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D’Esposito.  1991.  The Pharmacology of Memory. Abstract


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


Rypma, B, D'Esposito M.  2001.  Age-related changes in brain-behavior relationships: evidence from event-related functional MRI studies. Ageing and Executive Control. , Hove, UK: Psychology Press
Gazzaley, A, D'Esposito M.  2005.  BOLD fMRI and cognitive aging. Cognitive Neuroscience of Aging. : Oxford University Press Abstract


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
Johnson, MK, Hayes SM, D'Esposito M, Raye CL.  2001.  Confabulation. Handbook of Neuropsychology (2nd edition, volume 2). , Amsterdam: Elsevier Abstract


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


Cools, R, D'Esposito M.  2009.  Dopaminergic modulation of flexible cognitive control in humans. Dopamine Handbook. , Oxford, UK: Oxford University Press
D’esposito, M.  2003.  Executive function and frontal systems. Neuropsychiatry. , Baltimore: Williams and Wilkins Abstract


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


D'Esposito, M.  2008.  From cognitive to neural models of working memory. Mental Processes in the Human Brain. , Oxford, UK: Oxford University Press
Kimberg, DY, D'Esposito M.  2000.  Frontal lobes II: cognitive issues. Patient-Based Approaches to Cognitive Neuroscience. : Kluwer Academic Publishers Abstract


Kimberg, DY, D'Esposito M.  1997.  The frontal lobes: cognitive neuropsychological aspects. Behavioral Neurology and Neuropsychology. : McGraw-Hill Abstract


Wittmann, B, D'Esposito M.  2012.  Functional magnetic resonance imaging. Handbook of Research Methods in Psychology. , Washington, DC: American Psychological Association
D'Esposito, M, Kayser A, Chen A.  2009.  Functional MRI: applications in cognitive neuroscience. Functional MRI Techniques and Protocols. : Humana Press
D’esposito, M.  2006.  Functional MRI: cognitive neuroscience applications. Functional MRI. , Berlin: Springer-Verlag Abstractdespocogfmri.pdf


D'Esposito, M, Kayser A, Chen A.  2011.  Functional MRI: cognitive neuroscience applications. Functional Neuroradiology: Principles and Clinical Applications. , Berlin: Springer-Verlag
Turner, G, D'Esposito M.  2011.  Functional neuroimaging of aging. Clinical Neurology of Aging, 3rd Edition. , Oxford: Oxford University Press
Curtis, CE, D'Esposito M.  2008.  The inhibition of unwanted actions. Psychology of Action, Vol. 2. , Oxford: Oxford University Press2008curtis.pdf
Buchsbaum, BR, D'Esposito M.  2009.  Is there anything special about working memory? Neuroimaging of Human Memory: Linking Cognitive Process to Neural Systems. , Oxford: Oxford University Press Abstract2009buchsbaum.pdf


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


Kayser, A, D'Esposito M.  2012.  Neurotechnologies. Encyclopedia of Human Behavior, 2nd Edition. , Oxford: Elsevier
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.  2000.  Post-concussive syndrome. Penn Neurology 2000: Management of Common Neurological Problems. Abstract


Grossman, M, Peltzer L, D'Esposito M, Alavi A, Reivich M.  1995.  Recovery of function after focal cerebral insult: a PET activation study. Neuropsychological Explorations of Memory and Cognition: Essays in Honor of Nelson Butters. , New York: Plenum Press 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, 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


Buchsbaum, BR, D'Esposito M.  2008.  Short term and working memory systems. Learning and Memory: A Comprehensive Reference. , Oxford: Elsevier2008buchsbaum1.pdf
D'Esposito, M.  1997.  Specific stroke syndromes. Neurologic Rehabilitation: A Guide to Diagnosis, Prognosis, and Treatment Planning. , Cambridge: Blackwell Science Abstract


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


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


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


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


D'Esposito, M.  2001.  Working memory. Handbook of Functional Neuroimaging of Cognition. , Cambridge: MIT Press Abstract


Buchsbaum, B, D'Esposito M.  2013.  Working memory. Oxford Handbook of Cognitive Neuroscience. , Oxford: Oxford University Press
Journal Article
Kayser, AS, D’esposito M.  2012.  Abstract Rule Learning: The Differential Effects of Lesions in Frontal Cortex., 2012 Jan 31. Cerebral cortex (New York, N.Y. : 1991). Abstract2012_kayser.pdf

Learning progressively more abstract stimulus-response mappings requires progressively more anterior regions of the lateral frontal cortex. Using an individual differences approach, we studied subjects with frontal lesions performing a hierarchical reinforcement-learning task to investigate how frontal cortex contributes to abstract rule learning. We predicted that subjects with lesions of the left pre-premotor (pre-PMd) cortex, a region implicated in abstract rule learning, would demonstrate impaired acquisition of second-order, as opposed to first-order, rules. We found that 4 subjects with such lesions did indeed demonstrate a second-order rule-learning impairment, but that these subjects nonetheless performed better than subjects with other frontal lesions in a second-order rule condition. This finding resulted from both their restricted exploration of the feature space and the task structure of this condition, for which they identified partially representative first-order rules. Significantly, across all subjects, suboptimal but above-chance performance in this condition correlated with increasing disconnection of left pre-PMd from the putative functional hierarchy, defined by reduced functional connectivity between left pre-PMd and adjacent nodes. These findings support the theory that activity within lateral frontal cortex shapes the search for relevant stimulus-response mappings, while emphasizing that the behavioral correlate of impairments depends critically on task structure.

