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Aarts, E, Wallace DL, Dang LC, Jagust WJ, Cools R, D'Esposito M.  2014.  Dopamine and the Cognitive Downside of a Promised Bonus., 2014 Feb 13. Psychological science. Abstract

It is often assumed that the promise of a monetary bonus improves cognitive control. We show that in fact appetitive motivation can also impair cognitive control, depending on baseline levels of dopamine-synthesis capacity in the striatum. These data not only demonstrate that appetitive motivation can have paradoxical detrimental effects for cognitive control but also provide a mechanistic account of these effects.

Aguirre, GK, Zarahn E, D’Esposito.  1998.  The variability of human, BOLD hemodynamic responses., 1998 Nov. NeuroImage. 8:360-9. Abstractvariability.pdf

Cerebral hemodynamic responses to brief periods of neural activity are delayed and dispersed in time. The specific shape of these responses is of some importance to the design and analysis of blood oxygenation level-dependent (BOLD), functional magnetic resonance imaging (fMRI) experiments. Using fMRI scanning, we examine here the characteristics and variability of hemodynamic responses from the central sulcus in human subjects during an event-related, simple reaction time task. Specifically, we determine the contribution of subject, day, and scanning session (within a day) to variability in the shape of evoked hemodynamic response. We find that while there is significant and substantial variability in the shape of responses collected across subjects, responses collected during multiple scans within a single subject are less variable. The results are discussed in terms of the impact of response variability upon sensitivity and specificity of analyses of event-related fMRI designs.

Aguirre, GK, D’Esposito.  1997.  Environmental knowledge is subserved by separable dorsal/ventral neural areas., 1997 Apr 1. The Journal of neuroscience : the official journal of the Society for Neuroscience. 17:2512-8. Abstractenvironmental.pdf

Environmental psychology models propose that knowledge of large-scale space is stored as distinct landmark (place appearance) and survey (place position) information. Studies of brain-damaged patients suffering from "topographical disorientation" tentatively support this proposal. In order to determine if the components of psychologically derived models of environmental representation are realized as distinct functional, neuroanatomical regions, a functional magnetic resonance imaging (fMRI) study of environmental knowledge was performed. During scanning, subjects made judgments regarding the appearance and position of familiar locations within a virtual reality environment. The fMRI data were analyzed in a manner that has been empirically demonstrated to rigorously control type I error and provide optimum sensitivity, allowing meaningful results in the single subject. A direct comparison of the survey position and landmark appearance conditions revealed a dorsal/ventral dissociation in three of four subjects. These results are discussed in the context of the observed forms of topographical disorientation and are found to be in good agreement with the human lesion studies. This experiment confirms that environmental knowledge is not represented by a unitary system but is instead functionally distributed across the neocortex.

Aguirre, GK, Singh R, D’Esposito.  1999.  Stimulus inversion and the responses of face and object-sensitive cortical areas., 1999 Jan 18. Neuroreport. 10:189-94. Abstractinversion.pdf

Behavioral and neuropsychological studies suggest that upright and inverted face stimuli are processed by computationally and anatomically distinct systems. Specifically, inverted faces seem to be addressed by general object perception systems, avoiding face-specific processes. We tested this model by examining the fMRI signal response of a functionally defined fusiform face area and bilateral object-responsive cortical areas during the perception of upright and inverted stimuli (faces and cars). While inversion of face stimuli had no effect upon the magnitude of responses in the fusiform face area, inverted faces evoked greater neural responses compared to upright faces within object regions. This finding supports the assertion that object areas are involved to a greater degree in the perception of inverted vs upright faces.

Aguirre, GK, Zarahn E, D’Esposito.  1998.  An area within human ventral cortex sensitive to "building" stimuli: evidence and implications., 1998 Aug. Neuron. 21:373-83. Abstractaguirre1998.pdf

Isolated, ventral brain lesions in humans occasionally produce specific impairments in the ability to use landmarks, particularly buildings, for way-finding. Using functional MRI, we tested the hypothesis that there exists a cortical region specialized for the perception of buildings. Across subjects, a region straddling the right lingual sulcus was identified that possessed the functional correlates predicted for a specialized building area. A series of experiments discounted several alternative explanations for the behavior of this site. These results are discussed in terms of their impact upon our understanding of the functional structure of visual processing, disorders of topographical disorientation, and the influence of environmental conditions upon neural organization.

Aguirre, GK, Zarahn E, D’Esposito.  1998.  A critique of the use of the Kolmogorov-Smirnov (KS) statistic for the analysis of BOLD fMRI data., 1998 Mar. Magnetic resonance in medicine : official journal of the Society of Magnetic Resonance in Medicine / Society of Magnetic Resonance in Medicine. 39:500-5. Abstract1998aguirre.pdf

The use of the Kolmogorov-Smirnov (KS) statistic for testing hypotheses regarding activation in blood oxygenation level-dependent functional MRI data is critiqued on both theoretical and empirical grounds. Theoretically, it is argued that the KS test is formally unable to support inferences of interest to most neuro-imaging studies and has reduced sensitivity compared with parametric alternatives. Empirically, false-positive rates yielded by the KS test in human data collected under the null hypothesis were significantly in excess of tabular values. These excessive false-positive rates could be explained by the presence of temporal autocorrelation. We also present evidence that the distribution of blood oxygenation level-dependent functional MRI data is only slightly nonnormal, questioning the initial impetus for the use of the KS test in this context. Finally, it is noted that parametric alternatives exist that do provide adequate control of the false-positive rate and can support inferences of interest.

Aguirre, GK, D’Esposito.  1999.  Topographical disorientation: a synthesis and taxonomy., 1999 Sep. Brain : a journal of neurology. 122 ( Pt 9):1613-28. Abstracttopo.pdf

Over the last century, several dozen case reports have presented ’topographically disoriented’ patients who, in some cases, appear to have selectively lost their ability to find their way within large-scale, locomotor environments. A review is offered here that has as its aim the creation of a taxonomy that accurately reflects the behavioural impairments and neuroanatomical findings of this literature. This effort is guided by an appreciation of the models of normative way-finding offered by environmental psychology and recent neuroscience research. It is proposed that several varieties of topographical disorientation exist, resulting from damage to distinct neuroanatomical areas. The particular pattern of impairments that patients evidence is argued to be consonant with the known functions of these cortical regions and with recent neuroimaging results. The conflicting claims of previous reviews of this area are also considered and addressed.

