Publications

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

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Book Chapter
Boettiger, CA, D'Esposito M.  2006.  Addiction. Encyclopedia of the Brain and Learning. : Greenwood Publishing Group Abstract2006_boettiger.pdf

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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

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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
Kiyonaga, A, D'Esposito M.  2020.  Competition and Control During Working Memory. Elements in Perception. : Cambridge University Press2020_kiyonaga.pdf
Johnson, MK, Hayes SM, D'Esposito M, Raye CL.  2001.  Confabulation. Handbook of Neuropsychology (2nd edition, volume 2). , Amsterdam: Elsevier Abstract

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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 Abstract2007_gazzaley4.pdf

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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

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

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D'Esposito, M.  2008.  From cognitive to neural models of working memory. Mental Processes in the Human Brain. , Oxford, UK: Oxford University Press
Gazzaley, A, Lee TG, D'Esposito M.  2017.  The Frontal Lobes and Executive Control. The Human Frontal Lobes, 3rd Edition. , New York: Guilford Publications
Kimberg, DY, D'Esposito M.  2000.  Frontal lobes II: cognitive issues. Patient-Based Approaches to Cognitive Neuroscience. : Kluwer Academic Publishers Abstract

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

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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, Kayser AS, Chen AJ-W.  2016.  Functional MRI: Applications in Cognitive Neuroscience. Functional MRI Techniques and Protocols, 2nd Edition. , New York: Springer
D’esposito, M.  2006.  Functional MRI: cognitive neuroscience applications. Functional MRI. , Berlin: Springer-Verlag Abstract2006_despo_cogfmri.pdf

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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, Sreenivasan KK, Kayser A.  2015.  Functional MRI: Cognitive Neuroscience Applications. FMRI: From Nuclear Spins to Brain Function. , New York: Springer
Turner, G, D'Esposito M.  2011.  Functional neuroimaging of aging. Clinical Neurology of Aging, 3rd Edition. , Oxford: Oxford University Press
Cole, MA, Soda CN, D'Esposito M.  2016.  History of Functional Brain Imaging. The Oxford Handbook of the History of Clinical Neuropsychology. , Oxford, UK: Oxford University Press
Curtis, CE, D'Esposito M.  2008.  The inhibition of unwanted actions. Psychology of Action, Vol. 2. , Oxford: Oxford University Press2008_curtis.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 Abstract2009_buchsbaum.pdf

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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

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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

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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

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D'Esposito, M, Gazzaley A.  2005.  Neurorehabilitation of executive function. Textbook of Neural Repair and Rehabilitation. , Cambridge: Cambridge University Press Abstract2005_desposito_neurorehab.pdf

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Turner, GR, D'Esposito M.  2014.  Neurorehabilitation of Executive Functions. . Textbook of Neural Repair and Rehabilitation. , Cambridge, UK: Cambridge University Press
Kayser, A, D'Esposito M.  2012.  Neurotechnologies. Encyclopedia of Human Behavior, 2nd Edition. , Oxford: Elsevier
Kayser, AS, D'Esposito M.  2017.  Neurotechnologies. Reference Module in Neuroscience and Biobehavioral Psychology. , Oxford, UK: 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

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Chen, AJ-W, D'Esposito M.  2015.  Plasticity in prefrontal cortical networks after brain injury: finding the optimal paths. Cognitive Plasticity in Neurological Disorders. , Oxford, UK: Oxford University Press
D'Esposito, M.  2000.  Post-concussive syndrome. Penn Neurology 2000: Management of Common Neurological Problems. Abstract

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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

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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

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Buchsbaum, BR, D'Esposito M.  2017.  Short Term and Working Memory. Learning and Memory: A Comprehensive Reference, 2nd Edition. , Oxford, UK: Academic Press
Buchsbaum, BR, D'Esposito M.  2008.  Short term and working memory systems. Learning and Memory: A Comprehensive Reference. , Oxford: Elsevier2008_buchsbaum.pdf
D'Esposito, M.  1997.  Specific stroke syndromes. Neurologic Rehabilitation: A Guide to Diagnosis, Prognosis, and Treatment Planning. , Cambridge: Blackwell Science Abstract

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Gazzaley, A, D'Esposito M.  2007.  Top-down modulation in visual working memory. Working Memory: Behavioral and Neural Correlates. : Oxford University Press Abstract2007_gazzaley5.pdf

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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 Abstract2006_gazzaley_topdown.pdf

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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 Abstract2010_desposito.pdf

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Curtis, CE, D'Esposito M.  2006.  Working Memory. Handbook of Functional Neuroimaging of Cognition (2nd Edition). , Cambridge: MIT Press Abstract2006_curtis.pdf