Zorrilla, LT, Aguirre GK, Zarahn E, Cannon TD, D’Esposito.  1996.  Activation of the prefrontal cortex during judgments of recency: a functional MRI study., 1996 Nov 4. Neuroreport. 7:2803-6. Abstract

Animal and human lesion studies have consistently shown that damage to the prefrontal lobe disrupts performance on tasks requiring memory for temporal context. In this study, functional magnetic resonance imaging (fMRI) was used to explore the brain regions associated with judgements of relative recency in healthy humans. Bilateral dorsolateral prefrontal cortex (Brodmann’s area [BA] 9) was more active during a verbal recency judgment task than during a non-mnemonic control task. Activation related to temporal context recognition was also observed in midline supplementary motor area (BA 6) and left precuneus (BA 7). This study provides further evidence that memory for temporal context requires the prefrontal cortex and is the first to demonstrate this association in healthy humans. The current findings also suggest the possibility that recognition of context and recognition of episodic content may involve similar brain systems.

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.

Postle, BR, Berger JS, Taich AM, D’Esposito.  2000.  Activity in human frontal cortex associated with spatial working memory and saccadic behavior., 2000. Journal of cognitive neuroscience. 12 Suppl 2:2-14. Abstract

We examined, with event-related fMRI, two hypotheses about the organization of human working memory function in frontal cortex: (1) that a region immediately anterior to the frontal eye fields (FEF) (superior frontal cortex, SFC) is specialized for spatial working memory (Courtney, et al., 1998); and (2) that dorsolateral prefrontal cortex (PFC) plays a privileged role in the manipulation of spatial stimuli held in working memory (Owen, et al., 1996; Petrides 1994). Our delayed-response task featured 2-D arrays of irregularly arranged squares that were highlighted serially in a random sequence. The Forward Memory condition required maintenance of the spatio-temporal sequence, the Manipulate Memory condition required reordering this sequence into a new spatially defined order, the Guided Saccade condition required saccades to highlighted squares in the array, but no memory, and the Free Saccade condition required self-paced, horizontal saccades. The comparison of fMRI signal intensity associated with 2-D saccade generation (Guided Saccades) versus fMRI signal intensity associated with the delay period of the working memorials condition revealed no evidence for greater working memory-related activity than saccade-related activity in SFC in any individual subject, nor at the level of the group, and greater 2-D saccade than delay-period activity in three of five subjects. These results fail to support the hypothesis that spatial working memory-related activity is represented preferentially in a region of SFC anterior to the FEF (Courtney, et al., 1998). The comparison of maintenance versus manipulation of spatio-temporal information in working memory revealed significantly greater activity associated with the latter in dorsolateral PFC, but not in ventrolateral PFC or in SFC. These results suggest that the delay-related function of SFC is limited to the maintenance of spatial information, and that this region does not support the nonmnemonic executive control functions supported by dorsolateral PFC. These results also indicate that the preferential recruitment of dorsolateral PFC for the manipulation of information held in working memory applies to tasks employing spatial stimuli, as well as to tasks employing verbal stimuli (D’Esposito, et al., 1999); Petrides et al., 1993; Postle et al., 1999).

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

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

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

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

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

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

Mitchell, KJ, Johnson MK, Raye CL, Mather M, D’Esposito.  2000.  Aging and reflective processes of working memory: binding and test load deficits., 2000 Sep. Psychology and aging. 15:527-41. Abstract2000mitchell.pdf

It was hypothesized that age-related deficits in episodic memory for feature combinations (e.g., B. L. Chalfonte & M. K. Johnson, 1996) signal, in part, decrements in the efficacy of reflective component processes (e.g., M. K. Johnson, 1992) that support the short-term maintenance and manipulation of information during encoding (e.g., F. 1. M. Craik. R. G. Morris. & M. L. Gick, 1990; T. A. Salthouse, 1990). Consistent with this, age-related binding deficits in a working memory task were found in 2 experiments. Evidence for an age-related test load deficit was also found: Older adults had greater difficulty than young adults when tested on 2 features rather than 1, even when binding was not required. Thus, disruption of source memory in older adults may involve deficits in both encoding processes (binding deficits) and monitoring processes (difficulty accessing multiple features, evaluating them, or both).