Aguirre, GK, Zarahn E, D’Esposito.  1998.  The inferential impact of global signal covariates in functional neuroimaging analyses., 1998 Oct. NeuroImage. 8:302-6. Abstractinferential.pdf


Aguirre, GK, Zarahn E, D’Esposito.  1997.  Empirical analyses of BOLD fMRI statistics. II. Spatially smoothed data collected under null-hypothesis and experimental conditions., 1997 Apr. NeuroImage. 5:199-212. Abstractempiricalbold.pdf

In the companion to this paper (E. Zarahn, G. K. Aguirre, and M. D’Esposito, 1997, NeuroImage, 179-197), we describe an implementation of a general linear model for autocorrelated observations in which the voxel-wise false-positive rates in fMRI "noise" datasets were stabilized and brought close to theoretical values. Here, implementations of the model are tested for use with statistical parametric mapping analysis of spatially smoothed fMRI data. Analyses using varying models of intrinsic temporal autocorrelation and either including or excluding a global signal covariate were conducted upon human subject data collected under null hypothesis as well as under experimental conditions. We found that smoothing with an empirically derived impulse response function (IRF), combined with a model of the intrinsic temporal autocorrelation in spatially smoothed fMRI data, resulted in a map-wise false-positive rate which did not exceed a 5% level when a nominal alpha = 0.05 tabular threshold was applied. Use of other models of intrinsic temporal autocorrelation resulted in map-wise false-positive rates that significantly exceeded this level. fMRI data collected while subjects performed a behavioral task were used to examine (a) task-dependent global signal changes and (b) the dependence of sensitivity on the temporal smoothing kernel and inclusion/exclusion of a global signal covariate. The global signal changes within an fMRI dataset were shown to be influenced by the performance of a behavioral task. However, the inclusion of this measure as a covariate did not have an adverse affect upon our measure of sensitivity. Finally, use of an empirically derived estimate of the IRF of the system was shown to result in greater map-wise sensitivity for signal changes than the use of a broader (in time) Poisson (parameter = 8 s) kernel.

Aguirre, GK, D'Esposito M.  1999.  Experimental design for brain fMRI. Functional MRI. , Berlin: Springer-Verlag Abstract


Aguirre, GK, Detre JA, Alsop D, D’Esposito.  1996.  The parahippocampus subserves topographical learning in man., 1996 Nov-Dec. Cerebral cortex (New York, N.Y. : 1991). 6:823-9. Abstract1996aguirre.pdf

The hippocampus has been proposed as the site of neural representation of large-scale environmental space, based upon the identification of place cells (neurons with receptive fields for current position in the environment) within the rat hippocampus and the demonstration that hippocampal lesions impair place learning in the rat. The inability to identify place cells within the monkey hippocampus and the observation that unilateral hippocampal lesions do not selectively impair topographic behavior in humans suggest that alternate regions may subserve this function in man. To examine the contribution of the hippocampus and adjacent medial-temporal lobe structures to topographic learning in the human, a ’virtual’ maze was used as a task environment during functional magnetic resonance imaging studies. During the learning and recall of topographic information, medial-temporal activity was confined to the para- hippocampal gyri. This activity accords well with the lesion site known to produce topographical disorientation in humans. Activity was also observed in cortical areas known to project to the parahippocampus and previously proposed to contribute to a network subserving spatially guided behavior.

Aguirre, GK, Zarahn E, D’Esposito.  1998.  Neural components of topographical representation., 1998 Feb 3. Proceedings of the National Academy of Sciences of the United States of America. 95:839-46. Abstracttopographical.pdf

Studies of patients with focal brain damage suggest that topographical representation is subserved by dissociable neural subcomponents. This article offers a condensed review of the literature of "topographical disorientation" and describes several functional MRI studies designed to test hypotheses generated by that review. Three hypotheses are considered: (i) The parahippocampal cortex is critically involved in the acquisition of exocentric spatial information in humans; (ii) separable, posterior, dorsal, and ventral cortical regions subserve the perception and long term representation of position and identity, respectively, of landmarks; and (iii) there is a distinct area of the ventral occipitotemporal cortex that responds maximally to building stimuli and may play a role in the perception of salient landmarks. We conclude with a discussion of the inferential limitations of neuroimaging and lesion studies. It is proposed that combining these two approaches allows for inferences regarding the computational involvement of a neuroanatomical substrate in a given cognitive process although neither method can strictly support this conclusion alone.

Alsop, D, Detre JA, D’Esposito, Howard RS, Maldjian JA, Grossman M, Listerud J, Flamm ES, Judy KD, Atlas S.  1996.  Functional activation during an auditory comprehension task in patients with temporal lobe lesions., 1996 Aug. NeuroImage. 4:55-9. Abstract1996alsop.pdf

Functional magnetic resonance imaging (fMRI) was used to map regional brain activation during an auditory comprehension task in two normal controls and two patients with left temporal lobe lesions. Activity in the superior temporal and angular gyrus regions was detected in all normal subjects. In the patients, the spatial distribution of activation ipsilateral to the lesions differed from the pattern observed in contralateral cortex or in control subjects. These studies highlight the potential of fMRI for mapping abnormal functional anatomy in the human brain.

Altamirano, LJ, Fields HL, D’Esposito, Boettiger CA.  2011.  Interaction Between Family History of Alcoholism and Locus of Control in the Opioid Regulation of Impulsive Responding Under the Influence of Alcohol., 2011 May 13. Alcoholism, clinical and experimental research. Abstract2011_altamirano.pdf

{Background: Naltrexone (NTX) is an opioid antagonist indicated for the treatment of alcoholism, which is not universally effective. Thus, identifying individual predictors of NTX’s behavioral effects is critical to optimizing its therapeutic use. Moreover, given the high rate of relapse during treatment for alcoholism, understanding NTX’s behavioral effects when combined with moderate ethanol intake is important. Our previous study of abstinent alcoholics and control subjects showed that a more internal Locus of Control score predicted increased impulsive choice on NTX (Mitchell et al., 2007, Neuropsychopharmacology 32:439-449). Here, we tested whether this predictive relationship remains in the context of moderate alcohol intake. Methods: In this study, we tested the effect of acute NTX (50 mg) on impulsive choice, motor inhibition, and attentional bias after ingestion of moderate ethanol (\~{}0.3 g/kg

Ances, BM, D’Esposito.  2000.  Neuroimaging of recovery of function after stroke: implications for rehabilitation., 2000. Neurorehabilitation and neural repair. 14:171-9. Abstract

Stroke is a leading cause of morbidity and mortality in individuals. Many patients have good functional recovery after stroke. The mechanisms of recovery remain largely unknown. Neuroimaging of patients recovering from stroke may provide important insight into the mechanisms of recovery as well as assist in the development of new rehabilitation techniques. The first part of this article reviews previous neuroimaging studies that have monitored the reorganization within the motor and language areas after stroke. In the second section, a unifying theory based on John Hughlings Jackson’s "Principles of Compensation" is presented as a possible theory for recovery of function. In the final portion of the article, possible implications and future applications of neuroimaging studies for rehabilitation are presented.

