotional association learning. We show that the amygdala is more responsive to learning object-emotion associations from happy and fearful facial expressions than it is to the presentation of happy and fearful facial expressions alone. The results provide evidence that the amygdala uses social signals to rapidly and flexibly learn threatening and rewarding associations that ultimately serve to enhance survival.

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.

D’Esposito, Chen AJ-W.  2006.  Neural mechanisms of prefrontal cortical function: implications for cognitive rehabilitation., 2006. Progress in brain research. 157:123-139. Abstractdespositopbr2006.pdf

Understanding the role of the frontal lobes in cognition remains a challenge for neurologists and neuroscientists. It is proposed that goal-directed behavior, at the core of what we consider human, depends critically on the function of the frontal lobes, and, specifically, the prefrontal cortex (PFC). In this chapter, we put forth the hypothesis that further insight into the neural mechanisms underlying normal PFC function may ultimately help us understand the frontal-lobe syndrome, and importantly, potentially lead to effective therapeutic interventions for frontal-lobe dysfunction. Thus, the aim of this chapter is to review current hypotheses and knowledge about the neural mechanisms underlying the normal function of the PFC in cognition that could guide the development of therapeutic interventions.

Cools, R, Altamirano LJ, D’Esposito.  2006.  Reversal learning in Parkinson’s disease depends on medication status and outcome valence., 2006. Neuropsychologia. 44:1663-73. Abstractaltamirano2006.pdf

We investigated the role of dopamine in distinct forms of reversal shifting by comparing two groups of patients with mild Parkinson’s disease (PD), one ON and one OFF their normal dopaminergic medication. In accordance with our previous work, patients ON medication exhibited impaired reversal shifting relative to patients OFF medication. The present results extend previous studies by showing that the medication-induced deficit on reversal shifting was restricted to conditions where reversals were signaled by unexpected punishment. By contrast, patients ON medication performed as well as patients OFF medication and controls when the reversal was signaled by unexpected reward. The medication-induced deficit was particularly pronounced in patients on the dopamine D3 receptor agonist pramipexole. These data indicate that dopaminergic medication in PD impairs reversal shifting depending on the motivational valence of unexpected outcomes.

Boettiger, CA, D'Esposito M.  2006.  Addiction. Encyclopedia of the Brain and Learning. : Greenwood Publishing Group Abstractaddiction_for_encyl2.pdf


D’esposito, M.  2006.  Functional MRI: cognitive neuroscience applications. Functional MRI. , Berlin: Springer-Verlag Abstractdespocogfmri.pdf


Gazzaley, A, D'Esposito M.  2006.  Unifying the prefrontal cortex: executive control, neural networks and top-down modulation. The Human Frontal Lobes (2nd Edition). , New York: Guilford Publications Abstractgazzaleytopdown2006.pdf


Curtis, CE, D'Esposito M.  2006.  Working Memory. Handbook of Functional Neuroimaging of Cognition (2nd Edition). , Cambridge: MIT Press Abstractcurtis_desposito_handbookfmricognition.pdf


Curtis, CE, Cole MW, Rao VY, D’Esposito.  2005.  Canceling planned action: an FMRI study of countermanding saccades., 2005 Sep. Cerebral cortex (New York, N.Y. : 1991). 15:1281-9. Abstractcurtis2005_cancelling_planned_action_an_fmri_study_of_countermanding_saccades.pdf

We investigated the voluntary control of motor behavior by studying the process of deciding whether or not to execute a movement. We imaged the human dorsal cortex while subjects performed a countermanding task that allowed us to manipulate the probability that subjects would be able to cancel a planned saccade in response to an imperative stop signal. We modeled the behavioral data as a race between gaze-shifting mechanisms and gaze-holding mechanisms towards a finish line where a saccade is generated or canceled, and estimated that saccade cancelation took approximately 160 ms. The frontal eye fields showed greater activation on stop signal trials regardless of successful cancelation, suggesting coactivation of saccade and fixation mechanisms. The supplementary eye fields, however, distinguished between successful and unsuccessful cancelation, suggesting a role in monitoring performance. These oculomotor regions play distinct roles in the decision processes mediating saccadic choice.