Sadaghiani, S, Scheeringa R, Lehongre K, Morillon B, Giraud A-L, D'Esposito M, Kleinschmidt A.  2012.  Alpha-Band Phase Synchrony Is Related to Activity in the Fronto-Parietal Adaptive Control Network., 2012 Oct 10. The Journal of neuroscience : the official journal of the Society for Neuroscience. 32(41):14305-14310. Abstract2012_sadaghiani.pdf

Neural oscillations in the alpha band (8-12 Hz) are increasingly viewed as an active inhibitory mechanism that gates and controls sensory information processing as a function of cognitive relevance. Extending this view, phase synchronization of alpha oscillations across distant cortical regions could regulate integration of information. Here, we investigated whether such long-range cross-region coupling in the alpha band is intrinsically and selectively linked to activity in a distinct functionally specialized brain network. If so, this would provide new insight into the functional role of alpha band phase synchrony. We adapted the phase-locking value to assess fluctuations in synchrony that occur over time in ongoing activity. Concurrent EEG and functional magnetic resonance imaging (fMRI) were recorded during resting wakefulness in 26 human subjects. Fluctuations in global synchrony in the upper alpha band correlated positively with activity in several prefrontal and parietal regions (as measured by fMRI). fMRI intrinsic connectivity analysis confirmed that these regions correspond to the well known fronto-parietal (FP) network. Spectral correlations with this network's activity confirmed that no other frequency band showed equivalent results. This selective association supports an intrinsic relation between large-scale alpha phase synchrony and cognitive functions associated with the FP network. This network has been suggested to implement phasic aspects of top-down modulation such as initiation and change in moment-to-moment control. Mechanistically, long-range upper alpha band synchrony is well suited to support these functions. Complementing our previous findings that related alpha oscillation power to neural structures serving tonic control, the current findings link alpha phase synchrony to neural structures underpinning phasic control of alertness and task requirements.

D’Esposito, Deouell LY, Gazzaley A.  2003.  Alterations in the BOLD fMRI signal with ageing and disease: a challenge for neuroimaging., 2003 Nov. Nature reviews. Neuroscience. 4:863-72. Abstractdesposito_etal_nrn_2003.pdf


D’Esposito, Verfaellie M, Alexander M, Katz DI.  1995.  Amnesia following traumatic bilateral fornix transection., 1995 Aug. Neurology. 45:1546-50. Abstract1995desposito.pdf

There is controversy regarding the effect of isolated fornix damage on human memory. We report a patient who suffered a traumatic penetrating head injury that resulted in a significant and persistent anterograde amnesia. CT revealed a lesion that involved the region of the proximal, posterior portion of both fornices without evidence of damage to other hippocampal pathways or to other structures known to be critical for memory, such as the hippocampus, thalamus, or basal forebrain. The unique location of the lesion in this patient provides evidence supporting the role of isolated fornix lesions in amnesia.

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

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

Grossman, M, Mickanin J, Robinson KM, D’Esposito.  1996.  Anomaly judgments of subject-predicate relations in Alzheimer’s disease., 1996 Aug. Brain and language. 54:216-32. Abstract1996grossman.pdf

Claims that patients with probable Alzheimer’s disease (AD) have semantic memory difficulty have received equivocal support. A common assumption has been that defining or core information determines the truth value of word meaning on measures requiring semantic memory such as category membership judgments or confrontation naming, but this assumption may not be valid. In the present study, we assessed the comprehension of subject-predicate sentences independent of their truth value by asking AD patients to judge the coherence of statements such as "The tulip is tall" or "*The tulip is jealous." We found that AD patients are significantly more impaired than controls at judging the coherence of these simple subject-predicate sentences. Moreover, AD patients were more successful at judging the coherence of statements that contain attributes with a narrow scope of reference compared to attributes with a broad scope of reference. These findings support the hypothesis that AD patients have a semantic memory impairment and suggest a specific deficit processing the network of semantic relations underlying word meaning in semantic memory.

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

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

Wolfe, N, Babikian VL, Linn RT, Knoefel JE, D’Esposito, Albert ML.  1994.  Are multiple cerebral infarcts synergistic?, 1994 Feb Archives of neurology. 51:211-5. Abstract

OBJECTIVE: The goal of this study was to characterize the cumulative effects of multiple strokes on cognition. DESIGN: We conducted a prospective, longitudinal case study with neuropsychological, neurological, and radiological evaluations. SETTING: Research was conducted at the Boston (Mass) Veterans Administration Medical Center, Neurology Service, on successive inpatient hospital admissions. PATIENT: We followed up a 66-year-old right-handed man with multiple subcortical lacunae during a 3.5-year period during which he suffered two additional cortical infarctions. MAIN OUTCOME MEASURES: Each evaluation included approximately 3 hours of neuropsychological testing spanning a range of cognitive domains (attention, language, memory, visuospatial functions, response inhibition, and mental flexibility), full neurological examination, and computed tomographic scan. RESULTS: The patient’s stepwise cognitive decline was characterized by unexpected exacerbation of "frontal" neurobehavioral features following the occurrence of two posterior cortical lesions. At initial evaluation, the computed tomographic scan showed bilateral subcortical lacunae in basal ganglia and periventricular white matter, and symptoms included dysarthria and perseveration. The second evaluation, following a left posterior parietal lesion, revealed a range of new frontal features, including impulsivity, pull-to-stimulus, and difficulty shifting set. Following a subsequent right occipital infarct, further frontal lobe impairments emerged: forced grasp reflex and incontinence. CONCLUSIONS: We hypothesize that the cumulative effects of infarcts were synergistic. That is, the posterior cortical infarcts elicited frontal features that would not be expected from a simple sum of these lesions’ effects.

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.