Armstrong, C, Lewis T, D’Esposito, Freundlich B.  1997.  Eosinophilia-myalgia syndrome: selective cognitive impairment, longitudinal effects, and neuroimaging findings., 1997 Nov. Journal of neurology, neurosurgery, and psychiatry. 63:633-41. Abstract1997armstrong.pdf

OBJECTIVE: To identify the specific nature of the neurocognitive impairments of eosinophilia-myalgia syndrome (EMS) in an unselected population, and to present longitudinal patterns. METHODS: A consecutive sample of 23 patients with EMS and 18 age and education matched control subjects were assessed on a comprehensive neuropsychological battery. Longitudinal results were gathered from six patients. RESULTS: Neurocognitive impairments were found which represent a subset of deficits reported in previous group and case study reports. Deficits were limited to complex visual memory, conceptual set shifting, and attention, which suggest a selective dysexecutive syndrome. The motor slowing and verbal memory deficits previously reported were not found. Although depression, fatigue, sleep deprivation, and pain were significant symptoms, they were unassociated with deficits with the exception of an association of depression with one deficit. There was no pattern of overall decline over time in a subset of the group, although considerable heterogeneity in the longitudinal patterns of neurocognitive tests was found. Abnormalities of white matter appeared in the MRI of eight of 12 patients. CONCLUSIONS: The neurocognitive and neuroimaging findings contribute to the evidence which indicates that the neural substrate of EMS is white matter damage.

Armstrong, C, Onishi K, Robinson K, D’Esposito, Thompson H, Rostami A, Grossman M.  1996.  Serial position and temporal cue effects in multiple sclerosis: two subtypes of defective memory mechanisms., 1996 Sep. Neuropsychologia. 34:853-62. Abstract1996armstrong.pdf

Neurocognitive studies of multiple sclerosis (MS) have identified a robust long-term memory deficit. We hypothesized that this is due in part to the limited representation and use of serial order information. MS patients and controls were studied with a supraspan list learning procedure with post-encoding retrieval and recognition trials. MS patients demonstrated post-encoding negative recency with normal recognition, and word order recall was impaired. These findings appear to be in part to difficulty using temporal order cues in long-term memory. Two dissociable memory deficits were identified, suggesting that there are at least two neurocognitive mechanisms underlying memory impairment in MS.

Arnemann, KL, Chen AJ-W, Novakovic-Agopian T, Gratton C, Nomura EM, D'Esposito M.  2015.  Functional brain network modularity predicts response to cognitive training after brain injury., 2015 Mar 18. Neurology. Abstract

We tested the value of measuring modularity, a graph theory metric indexing the relative extent of integration and segregation of distributed functional brain networks, for predicting individual differences in response to cognitive training in patients with brain injury.

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.

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?

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.

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.

Bahlmann, J, Blumenfeld RS, D'Esposito M.  2014.  The Rostro-Caudal Axis of Frontal Cortex Is Sensitive to the Domain of Stimulus Information., 2014 Jan 22. Cerebral cortex (New York, N.Y. : 1991). Abstract

Evidence suggests that lateral frontal cortex implements cognitive control processing along its rostro-caudal axis, yet other evidence supports a dorsal-ventral functional organization for processes engaged by different stimulus domains (e.g., spatial vs. nonspatial). This functional magnetic resonance imaging study investigated whether separable dorsolateral and ventrolateral rostro-caudal gradients exist in humans, while participants performed tasks requiring cognitive control at 3 levels of abstraction with language or spatial stimuli. Abstraction was manipulated by using 3 different task sets that varied in relational complexity. Relational complexity refers to the process of manipulating the relationship between task components (e.g., to associate a particular cue with a task) and drawing inferences about that relationship. Tasks using different stimulus domains engaged distinct posterior regions, but within the lateral frontal cortex, we found evidence for a single rostro-caudal gradient that was organized according to the level of abstraction and was independent of processing of the stimulus domain. However, a pattern of dorsal/ventral segregation of processing engaged by domain-specific information was evident in each separable frontal region only within the most rostral region recruited by task demands. These results suggest that increasingly abstract information is represented in the frontal cortex along distinct rostro-caudal gradients that also segregate along a dorsal-ventral axis dependent on task demands.

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

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

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.

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.

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.

Bertolero, MA, Yeo TBT, D'Esposito M.  2015.  The modular and integrative functional architecture of the human brain., 2015 Nov 23. Proceedings of the National Academy of Sciences of the United States of America. Abstract

Network-based analyses of brain imaging data consistently reveal distinct modules and connector nodes with diverse global connectivity across the modules. How discrete the functions of modules are, how dependent the computational load of each module is to the other modules' processing, and what the precise role of connector nodes is for between-module communication remains underspecified. Here, we use a network model of the brain derived from resting-state functional MRI (rs-fMRI) data and investigate the modular functional architecture of the human brain by analyzing activity at different types of nodes in the network across 9,208 experiments of 77 cognitive tasks in the BrainMap database. Using an author-topic model of cognitive functions, we find a strong spatial correspondence between the cognitive functions and the network's modules, suggesting that each module performs a discrete cognitive function. Crucially, activity at local nodes within the modules does not increase in tasks that require more cognitive functions, demonstrating the autonomy of modules' functions. However, connector nodes do exhibit increased activity when more cognitive functions are engaged in a task. Moreover, connector nodes are located where brain activity is associated with many different cognitive functions. Connector nodes potentially play a role in between-module communication that maintains the modular function of the brain. Together, these findings provide a network account of the brain's modular yet integrated implementation of cognitive functions.

Biassou, N, Grossman M, Onishi K, Mickanin J, Hughes E, Robinson KM, D’Esposito.  1995.  Phonologic processing deficits in Alzheimer’s disease., 1995 Dec. Neurology. 45:2165-9. Abstract1995biassou.pdf

We investigated phonologic production in patients with mild to moderate Alzheimer’s disease (AD) on a repetition task. AD patients produced significantly more speech errors than age-matched controls. AD patients’ errors, unlike those of controls, resulted in the transformation of real words into pseudowords, occurred disproportionately in word-initial positions, and were not influenced by the phonologic environment. This pattern of errors suggests a lexical phonologic retrieval deficit in AD.

Bloemendaal, M, van Schouwenburg MR, Miyakawa A, Aarts E, D'Esposito M, Cools R.  2014.  Dopaminergic modulation of distracter-resistance and prefrontal delay period signal., 2014 Oct 11. Psychopharmacology. Abstract

Dopamine has long been implicated in the online maintenance of information across short delays. Specifically, dopamine has been proposed to modulate the strength of working memory representations in the face of intervening distracters. This hypothesis has not been tested in humans. We fill this gap using pharmacological neuroimaging. Healthy young subjects were scanned after intake of the dopamine receptor agonist bromocriptine or placebo (in a within-subject, counterbalanced, and double-blind design). During scanning, subjects performed a delayed match-to-sample task with face stimuli. A face or scene distracter was presented during the delay period (between the cue and the probe). Bromocriptine altered distracter-resistance, such that it impaired performance after face relative to scene distraction. Individual differences in the drug effect on distracter-resistance correlated negatively with drug effects on delay period signal in the prefrontal cortex, as well as on functional connectivity between the prefrontal cortex and the fusiform face area. These results provide evidence for the hypothesis that dopaminergic modulation of the prefrontal cortex alters resistance of working memory representations to distraction. Moreover, we show that the effects of dopamine on the distracter-resistance of these representations are accompanied by modulation of the functional strength of connections between the prefrontal cortex and stimulus-specific posterior cortex.