McGlinchey-Berroth, R, Bullis DP, Milberg WP, Verfaellie M, Alexander M, D’Esposito.  1996.  Assessment of neglect reveals dissociable behavioral but not neuroanatomical subtypes., 1996 Sep. Journal of the International Neuropsychological Society : JINS. 2:441-51. Abstract

In the current study, we investigated whether standard assessment techniques of visuospatial neglect are sensitive to detecting dissociable subtypes. We administered a battery of tasks commonly used to detect the presence of visuospatial neglect to 120 patients with unilateral right hemisphere infarcts and, in most cases, performed a systematic analysis of their lesions to quantify and localize brain damage. Using a factor analysis, we discovered seven relatively independent constructs, three of which were specifically related to the presence of left hemispatial neglect: Left Attentional Processing, Line Bisection, and Word Reading. Impairments in two of these factors, Left Attentional Processing and Line Bisection, occurred together in most cases but also occurred independently in 38 cases. There were no cases in whom Word Reading was present without concomitant deficits in one or the other two factors. These three factors could not be distinguished neuroanatomically; that is, lesions were equally likely in the temporal/parietal cortex, dorsolateral frontal cortex, or in deep frontal structures. These data confirm the notion that hemispatial neglect is a complex and multifaceted disorder composed of cognitively independent processes. These processes, however, cannot be dissociated neuroanatomically based on currently available assessment techniques.

Novakovic-Agopian, T, Chen AJ-W, Rome S, Rossi A, Abrams G, Dʼesposito M, Turner G, McKim R, Muir J, Hills N, Kennedy C, Garfinkle J, Murphy M, Binder D, Castelli H.  2012.  Assessment of Subcomponents of Executive Functioning in Ecologically Valid Settings: The Goal Processing Scale., 2012 Oct 16. The Journal of head trauma rehabilitation. Abstract

OBJECTIVES:: To validate a new functional assessment tool, the Goal Processing Scale (GPS), and to apply it for testing for sources of dysfunction in patients with acquired brain injury. Determining which component processes of executive functioning underlie poor performance in complex, low-structure settings would be valuable for the assessment of deficits and for evaluating the effectiveness of treatments. PARTICIPANTS:: Nineteen individuals with chronic acquired brain injury (mean age = 41.4 years; chronicity: 6 months to 39 years). MAIN MEASURES:: Two functional assessment tasks: (1) GPS, which evaluates functional performance in the context of achieving a goal in a "real-world" setting, with rating scales measuring overall performance and 8 subdomains of executive functioning; (2) Multiple Errands Test, an unstructured assessment of ability to adhere to rules and complete multiple "real-world" tasks in a short time; and (3) a neuropsychological battery. RESULTS:: Intraclass correlation coefficients for 2 independent raters ranged from 0.75 to 0.98 for the GPS overall composite score and the subdomain scores. Performance on GPS overall and several subdomain scores correlated with performance on the Multiple Errands Test. Working memory and learning/memory neuropsychological measures predicted functional performance as measured using the GPS. DISCUSSION:: The GPS shows high interrater reliability, suggesting convergent validity with an established functional performance measure, and produces useful information regarding strengths and weaknesses in different subdomains of executive functioning. Working memory and learning/memory appear to be key determinants of goal-directed functioning for these individuals with brain injury.

Gratton, C, Sreenivasan KK, Silver MA, D'Esposito M.  2013.  Attention selectively modifies the representation of individual faces in the human brain., 2013 Apr 17. The Journal of neuroscience : the official journal of the Society for Neuroscience. 33(16):6979-89. Abstract2013_gratton.pdf

Attention modifies neural tuning for low-level features, but it is unclear how attention influences tuning for complex stimuli. We investigated this question in humans using fMRI and face stimuli. Participants were shown six faces (F1-F6) along a morph continuum, and selectivity was quantified by constructing tuning curves for individual voxels. Face-selective voxels exhibited greater responses to their preferred face than to nonpreferred faces, particularly in posterior face areas. Anterior face areas instead displayed tuning for face categories: voxels in these areas preferred either the first (F1-F3) or second (F4-F6) half of the morph continuum. Next, we examined the effects of attention on voxel tuning by having subjects direct attention to one of the superimposed images of F1 and F6. We found that attention selectively enhanced responses in voxels preferring the attended face. Together, our results demonstrate that single voxels carry information about individual faces and that the nature of this information varies across cortical face areas. Additionally, we found that attention selectively enhances these representations. Our findings suggest that attention may act via a unitary principle of selective enhancement of responses to both simple and complex stimuli across multiple stages of the visual hierarchy.

Postle, BR, Berger JS, Goldstein JH, Curtis CE, D’Esposito.  2001.  Behavioral and neurophysiological correlates of episodic coding, proactive interference, and list length effects in a running span verbal working memory task., 2001 Mar. Cognitive, affective & behavioral neuroscience. 1:10-21. Abstractpostle2001.pdf

Updating refers to (1) discarding items from, (2) repositioning items in, and (3) adding items to a running working memory span. Our behavioral and fMRI experiments varied three factors: trial length, proactive interference (PI), and group integrity. Group integrity reflected whether the grouping of items at the encoding stage was violated at discarding. Behavioral results were consistent with the idea that updating processes have a relatively short refractory period and may not fatigue, and they revealed that episodic information about group context is encoded automatically in working memory stimulus representations. The fMRI results did not show evidence that updating requirements in a task recruit executive control processes other than those supporting performance on nonupdating trials. They did reveal an item-accumulation effect, in which signal increased monotonically with the number of items presented during the trial, despite the insensitivity of behavioral measures to this factor. Behavioral and fMRI correlates of PI extended previous results and rejected an alternative explanation of PI effects in working memory.

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

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

D’Esposito, Weksler ME.  2000.  Brain aging and memory: new findings help differentiate forgetfulness and dementia., 2000 Jun. Geriatrics. 55:55-8,61-2. Abstract

Geriatrics is pleased to highlight the clinical implications of research topics supported by the American Federation for Aging Research (AFAR). AFAR is a leading private organization supporting research on the aging process and diseases of older populations. More than 900 physicians, scientists, and students have received AFAR grants totaling more than $20 million since AFAR was founded by Irving S. Wright, MD, in 1981. The articles in the New Frontiers series are designed to provide primary care physicians with insight into the pathogenesis, diagnosis, prevention, and treatment of the diseases of aging.

Adnan, A, Chen AJW, Novakovic-Agopian T, D'Esposito M, Turner GR.  2017.  Brain Changes Following Executive Control Training in Older Adults., 2017 Sep 01. Neurorehabilitation and neural repair. :1545968317728580. Abstract

While older adults are able to attend to goal-relevant information, the capacity to ignore irrelevant or distracting information declines with advancing age. This decline in selective attention has been associated with poor modulation of brain activity in sensory cortices by anterior brain regions implicated in cognitive control.

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

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

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


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.

Robinson, KM, Grossman M, White-Devine T, D’Esposito.  1996.  Category-specific difficulty naming with verbs in Alzheimer’s disease., 1996 Jul. Neurology. 47:178-82. Abstract1996robinson.pdf

We studied 20 patients with Alzheimer’s disease (AD) on a picture-naming task consisting of frequency-matched pairs of nouns and verbs that were homophonic and homographic (e.g., paint). Intragroup comparisons revealed that verb naming is significantly more difficult for patients with AD than noun naming. An error analysis demonstrated that patients with AD produce significantly more semantic and descriptive errors for verbs than nouns. We correlated verb naming and noun naming with measures of grammatical comprehension, lexical retrieval, and visuoperceptual processing, but there were no selective effects for verbs compared with nouns. Differences in the mental representation of concepts underlying verbs and nouns may account, in part, for the relative difficulty naming with verbs in AD.

Ranganath, C, DeGutis J, D’Esposito.  2004.  Category-specific modulation of inferior temporal activity during working memory encoding and maintenance., 2004 Jun. Brain research. Cognitive brain research. 20:37-45. Abstract2004ranganath_cognitivebrainresearch.pdf

Findings from neurophysiology have supported the view that visual working memory (WM) relies on modulation of activity in object-selective populations of neurons in inferior temporal cortex. Here, using event-related functional magnetic resonance imaging, we investigated whether similar mechanisms support human visual working memory encoding and maintenance processes. We identified regions in inferior temporal cortex that exhibited category-specific responses during perception of faces (fusiform face area [FFA]) or scenes (parahippocampal place area [PPA]) and investigated whether activity in these regions would be modulated by demands to actively encode and maintain faces and scenes. Results showed that independent of perceptual stimulation, the FFA and PPA exhibited greater encoding- and maintenance-related activity when their favored stimulus was relevant to the recognition task. In contrast, maintenance-related activity in the dorsolateral prefrontal cortex (PFC) was modulated by memory load, regardless of the type of information that was task relevant. These results are consistent with the view that visual working memory encoding and maintenance processes are implemented through modulation of inferior temporal activity by prefrontal cortex.

Rahnev, D, Nee DE, Riddle J, Larson AS, D'Esposito M.  2016.  Causal evidence for frontal cortex organization for perceptual decision making., 2016 May 9. Proceedings of the National Academy of Sciences of the United States of America. Abstract

Although recent research has shown that the frontal cortex has a critical role in perceptual decision making, an overarching theory of frontal functional organization for perception has yet to emerge. Perceptual decision making is temporally organized such that it requires the processes of selection, criterion setting, and evaluation. We hypothesized that exploring this temporal structure would reveal a large-scale frontal organization for perception. A causal intervention with transcranial magnetic stimulation revealed clear specialization along the rostrocaudal axis such that the control of successive stages of perceptual decision making was selectively affected by perturbation of successively rostral areas. Simulations with a dynamic model of decision making suggested distinct computational contributions of each region. Finally, the emergent frontal gradient was further corroborated by functional MRI. These causal results provide an organizational principle for the role of frontal cortex in the control of perceptual decision making and suggest specific mechanistic contributions for its different subregions.