Blumenfeld, RS, Nomura EM, Gratton C, D'Esposito M.  2012.  Lateral Prefrontal Cortex is Organized into Parallel Dorsal and Ventral Streams Along the Rostro-Caudal Axis., 2012 Aug 9. Cerebral cortex (New York, N.Y. : 1991). Abstract

Anatomical connectivity differences between the dorsal and ventral lateral prefrontal cortex (PFC) of the non-human primate strongly suggests that these regions support different functions. However, after years of study, it remains unclear whether these regions are functionally distinct. In contrast, there has been a groundswell of recent studies providing evidence for a rostro-caudal functional organization, along the lateral as well as dorsomedial frontal cortex. Thus, it is not known whether dorsal and ventral regions of lateral PFC form distinct functional networks and how to reconcile any dorso-ventral organization with the medio-lateral and rostro-caudal axes. Here, we used resting-state connectivity data to identify parallel dorsolateral and ventrolateral streams of intrinsic connectivity with the dorsomedial frontal cortex. Moreover, we show that this connectivity follows a rostro-caudal gradient. Our results provide evidence for a novel framework for the intrinsic organization of the frontal cortex that incorporates connections between medio-lateral, dorso-ventral, and rostro-caudal axes.

Blumenfeld, RS, Lee T, D'Esposito M.  2013.  The effects of lateral prefrontal transcranial magnetic stimulation on item memory encoding., 2013 Dec 4. Neuropsychologia. Abstract

Previous neuroimaging research has established that the left ventrolateral prefrontal cortex (VLPFC) is involved in long-term memory (LTM) encoding for individual items. Dorsolateral prefrontal cortex (DLPFC) is implicated less frequently, and one theory that has gained support to explain this discrepancy is that DLPFC is involved in forming item-item relational but not item LTM. Given that neuroimaging results are correlational, complimentary methods such as repetitive transcranial magnetic stimulation (TMS) have been used to test causal hypotheses generated from imaging data. Most TMS studies of LTM encoding have found that disruption of lateral PFC activity impairs subsequent memory. However these studies have lacked methods to precisely localize and directly compare TMS effects from frontal subregions implicated by the neuroimaging literature. Here, we target specific subregions of lateral PFC with TMS to test the prediction from the item/relational framework that temporary disruption of VLPFC during encoding will impair subsequent memory whereas TMS to DLPFC during item encoding will not. Frontal TMS was administered prior to a LTM encoding task in which participants were presented with a list of individual nouns and asked to judge whether each noun was concrete or abstract. After a 40min delay period, item recognition memory was tested. Results indicate that VLPFC and DLPFC TMS have differential effects on subsequent item memory. VLPFC TMS reliably disrupted subsequent item memory whereas DLPFC TMS led to numerical enhancement in item memory, relative to TMS to a control region.

Blumenfeld, RS, Bliss DP, Perez F, D'Esposito M.  2013.  CoCoTools: Open-source Software for Building Connectomes Using the CoCoMac Anatomical Database., 2013 Oct 11. Journal of cognitive neuroscience. Abstract

Neuroanatomical tracer studies in the nonhuman primate macaque monkey are a valuable resource for cognitive neuroscience research. These data ground theories of cognitive function in anatomy, and with the emergence of graph theoretical analyses in neuroscience, there is high demand for these data to be consolidated into large-scale connection matrices ("macroconnectomes"). Because manual review of the anatomical literature is time consuming and error prone, computational solutions are needed to accomplish this task. Here we describe the "CoCoTools" open-source Python library, which automates collection and integration of macaque connectivity data for visualization and graph theory analysis. CoCoTools both interfaces with the CoCoMac database, which houses a vast amount of annotated tracer results from 100 years (1905-2005) of neuroanatomical research and implements coordinate-free registration algorithms, which allow studies that use different parcellations of the brain to be translated into a single graph. We show that using CoCoTools to translate all of the data stored in CoCoMac produces graphs with properties consistent with what is known about global brain organization. Moreover, in addition to describing CoCoTools' processing pipeline, we provide worked examples, tutorials, links to on-line documentation, and detailed appendices to aid scientists interested in using CoCoTools to gather and analyze CoCoMac data.

Boettiger, CA, D’Esposito.  2005.  Frontal networks for learning and executing arbitrary stimulus-response associations., 2005 Mar 9. The Journal of neuroscience : the official journal of the Society for Neuroscience. 25:2723-32. Abstractfrontal_networks_for_learning_and_executing_arbitrary_stimulus-response_associations.pdf

Flexible rule learning, a behavior with obvious adaptive value, is known to depend on an intact prefrontal cortex (PFC). One simple, yet powerful, form of such learning consists of forming arbitrary stimulus-response (S-R) associations. A variety of evidence from monkey and human studies suggests that the PFC plays an important role in both forming new S-R associations and in using learned rules to select the contextually appropriate response to a particular stimulus cue. Although monkey lesion studies more strongly implicate the ventrolateral PFC (vlPFC) in S-R learning, clinical data and neurophysiology studies have implicated both the vlPFC and the dorsolateral region (dlPFC) in associative rule learning. Previous human imaging studies of S-R learning tasks, however, have not demonstrated involvement of the dlPFC. This may be because of the design of previous imaging studies, which used few stimuli and used explicitly stated one-to-one S-R mapping rules that were usually practiced before scanning. Humans learn these rules very quickly, limiting the ability of imaging techniques to capture activity related to rule acquisition. To address these issues, we performed functional magnetic resonance imaging while subjects learned by trial and error to associate sets of abstract visual stimuli with arbitrary manual responses. Successful learning of this task required discernment of a categorical type of S-R rule in a block design expected to yield sustained rule representation. Our results show that distinct components of the dorsolateral, ventrolateral, and anterior PFC, lateral premotor cortex, supplementary motor area, and the striatum are involved in learning versus executing categorical S-R rules.

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.

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.

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


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


Buchsbaum, B, D'Esposito M.  2013.  Working memory. Oxford Handbook of Cognitive Neuroscience. , Oxford: Oxford University Press
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.

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.

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.

Buchsbaum, BR, D'Esposito M.  2008.  Short term and working memory systems. Learning and Memory: A Comprehensive Reference. , Oxford: Elsevier2008buchsbaum1.pdf
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.

Cameron, IGM, Riddle JM, D'Esposito M.  2015.  Dissociable Roles of Dorsolateral Prefrontal Cortex and Frontal Eye Fields During Saccadic Eye Movements., 2015. Frontiers in human neuroscience. 9:613. Abstract

The dorsolateral prefrontal cortex (DLPFC) and the frontal eye fields (FEF) have both been implicated in the executive control of saccades, yet possible dissociable roles of each region have not been established. Specifically, both establishing a "task set" as well as suppressing an inappropriate response have been linked to DLPFC and FEF activity, with behavioral outcome measures of these mechanisms mainly being the percentage of pro-saccade errors made on anti-saccade trials. We used continuous theta-burst stimulation (cTBS) to disrupt FEF or DLPFC function in humans during an anti-saccade task to assess the causal role of these regions in these executive control processes, and in programming saccades towards (pro-saccade) or away (anti-saccade) from visual targets. After right FEF cTBS, as compared to control cTBS to the right primary somatosensory cortex (rS1), anti-saccade amplitude of the first saccade decreased and the number of anti-saccades to acquire final position increased; however direction errors to the visual target were not different. In contrast, after left DLPFC cTBS, as compared to left S1 cTBS, subjects displayed greater direction errors for contralateral anti-saccades; however, there were no impairments on the number of saccades or the saccade amplitude. These results are consistent with the notion that DLPFC is necessary for executive control of saccades, whereas FEF is necessary for visuo-motor aspects of anti-saccade programming.