Nee, DE, D'Esposito M.  2017.  Causal evidence for lateral prefrontal cortex dynamics supporting cognitive control., 2017 Sep 13. eLife. 6 Abstract

The lateral prefrontal cortex (LPFC) is essential for higher-level cognition, but how its interactions support cognitive control remains elusive. Previously (Nee and D'Esposito, 2016), dynamic causal modeling (DCM) indicated that mid LPFC integrates abstract, rostral and concrete, caudal influences to inform context-appropriate action. Here, we use continuous theta-burst transcranial magnetic stimulation (cTBS) to causally test this model. cTBS was applied to three LPFC sites and a control site in counterbalanced sessions. Behavioral modulations resulting from cTBS were largely predicted by information flow within the previously estimated DCM. However, cTBS to caudal LPFC unexpectedly impaired processes presumed to involve rostral LPFC. Adding a pathway from caudal to mid-rostral LPFC significantly improved the model fit and accounted for the observed behavioral findings. These data provide causal evidence for LPFC dynamics supporting cognitive control and demonstrate the utility of combining DCM with causal manipulations to test and refine models of cognition.

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.

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

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

Gratton, C, Yousef S, Aarts E, Wallace DL, D'Esposito M, Silver MA.  2017.  Cholinergic, but not dopaminergic or noradrenergic, enhancement sharpens visual spatial perception in humans., 2017 Mar 23. The Journal of neuroscience : the official journal of the Society for Neuroscience. Abstract

The neuromodulator acetylcholine (ACh) modulates spatial integration in visual cortex by altering the balance of inputs that generate neuronal receptive fields. These cholinergic effects may provide a neurobiological mechanism underlying the modulation of visual representations by visual spatial attention. However, the consequences of cholinergic enhancement on visuospatial perception in humans are unknown. We conducted two experiments to test whether enhancing cholinergic signaling selectively alters perceptual measures of visuospatial interactions in human subjects. In Experiment 1, a double-blind placebo-controlled pharmacology study, we measured how flanking distractors influenced detection of a small contrast decrement of a peripheral target, as a function of target/flanker distance. We found that cholinergic enhancement with the cholinesterase inhibitor donepezil improved target detection, and modeling suggested that this was mainly due to a narrowing of the extent of facilitatory perceptual spatial interactions. In Experiment 2, we tested whether these effects were selective to the cholinergic system or would also be observed following enhancements of related neuromodulators dopamine (DA) or norepinephrine (NE). Unlike cholinergic enhancement, DA (bromocriptine) and NE (guanfacine) manipulations did not improve performance or systematically alter the spatial profile of perceptual interactions between targets and distractors. These findings reveal mechanisms by which cholinergic signaling influences visual spatial interactions in perception and improves processing of a visual target among distractors - effects that are notably similar to those of spatial selective attention.Significance StatementAcetylcholine influences how visual cortical neurons integrate signals across space - perhaps providing a neurobiological mechanism for the effects of visual selective attention. However, the influence of cholinergic enhancement on visuospatial perception remains unknown. Here we demonstrate that cholinergic enhancement improves detection of a target flanked by distractors, consistent with sharpened visuospatial perceptual representations. Furthermore, while most pharmacological studies focus on a single neurotransmitter, many neuromodulators can have related effects on cognition and perception. Thus, we also demonstrate that enhancing noradrenergic and dopaminergic systems does not systematically improve visuospatial perception or alter its tuning. Our results link visuospatial tuning effects of acetylcholine at the neuronal and perceptual levels and provide insights into the connection between cholinergic signaling and visual attention.

Grossman, M, Galetta S, Ding X-S, Morrison D, D’Esposito, Robinson K, Jaggi J, Alavi A, Reivich M.  1996.  Clinical and positron emission tomography studies of visual apperceptive agnosia. Neuropsychiatry, Neuropsychology & Behavioral Neurology. AbstractWebsite


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


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.

D’Esposito.  1999.  Cognitive aging: new answers to old questions., 1999 Dec 16-30. Current biology : CB. 9:R939-41. Abstract1999desposito.pdf

The use of techniques for functional brain imaging is beginning to provide insights into the psychological and neural mechanisms that underlie age-related changes in cognitive performance.

Kounios, J, Smith RW, Yang W, Bachman P, D’Esposito.  2001.  Cognitive association formation in human memory revealed by spatiotemporal brain imaging., 2001 Jan. Neuron. 29:297-306. Abstractkounios2001.pdf

Cognitive theory posits association by juxtaposition or by fusion. We employed the measurement of event-related brain potentials (ERPs) to a concept fusion task in order to explore memory encoding of these two types of associations between word pairs, followed by a memory test for original pair order. Encoding processes were isolated by subtracting fusion task ERPs corresponding to pairs later retrieved quickly from ERPs corresponding to pairs later retrieved slowly, separately for pairs fused successfully and unsuccessfully (i.e., juxtaposed). Analyses revealed that the encoding of these two types of associations yields different ERP voltage polarities, scalp topographies, and brain sources extending over the entire time course of processing.

Kimberg, DY, D’Esposito.  2003.  Cognitive effects of the dopamine receptor agonist pergolide., 2003. Neuropsychologia. 41:1020-7. Abstractkimberg2003.pdf

Although dopamine has been closely associated with prefrontal function, and with working memory in monkeys, the effects of dopamine agonists on human cognitive performance are poorly understood. We report the effects of a single dose of pergolide on young healthy subjects performing a variety of cognitive tests, including tests of memory and of frontal/executive function. Across this battery of tasks, the only tasks reliably affected by pergolide were delayed response tasks. Across four variants, we observed that the effect of pergolide was more beneficial for subjects with greater working memory capacities. We discuss this in light of the variable results obtained from previous studies of dopamine agonists in human subjects.

Kimberg, DY, D’Esposito.  1997.  Cognitive functions in the prefrontal cortex: working memory and executive control. Current Directions in Psychological Science. Abstract1997kimberg.pdfWebsite


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.

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.

Kroll, NEA, Knight RT, Metcalfed E, Wolfe ES, Tulving E.  1996.  Cohesion failure as a source of memory illusions. Journal of Memory and Language. Abstract1996kroll.pdf


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

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

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.

Rahnev, D, Koizumi A, McCurdy LY, D'Esposito M, Lau H.  2015.  Confidence Leak in Perceptual Decision Making., 2015 Sep 25. Psychological science. Abstract

People live in a continuous environment in which the visual scene changes on a slow timescale. It has been shown that to exploit such environmental stability, the brain creates a continuity field in which objects seen seconds ago influence the perception of current objects. What is unknown is whether a similar mechanism exists at the level of metacognitive representations. In three experiments, we demonstrated a robust intertask confidence leak-that is, confidence in one's response on a given task or trial influencing confidence on the following task or trial. This confidence leak could not be explained by response priming or attentional fluctuations. Better ability to modulate confidence leak predicted higher capacity for metacognition as well as greater gray matter volume in the prefrontal cortex. A model based on normative principles from Bayesian inference explained the results by postulating that observers subjectively estimate the perceptual signal strength in a stable environment. These results point to the existence of a novel metacognitive mechanism mediated by regions in the prefrontal cortex.

Grossman, M, Payer F, Onishi K, White-Devine T, Morrison D, D’Esposito, Robinson K, Alavi A.  1997.  Constraints on the cerebral basis for semantic processing from neuroimaging studies of Alzheimer’s disease., 1997 Aug. Journal of neurology, neurosurgery, and psychiatry. 63:152-8. Abstract1997grossman2.pdf

OBJECTIVE: Functional activation studies of semantic processing in healthy adults have yielded conflicting results. The purpose was to evaluate the relative role of the brain regions implicated in semantic processing with converging evidence from imaging studies of patients with impaired semantic processing. METHODS: Semantic memory was assessed in patients with Alzheimer’s disease using two measures, and these performance patterns were related to profiles of reduced cerebral functioning obtained with high resolution single photon emission computed tomography (SPECT). Patients with frontotemporal degeneration were similarly evaluated as a control group. RESULTS: Reduced relative cerebral perfusion was seen in parietal and posterior temporal brain regions of patients with Alzheimer’s disease but not patients with frontotemporal degeneration. Impairments on semantically guided category membership decision tasks were also seen in patients with Alzheimer’s disease but not those with frontotemporal degeneration. Performance on the semantic measures correlated with relative cerebral perfusion in inferior parietal and superior temporal regions of the left hemisphere only in Alzheimer’s disease. Relative perfusion was significantly lower in these regions in patients with Alzheimer’s disease with semantic difficulty compared with patients with Alzheimer’s disease with relatively preserved semantic processing. CONCLUSION: These findings provide converging evidence to support the contribution of superior temporal and inferior parietal regions of the left hemisphere to semantic processing.

Handwerker, DA, Gonzalez-Castillo J, D'Esposito M, Bandettini PA.  2012.  The continuing challenge of understanding and modeling hemodynamic variation in fMRI., 2012 Feb 14. NeuroImage. Abstract2012_handwerker.pdf

Interpretation of fMRI data depends on our ability to understand or model the shape of the hemodynamic response (HR) to a neural event. Although the HR has been studied almost since the beginning of fMRI, we are still far from having robust methods to account for the full range of known HR variation in typical fMRI analyses. This paper reviews how the authors and others contributed to our understanding of HR variation. We present an overview of studies that describe HR variation across voxels, healthy volunteers, populations, and dietary or pharmaceutical modulations. We also describe efforts to minimize the effects of HR variation in intrasubject, group, population, and connectivity analyses and the limits of these methods.

Gazzaley, A, D’Esposito.  2003.  The contribution of functional brain imaging to our understanding of cognitive aging., 2003 Jan 29. Science of aging knowledge environment : SAGE KE. 2003:PE2. Abstract

The study of cognitive aging seeks to determine the psychological and neural mechanisms underlying age-related decline in cognitive performance. New methods in functional brain imaging are beginning to provide possible answers to questions regarding age-related cognitive decline.

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.

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.

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

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

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.

D’Esposito, Postle BR.  1999.  The dependence of span and delayed-response performance on prefrontal cortex., 1999 Oct. Neuropsychologia. 37:1303-15. Abstractdependence.pdf

Theoretical and empirical research on the cognitive functions of the prefrontal cortex have established that this region mediates what have been called ’executive’ processes that can influence working and long-term memory. Despite the accumulation of such empirical evidence, the dependence of purely mnemonic portions of memory tasks on PFC remains unresolved. To address this issue, we performed an analysis of reports of performance on tests of working memory of patients with lesions of the dorsolateral prefrontal cortex, focusing on published reports in the literature of simple span and delayed-response tasks. We found that none of the eleven studies of forward verbal and spatial span in patients with prefrontal cortical lesions that we reviewed (reflecting the performance of 166 individual patients) demonstrated a statistically significant deficit relative to normal controls. In contrast, our review of the delayed-response literature indicated that there are conditions under which PFC lesions disrupt delayed-response performance. Based on the results of our review of the literature, we present testable hypotheses about the working memory functions of the PFC.