Chapman, SB, Aslan S, Spence JS, Keebler MW, DeFina LF, Didehbani N, Perez AM, Lu H, D'Esposito M.  2016.  Distinct Brain and Behavioral Benefits from Cognitive vs. Physical Training: A Randomized Trial in Aging Adults., 2016. Frontiers in human neuroscience. 10:338. Abstract

Insidious declines in normal aging are well-established. Emerging evidence suggests that non-pharmacological interventions, specifically cognitive and physical training, may counter diminishing age-related cognitive and brain functions. This randomized trial compared effects of two training protocols: cognitive training (CT) vs. physical training (PT) on cognition and brain function in adults 56-75 years. Sedentary participants (N = 36) were randomized to either CT or PT group for 3 h/week over 12 weeks. They were assessed at baseline-, mid-, and post-training using neurocognitive, MRI, and physiological measures. The CT group improved on executive function whereas PT group's memory was enhanced. Uniquely deploying cerebral blood flow (CBF) and cerebral vascular reactivity (CVR) MRI, the CT cohort showed increased CBF within the prefrontal and middle/posterior cingulate cortex (PCC) without change to CVR compared to PT group. Improvements in complex abstraction were positively associated with increased resting CBF in dorsal anterior cingulate cortex (dACC). Exercisers with higher CBF in hippocampi bilaterally showed better immediate memory. The preliminary evidence indicates that increased cognitive and physical activity improves brain health in distinct ways. Reasoning training enhanced frontal networks shown to be integral to top-down cognitive control and brain resilience. Evidence of increased resting CBF without changes to CVR implicates increased neural health rather than improved vascular response. Exercise did not improve cerebrovascular response, although CBF increased in hippocampi of those with memory gains. Distinct benefits incentivize testing effectiveness of combined protocols to strengthen brain health.

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.

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.

Chen, AJ-W, Britton M, Turner GR, Vytlacil J, Thompson TW, D'Esposito M.  2012.  Goal-directed attention alters the tuning of object-based representations in extrastriate cortex., 2012. Frontiers in human neuroscience. 6:187. Abstract

Humans survive in environments that contain a vast quantity and variety of visual information. All items of perceived visual information must be represented within a limited number of brain networks. The human brain requires mechanisms for selecting only a relevant fraction of perceived information for more in-depth processing, where neural representations of that information may be actively maintained and utilized for goal-directed behavior. Object-based attention is crucial for goal-directed behavior and yet remains poorly understood. Thus, in the study we investigate how neural representations of visual object information are guided by selective attention. The magnitude of activation in human extrastriate cortex has been shown to be modulated by attention; however, object-based attention is not likely to be fully explained by a localized gain mechanism. Thus, we measured information coded in spatially distributed patterns of brain activity with fMRI while human participants performed a task requiring selective processing of a relevant visual object category that differed across conditions. Using pattern classification and spatial correlation techniques, we found that the direction of selective attention is implemented as a shift in the tuning of object-based information representations within extrastriate cortex. In contrast, we found that representations within lateral prefrontal cortex (PFC) coded for the attention condition rather than the concrete representations of object category. In sum, our findings are consistent with a model of object-based selective attention in which representations coded within extrastriate cortex are tuned to favor the representation of goal-relevant information, guided by more abstract representations within lateral PFC.

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.

Chiong, W, Wilson SM, D'Esposito M, Kayser AS, Grossman SN, Poorzand P, Seeley WW, Miller BL, Rankin KP.  2013.  The salience network causally influences default mode network activity during moral reasoning., 2013 Apr 9. Brain : a journal of neurology. Abstract2013_chiong.pdf

Large-scale brain networks are integral to the coordination of human behaviour, and their anatomy provides insights into the clinical presentation and progression of neurodegenerative illnesses such as Alzheimer's disease, which targets the default mode network, and behavioural variant frontotemporal dementia, which targets a more anterior salience network. Although the default mode network is recruited when healthy subjects deliberate about 'personal' moral dilemmas, patients with Alzheimer's disease give normal responses to these dilemmas whereas patients with behavioural variant frontotemporal dementia give abnormal responses to these dilemmas. We hypothesized that this apparent discrepancy between activation- and patient-based studies of moral reasoning might reflect a modulatory role for the salience network in regulating default mode network activation. Using functional magnetic resonance imaging to characterize network activity of patients with behavioural variant frontotemporal dementia and healthy control subjects, we present four converging lines of evidence supporting a causal influence from the salience network to the default mode network during moral reasoning. First, as previously reported, the default mode network is recruited when healthy subjects deliberate about 'personal' moral dilemmas, but patients with behavioural variant frontotemporal dementia producing atrophy in the salience network give abnormally utilitarian responses to these dilemmas. Second, patients with behavioural variant frontotemporal dementia have reduced recruitment of the default mode network compared with healthy control subjects when deliberating about these dilemmas. Third, a Granger causality analysis of functional neuroimaging data from healthy control subjects demonstrates directed functional connectivity from nodes of the salience network to nodes of the default mode network during moral reasoning. Fourth, this Granger causal influence is diminished in patients with behavioural variant frontotemporal dementia. These findings are consistent with a broader model in which the salience network modulates the activity of other large-scale networks, and suggest a revision to a previously proposed 'dual-process' account of moral reasoning. These findings also characterize network interactions underlying abnormal moral reasoning in frontotemporal dementia, which may serve as a model for the aberrant judgement and interpersonal behaviour observed in this disease and in other disorders of social function. More broadly, these findings link recent work on the dynamic interrelationships between large-scale brain networks to observable impairments in dementia syndromes, which may shed light on how diseases that target one network also alter the function of interrelated networks.

Cohen, JR, Gallen CL, Jacobs EG, Lee TG, D'Esposito M.  2014.  Quantifying the Reconfiguration of Intrinsic Networks during Working Memory., 2014. PloS one. 9(9):e106636. Abstract

Rapid, flexible reconfiguration of connections across brain regions is thought to underlie successful cognitive control. Two intrinsic networks in particular, the cingulo-opercular (CO) and fronto-parietal (FP), are thought to underlie two operations critical for cognitive control: task-set maintenance/tonic alertness and adaptive, trial-by-trial updating. Using functional magnetic resonance imaging, we directly tested whether the functional connectivity of the CO and FP networks was related to cognitive demands and behavior. We focused on working memory because of evidence that during working memory tasks the entire brain becomes more integrated. When specifically probing the CO and FP cognitive control networks, we found that individual regions of both intrinsic networks were active during working memory and, as expected, integration across the two networks increased during task blocks that required cognitive control. Crucially, increased integration between each of the cognitive control networks and a task-related, non-cognitive control network (the hand somatosensory-motor network; SM) was related to increased accuracy. This implies that dynamic reconfiguration of the CO and FP networks so as to increase their inter-network communication underlies successful working memory.