McDowell, S, Whyte J, D’Esposito.  1998.  Differential effect of a dopaminergic agonist on prefrontal function in traumatic brain injury patients., 1998 Jun. Brain : a journal of neurology. 121 ( Pt 6):1155-64. Abstractdifferential.pdf

We examined the effects of low-dose bromocriptine, a D2 dopamine receptor agonist, on processes thought to be subserved by the prefrontal cortex, including working memory and executive function, in individuals with traumatic brain injury. A group of 24 subjects was tested using a double-blind, placebo-controlled crossover trial, counterbalanced for order. Bromocriptine was found to improve performance on some tasks thought to be subserved by prefrontal function, but not others. Specifically, there was improvement in performance on clinical measures of executive function and in dual-task performance, but not measures that tap the ability to maintain information in working memory without significant executive demands. Also, on control tasks not thought to be dependent on the prefrontal cortex, no improvement on bromocriptine was noted. These results demonstrate a selective effect of bromocriptine on cognitive processes which involve executive control, and provide a foundation for potential therapies for patients with prefrontal damage causing dysexecutive syndromes.

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

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

Ranganath, C, D’Esposito.  2005.  Directing the mind’s eye: prefrontal, inferior and medial temporal mechanisms for visual working memory., 2005 Apr. Current opinion in neurobiology. 15:175-82. Abstractr0bckq4.pdf

Human and nonhuman primates have a remarkable ability to recall, maintain and manipulate visual images in the absence of external sensory stimulation. Evidence from lesion, single-unit neurophysiological and neuroimaging studies shows that these visual working memory processes are consistently associated with sustained activity in object-selective inferior temporal neurons. Furthermore, results from these studies suggest that mnemonic activity in the inferior temporal cortex is, in turn, supported by top-down inputs from multimodal regions in prefrontal and medial temporal cortex, and under some circumstances, from the hippocampus.

Lee, TG, Blumenfeld RS, D'Esposito M.  2013.  Disruption of dorsolateral but not ventrolateral prefrontal cortex improves unconscious perceptual memories., 2013 Aug 7. The Journal of neuroscience : the official journal of the Society for Neuroscience. 33(32):13233-7. Abstract2013_lee.pdf

Attentive encoding often leads to more accurate responses in recognition memory tests. However, previous studies have described conditions under which taxing explicit memory resources by attentional distraction improved perceptual recognition memory without awareness. These findings lead to the hypothesis that explicit memory processes mediated by the prefrontal cortex (PFC) can interfere with memory processes necessary for implicit recognition memory. The present study directly tested this hypothesis by applying transcranial magnetic stimulation separately over either dorsolateral (DLPFC) or ventrolateral PFC (VLPFC) in humans before performance of a visual memory task. Disruption of DLPFC function led to improvement in recognition accuracy only in responses in which the participant's awareness of memory retrieval was absent. However, disruption of VLPFC function led to subtle shifts in recollection and familiarity accuracy. We conclude that explicit memory processes mediated by the DLPFC can indirectly interfere with implicit recognition memory.

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, McGlinchey-Berroth R, Alexander M, Verfaellie M, Milberg WP.  1993.  Dissociable cognitive and neural mechanisms of unilateral visual neglect., 1993 Dec. Neurology. 43:2638-44. Abstract

We administered two experimental tasks to 16 patients with neglect following unilateral right hemisphere strokes, designed to probe processing of information in the neglected left visual field. A semantic priming/lexical decision task examined implicit processing of stimuli presented to the neglected field, and a discrimination task required explicit recognition of the same stimuli. We grouped patients according to three patterns of performance: (1) poor discrimination in the left visual field but intact priming, (2) normal priming and discrimination in both fields, and (3) normal priming but poor discrimination in both fields. Although patients in group 1 had posterior lesions, patients in groups 2 and 3 had extensive deep anterior lesions. These results suggest that the clinical phenomenon of unilateral visual neglect can be the surface manifestation of deficits in two different and interacting processes–attentional processes (group 1) and intentional processes (group 2)–or it may be a global attentional disturbance superimposed on these deficits (group 3).

Ranganath, C, Yonelinas AP, Cohen MX, Dy CJ, Tom SM, D’Esposito.  2004.  Dissociable correlates of recollection and familiarity within the medial temporal lobes., 2004. Neuropsychologia. 42:2-13. Abstractranganath_etal_neuropsychol_2004.pdf

Regions in the medial temporal lobes (MTL) have long been implicated in the formation of new memories for events, however, it is unclear whether different MTL subregions support different memory processes. Here, we used event-related functional magnetic resonance imaging (fMRI) to examine the degree to which two recognition memory processes-recollection and familiarity-were supported by different MTL subregions. Results showed that encoding activity in the rhinal cortex selectively predicted familiarity-based recognition, whereas, activity in the hippocampus and posterior parahippocampal cortex selectively predicted recollection. Collectively, these results support the view that different subregions within the MTL memory system implement unique encoding processes that differentially support familiarity and recollection.