Cohen, JR, Sreenivasan KK, D'Esposito M.  2012.  Correspondence Between Stimulus Encoding- and Maintenance-Related Neural Processes Underlies Successful Working Memory., 2012 Nov 11. Cerebral cortex (New York, N.Y. : 1991). Abstract2012_cohen.pdf

The ability to actively maintain information in working memory (WM) is vital for goal-directed behavior, but the mechanisms underlying this process remain elusive. We hypothesized that successful WM relies upon a correspondence between the neural processes associated with stimulus encoding and the neural processes associated with maintenance. Using functional magnetic resonance imaging, we identified regional activity and inter-regional connectivity during stimulus encoding and the maintenance of those stimuli when they were no longer present. We compared correspondence in these neural processes across encoding and maintenance epochs with WM performance. Critically, greater correspondence between encoding and maintenance in 1) regional activity in the lateral prefrontal cortex (PFC) and 2) connectivity between lateral PFC and extrastriate cortex was associated with increased performance. These findings suggest that the conservation of neural processes across encoding and maintenance supports the integrity of representations in WM.

Cohen, JR, D'Esposito M.  2016.  The Segregation and Integration of Distinct Brain Networks and Their Relationship to Cognition., 2016 Nov 30. The Journal of neuroscience : the official journal of the Society for Neuroscience. 36(48):12083-12094. Abstract

A critical feature of the human brain that gives rise to complex cognition is its ability to reconfigure its network structure dynamically and adaptively in response to the environment. Existing research probing task-related reconfiguration of brain network structure has concluded that, although there are many similarities in network structure during an intrinsic, resting state and during the performance of a variety of cognitive tasks, there are meaningful differences as well. In this study, we related intrinsic, resting state network organization to reconfigured network organization during the performance of two tasks: a sequence tapping task, which is thought to probe motor execution and likely engages a single brain network, and an n-back task, which is thought to probe working memory and likely requires coordination across multiple networks. We implemented graph theoretical analyses using functional connectivity data from fMRI scans to calculate whole-brain measures of network organization in healthy young adults. We focused on quantifying measures of network segregation (modularity, system segregation, local efficiency, number of provincial hub nodes) and measures of network integration (global efficiency, number of connector hub nodes). Using these measures, we found converging evidence that local, within-network communication is critical for motor execution, whereas integrative, between-network communication is critical for working memory. These results confirm that the human brain has the remarkable ability to reconfigure its large-scale organization dynamically in response to current cognitive demands and that interpreting reconfiguration in terms of network segregation and integration may shed light on the optimal network structures underlying successful cognition.

Cole, MA, Muir JJ, Gans JJ, Shin LM, D'Esposito M, Harel BT, Schembri A.  2015.  Simultaneous Treatment of Neurocognitive and Psychiatric Symptoms in Veterans with Post-Traumatic Stress Disorder and History of Mild Traumatic Brain Injury: A Pilot Study of Mindfulness-Based Stress Reduction., 2015 Sep. Military medicine. 180(9):956-63. Abstract

Treating patient populations with significant psychiatric and neurocognitive symptomatology can present a unique clinical dilemma: progress in psychotherapy can be significantly fettered by cognitive deficits, whereas neurocognitive rehabilitation efforts can be ineffective because of psychiatric overlay. Application of mindfulness-based interventions to address either cognitive or psychiatric symptoms in isolation appears efficacious in many contexts; however, it remains unclear whether this type of intervention might help address simultaneous neurocognitive and psychiatric symptomatology. In a pre-post mixed methods design pilot study, nine Veterans with post-traumatic stress disorder (PTSD) and a history of mild traumatic brain injury with chronic cognitive complaints participated in Mindfulness-Based Stress Reduction (MBSR). Clinical interview, questionnaires, and attention and PTSD measures were administered immediately before, immediately after, and 3 months after MBSR completion. Qualitative and quantitative findings suggest high levels of safety, feasibility, and acceptability. Measurement of attention revealed significant improvement immediately following MBSR (p < 0.05, d = 0.57) and largely sustained improvement 3 months after completion of MBSR (p < 0.10, d = 0.48). Significant reduction in PTSD symptoms was found immediately after MBSR (p < 0.05, d = -1.56), and was sustained 3 months following MBSR completion (p < 0.05, d = -0.93). These results warrant a randomized controlled trial follow-up. Potential mechanisms for the broad effects observed will be explored.

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.

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.

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.

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.

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.

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.

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.

Cools, R, D'Esposito M.  2009.  Dopaminergic modulation of flexible cognitive control in humans. Dopamine Handbook. , 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
Curtis, CE, Rao VY, D’Esposito.  2004.  Maintenance of spatial and motor codes during oculomotor delayed response tasks., 2004 Apr 21. The Journal of neuroscience : the official journal of the Society for Neuroscience. 24:3944-52. Abstractcurtis_ce_maintenance_of_spatial_and_motor_codes_during_oculomotor_delayed_response_tasks_j_neurosci_2004.pdf

The most compelling neural evidence for working memory is persistent neuronal activity bridging past sensory cues and their contingent future motor acts. This observation, however, does not answer what is actually being remembered or coded for by this activity. To address this fundamental issue, we imaged the human brain during maintenance of spatial locations and varied whether the memory-guided saccade was selected before or after the delay. An oculomotor delayed matching-to-sample task (match) was used to measure maintained motor intention because the direction of the forthcoming saccade was known throughout the delay. We used a nonmatching-to-sample task (nonmatch) in which the saccade was unpredictable to measure maintained spatial attention. Oculomotor areas were more active during match delays, and posterior parietal cortex and inferior frontal cortex were more active during nonmatch delays. Additionally, the fidelity of the memory was predicted by the delay-period activity of the frontal eye fields; the magnitude of delay-period activity correlated with the accuracy of the memory-guided saccade. Experimentally controlling response selection allowed us to functionally separate nodes of a network of frontal and parietal areas that usually coactivate in studies of working memory. We propose that different nodes in this network maintain different representational codes, motor and spatial. Which code is being represented by sustained neural activity is biased by when in the transformation from perception to action the response can be selected.

Curtis, CE, D’Esposito.  2003.  Success and failure suppressing reflexive behavior., 2003 Apr 1. Journal of cognitive neuroscience. 15:409-18. Abstractcurtis2003.pdf

The dynamic interplay between reflexive and controlled determinants of behavior is one of the most general organizing principles of brain function. A powerful analogue of this interplay is seen in the antisaccade task, which pits reflexive and willed saccadic mechanisms against one another. Event-related functional magnetic resonance imaging of the human brain showed greater prestimulus preparatory activity in the pre-supplementary motor area before voluntary antisaccades (saccades away from a target) compared with reflexive prosaccades (saccades to a target). Moreover, this preparatory activity was critically associated with reflex suppression; it predicted whether the reflex was later successfully inhibited in the trial. These dataillustrate a mechanism for top-down control over reflexive behavior.

Curtis, CE, D’Esposito.  2003.  Persistent activity in the prefrontal cortex during working memory., 2003 Sep. Trends in cognitive sciences. 7:415-423. Abstractcurtis_tics03.pdf

The dorsolateral prefrontal cortex (DLPFC) plays a crucial role in working memory. Notably, persistent activity in the DLPFC is often observed during the retention interval of delayed response tasks. The code carried by the persistent activity remains unclear, however. We critically evaluate how well recent findings from functional magnetic resonance imaging studies are compatible with current models of the role of the DLFPC in working memory. These new findings suggest that the DLPFC aids in the maintenance of information by directing attention to internal representations of sensory stimuli and motor plans that are stored in more posterior regions.

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, D’Esposito.  2004.  The effects of prefrontal lesions on working memory performance and theory., 2004 Dec. Cognitive, affective & behavioral neuroscience. 4:528-39. Abstractcurtis2005the_effects_of_prefrontal_lesions_on_working_memory_performance_and_theory.pdf

The effects of experimental lesions of the monkey prefrontal cortex have played a predominant role in current conceptualizations of the functional organization of the lateral prefrontal cortex, especially with regard to working memory. The loss or sparing of certain performance abilities has been shown to be attributable to differences in the specific requirements of behavioral testing (e.g., spatial vs. non-spatial memoranda) along with differences in the specific locations of applied ablations (e.g., dorsal vs. ventral prefrontal cortex). Such findings, which have accumulated now for over a century, have led to widespread acceptance that the dorsolateral and ventrolateral aspects of the prefrontal cortex may perform different, specialized roles in higher order cognition. Nonetheless, it remains unclear and controversial how the lateral prefrontal cortex is functionally organized. Two main views propose different types of functional specialization of the dorsal and ventral prefrontal cortex. The first contends that the lateral prefrontal cortex is segregated according to the processing of spatial and nonspatial domains of information. The second contends that domain specialization is not the key to the organization of the prefrontal cortex, but that instead, the dorsal and ventral prefrontal cortices perform qualitatively different operations. This report critically reviews all relevant monkey lesion studies that have served as the foundation for current theories regarding the functional organization of the prefrontal cortex. Our goals are to evaluate how well the existing lesion data support each theory and to enumerate caveats that must be considered when interpreting the relevant literature.

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.

Curtis, CE, Sun FT, Miller LM, D’Esposito.  2005.  Coherence between fMRI time-series distinguishes two spatial working memory networks., 2005 May 15. NeuroImage. 26:177-83. Abstractcurtis2005_coherence_between_fmri_time-series_distinguishes_two_spatial_working_memory_networks.pdf

Widespread and distributed brain regions are thought to form networks that together support working memory. We recently demonstrated that different cortical areas maintain relatively different codes across a memory delay (Curtis et. al., J Neurosci, 2004; 24:3944-3952). The frontal eye fields (FEF), for example, were more active during the delay when the direction of the memory-guided saccade was known compared to when it was not known throughout the delay. Other areas showed the opposite pattern. Despite these task-dependent differences in regional activity, we could only assume but not address the functional interactions between the identified nodes of the putative network. Here, we use a bivariate technique, coherence, to formally characterize functional interactions between a seed region and other brain areas. We find that the type of representational codes that are being maintained in working memory biases frontal-parietal interactions. For example, coherence between FEF and other oculomotor areas was greater when a motor representation was an efficient strategy to bridge the delay period. However, coherence between the FEF and higher-order heteromodal areas, e.g., dorsolateral prefrontal cortex, was greater when a sensory representation must be maintained in working memory.

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.

D'Esposito, M.  2000.  The neural basis of working memory: evidence from neuropsychological, pharmacological and neuroimaging studies. Neurobehavior of Language and Cognition: Studies of Normal Aging and Brain Damage. : Kluwer Academic Publishers Abstract


D'Esposito, M, Gazzaley A.  2005.  Neurorehabilitation of executive function. Textbook of Neural Repair and Rehabilitation. , Cambridge: Cambridge University Press Abstractdespositoneurorehab05.pdf


D'Esposito, M, Postle BR, Rypma B.  2002.  The role of lateral prefrontal cortex in working memory: evidence from event-related fMRI studies. Recent Advances in Human Brain Mapping. , New York: Elsevier Abstract


D'Esposito, M, Chen A.  2012.  Remediating frontal lobe dysfunction: from bench to bedside. The Oxford Handbook of Frontal Lobe Functions. , New York: Oxford University Press
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.  2008.  From cognitive to neural models of working memory. Mental Processes in the Human Brain. , Oxford, UK: Oxford University Press
D'Esposito, M, Postle BR.  2000.  Neural correlates of component processes of working memory: evidence from neuropsychological and pharmacological studies. Control of Cognitive Processes: Attention & Performance XVIII. Abstract


D'Esposito, M, Postle BR.  2002.  The organization of working memory function in lateral prefrontal cortex: evidence from event-related functional MRI. Principles of Frontal Lobe Function. , New York: Oxford University Press Abstract


D'Esposito, M, Kayser A, Chen A.  2009.  Functional MRI: applications in cognitive neuroscience. Functional MRI Techniques and Protocols. : Humana Press
D'Esposito, M.  2001.  Working memory. Handbook of Functional Neuroimaging of Cognition. , Cambridge: MIT Press Abstract


D'Esposito, M.  1997.  Specific stroke syndromes. Neurologic Rehabilitation: A Guide to Diagnosis, Prognosis, and Treatment Planning. , Cambridge: Blackwell Science Abstract


D'Esposito, M, Gazzaley A.  2011.  Can age-associated memory decline be treated?, 2011 Oct 6 The New England journal of medicine. 365(14):1346-7. Abstract2011_desposito_nejm.pdf


D'Esposito, M, Postle BR.  2014.  The Cognitive Neuroscience of Working Memory., 2014 Sep 19. Annual review of psychology. Abstract

For more than 50 years, psychologists and neuroscientists have recognized the importance of a working memory to coordinate processing when multiple goals are active and to guide behavior with information that is not present in the immediate environment. In recent years, psychological theory and cognitive neuroscience data have converged on the idea that information is encoded into working memory by allocating attention to internal representations, whether semantic long-term memory (e.g., letters, digits, words), sensory, or motoric. Thus, information-based multivariate analyses of human functional MRI data typically find evidence for the temporary representation of stimuli in regions that also process this information in non-working memory contexts. The prefrontal cortex (PFC), on the other hand, exerts control over behavior by biasing the salience of mnemonic representations and adjudicating among competing, context-dependent rules. The "control of the controller" emerges from a complex interplay between PFC and striatal circuits and ascending dopaminergic neuromodulatory signals. Expected final online publication date for the Annual Review of Psychology Volume 66 is November 30, 2014. Please see for revised estimates.

D'Esposito, M.  2000.  Post-concussive syndrome. Penn Neurology 2000: Management of Common Neurological Problems. Abstract


D'Esposito, M, Postle BR.  2002.  The neural basis of working memory storage, rehearsal and control processes: evidence from patient and functional MRI studies. Neuropsychology of Memory, 3rd edition. , New York: Guilford Abstract


D'Esposito, M, Kayser A, Chen A.  2011.  Functional MRI: cognitive neuroscience applications. Functional Neuroradiology: Principles and Clinical Applications. , Berlin: Springer-Verlag
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


Daffner, KR, Gale SA, Barrett AM, Boeve BF, Chatterjee A, Coslett BH, D'Esposito M, Finney GR, Gitelman DR, Hart JJ, Lerner AJ, Meador KJ, Pietras AC, Voeller KS, Kaufer DI.  2015.  Improving clinical cognitive testing: Report of the AAN Behavioral Neurology Section Workgroup., 2015 Jul 10. Neurology. Abstract

To evaluate the evidence basis of single-domain cognitive tests frequently used by behavioral neurologists in an effort to improve the quality of clinical cognitive assessment.

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.

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.

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.

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.

Detre, JA, Maccotta L, King D, Alsop D, Glosser G, D’Esposito, Zarahn E, Aguirre GK, French JA.  1998.  Functional MRI lateralization of memory in temporal lobe epilepsy., 1998 Apr. Neurology. 50:926-32. Abstract1998detre.pdf

OBJECTIVE: To determine the feasibility of using functional magnetic resonance imaging (fMRI) to detect asymmetries in the lateralization of memory activation in patients with temporal lobe epilepsy (TLE). BACKGROUND: Assessment of mesial temporal lobe function is a critical aspect of the preoperative evaluation for epilepsy surgery, both for predicting postoperative memory deficits and for seizure lateralization. fMRI offers several potential advantages over the current gold standard, intracarotid amobarbital testing (IAT). fMRI has already been successfully applied to language lateralization in TLE. METHODS: fMRI was carried out in eight normal subjects and 10 consecutively recruited patients with TLE undergoing preoperative evaluation for epilepsy surgery. A complex visual scene encoding task known to activate mesial temporal structures was used during fMRI. Asymmetry ratios for mesial temporal activation were calculated, using regions of interest defined in normals. Patient findings were compared with the results of IAT performed as part of routine clinical evaluation. RESULTS: Task activation was nearly symmetric in normal subjects, whereas in patients with TLE, significant asymmetries were observed. In all nine patients in whom the IAT result was interpretable, memory asymmetry by fMRI concurred with the findings of IAT including two patients with paradoxical IAT memory lateralization ipsilateral to seizure focus. CONCLUSIONS: fMRI can be used to detect asymmetries in memory activation in patients with TLE. Because fMRI studies are noninvasive and provide excellent spatial resolution for functional activation, these preliminary results suggest a promising role for fMRI in improving the preoperative evaluation for epilepsy surgery.

Druzgal, TJ, D’Esposito.  2001.  A neural network reflecting decisions about human faces., 2001 Dec 6. Neuron. 32:947-55. Abstractdruzgal2001.pdf

Anatomic structures have been linked to the mnemonic component of working memory, but the neural network underlying associated decision processes remains elusive. Here we present an event-related functional magnetic resonance imaging study that measured activity during the decision period of a delayed face recognition task. A double dissociation of activity between anterior cingulate cortex (ACC), and a network including left fusiform face area (FFA) and left dorsolateral prefrontal cortex (DLPFC), reflected whether a probe face matched the remembered face at the time of decision. Greater activity in the left FFA and left DLPFC correlated with probe faces that matched the remembered face; in contrast, activity in ACC was greater when the probe face did not match the remembered face. These results support a model where frontal regions act in concert with stimulus-specific temporal structures to make recognition decisions about visual stimuli.

Druzgal, TJ, D’Esposito.  2001.  Activity in fusiform face area modulated as a function of working memory load., 2001 Jan. Brain research. Cognitive brain research. 10:355-64. Abstractdruzgal.pdf

Previous fMRI results suggest that extrastriate visual areas have a predominant role in perceptual processing while the prefrontal cortex (PFC) has a predominant role in working memory. In contrast, single-unit recording studies in monkeys have demonstrated a relationship between extrastriate visual areas and visual working memory tasks. In this study we tested whether activity in both the PFC and fusiform face area (FFA) changed with increasing demands of an n-back task for gray-scale faces. Since stimulus presentation was identical across conditions, the n-back task allowed us to parametrically vary working memory demands across conditions while holding perceptual and motor demands constant. This study replicated the result of PFC areas of activation that increased directly with load n of the task. The novel finding in all subjects was FFA activation that also increased directly with load n of the task. Since perceptual demands were equivalent across the three task conditions, these findings suggest that activity in both the PFC and the FFA vary with face working memory demands.

Druzgal, TJ, D’Esposito.  2003.  Dissecting contributions of prefrontal cortex and fusiform face area to face working memory., 2003 Aug 15. Journal of cognitive neuroscience. 15:771-84. Abstract2003druzgal.pdf

Interactions between prefrontal cortex (PFC) and stimulus-specific visual cortical association areas are hypothesized to mediate visual working memory in behaving monkeys. To clarify the roles for homologous regions in humans, event-related fMRI was used to assess neural activity in PFC and fusiform face area (FFA) of subjects performing a delay-recognition task for faces. In both PFC and FFA, activity increased parametrically with memory load during encoding and maintenance of face stimuli, despite quantitative differences in the magnitude of activation. Moreover, timing differences in PFC and FFA activation during memory encoding and retrieval implied a context dependence in the flow of neural information. These results support existing neurophysiological models of visual working memory developed in the nonhuman primate.

D’Esposito, Aguirre GK, Zarahn E, Ballard D, Shin RK, Lease J.  1998.  Functional MRI studies of spatial and nonspatial working memory., 1998 Jul. Brain research. Cognitive brain research. 7:1-13. Abstract1998desposito.pdf

Single-unit recordings in monkeys have revealed neurons in the lateral prefrontal cortex that increase their firing during a delay between the presentation of information and its later use in behavior. Based on monkey lesion and neurophysiology studies, it has been proposed that a dorsal region of lateral prefrontal cortex is necessary for temporary storage of spatial information whereas a more ventral region is necessary for the maintenance of nonspatial information. Functional neuroimaging studies, however, have not clearly demonstrated such a division in humans. We present here an analysis of all reported human functional neuroimaging studies plotted onto a standardized brain. This analysis did not find evidence for a dorsal/ventral subdivision of prefrontal cortex depending on the type of material held in working memory, but a hemispheric organization was suggested (i.e., left-nonspatial; right-spatial). We also performed functional MRI studies in 16 normal subjects during two tasks designed to probe either nonspatial or spatial working memory, respectively. A group and subgroup analysis revealed similarly located activation in right middle frontal gyrus (Brodmann’s area 46) in both spatial and nonspatial [working memory-control] subtractions. Based on another model of prefrontal organization [M. Petrides, Frontal lobes and behavior, Cur. Opin. Neurobiol., 4 (1994) 207-211], a reconsideration of the previous imaging literature data suggested that a dorsal/ventral subdivision of prefrontal cortex may depend upon the type of processing performed upon the information held in working memory.

D’Esposito, Alexander M.  1995.  The clinical profiles, recovery and rehabilitation of memory disorders. Neurorehabilitation. Abstract