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

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Buchsbaum, B, D'Esposito M.  2013.  Working memory. Oxford Handbook of Cognitive Neuroscience. , Oxford: Oxford University Press
Nee, DE, D'Esposito M.  2015.  Working Memory. Brain Mapping: An Encyclopedic Reference. : Academic Press: Elsevier
Nee, DE, D'Esposito M.  2018.  Working memory: An evolving concept. The Stevens' Handbook of Experimental Psychology and Cognitive Neuroscience, 4th Edition. : John Wiley and Sons
Conference Proceedings
Millman, J, D'Esposito M.  2006.  Data and Analysis Management for Functional Magnetic Resonance Imaging Studies. 2nd International Advanced Database Conference. :24-28.: US Education Service
Journal Article
Kayser, AS, D’esposito M.  2012.  Abstract Rule Learning: The Differential Effects of Lesions in Frontal Cortex., 2012 Jan 31. Cerebral Cortex. 23(1):230-240. 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(15-17):2803-2806. Abstract1996_zorrilla.pdf

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(3):355-364. Abstract2001_druzgal.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. Abstract2000_postle_jocn.pdf

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(6):717-757. Abstract2009_vanboven.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(5):532-539. Abstract2007_gazzaley_np.pdf

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(35):13122-6. Abstract2008_gazzaley.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(3):527-541. Abstract2000_mitchell.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. Journal of 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(11):863-872. Abstract2003_desposito.pdf

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D’Esposito, Verfaellie M, Alexander M, Katz DI.  1995.  Amnesia following traumatic bilateral fornix transection., 1995 Aug. Neurology. 45(8):1546-1550. Abstract1995_desposito.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. Journal of Neuroscience. 26(35):8915-8922. Abstract2006_hooker.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(2):216-232. Abstract1996_grossman.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. Abstract2014_vytlacil.pdf

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.

D'Esposito, M.  2019.  Are individual differences in human brain organization measured with functional MRI meaningful?, 2019 Oct 16 Proceedings of the National Academy of Sciences of the United States of America. 116(45):22432-22434.2019_despo_pnas.pdf
Wolfe, N, Babikian VL, Linn RT, Knoefel JE, D’Esposito, Albert ML.  1994.  Are multiple cerebral infarcts synergistic?, 1994 Feb Archives of Neurology. 51(2):211-215. Abstract1994_wolfe.pdf

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(2):373-383. Abstract1998_aguirre_neuron.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. 2(5):441-451. Abstract1996_mcglinchey_jins.pdf

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. Journal of Head Trauma Rehabilitation. 29(2):136-146. Abstract2012_novakovic.pdf

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. Journal of Neuroscience. 33(16):6979-6989. 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(1):10-21. Abstract2001_postle.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(2):140-146. Abstract2009_rajah.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(6):55-58,61-62. Abstract2000_despo.pdf

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. 31(10-11):910–922. Abstract2017_adnan.pdf

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.

Gallen, CL, D'Esposito M.  2019.  Brain Modularity: A Biomarker of Intervention-related Plasticity., 2019 Feb 27. Trends in Cognitive Sciences. 23(4):293-304. Abstract2019_gallen.pdf

Interventions using methods such as cognitive training and aerobic exercise have shown potential to enhance cognitive abilities. However, there is often pronounced individual variability in the magnitude of these gains. Here, we propose that brain network modularity, a measure of brain subnetwork segregation, is a unifying biomarker of intervention-related plasticity. We present work from multiple independent studies demonstrating that individual differences in baseline brain modularity predict gains in cognitive control functions across several populations and interventions, spanning healthy adults to patients with clinical deficits and cognitive training to aerobic exercise. We believe that this predictive framework provides a foundation for developing targeted, personalized interventions to improve cognition.

Baniqued, PL, Gallen CL, Kranz MB, Kramer AF, D'Esposito M.  2019.  Brain network modularity predicts cognitive training-related gains in young adults., 2019 May 24. Neuropsychologia. 131:205-215. Abstract2019_baniqued.pdf

The brain operates via networked activity in separable groups of regions called modules. The quantification of modularity compares the number of connections within and between modules, with high modularity indicating greater segregation, or dense connections within sub-networks and sparse connections between sub-networks. Previous work has demonstrated that baseline brain network modularity predicts executive function outcomes in older adults and patients with traumatic brain injury after cognitive and exercise interventions. In healthy young adults, however, the functional significance of brain modularity in predicting training-related cognitive improvements is not fully understood. Here, we quantified brain network modularity in young adults who underwent cognitive training with casual video games that engaged working memory and reasoning processes. Network modularity assessed at baseline was positively correlated with training-related improvements on untrained tasks. The relationship between baseline modularity and training gain was especially evident in initially lower performing individuals and was not present in a group of control participants that did not show training-related gains. These results suggest that a more modular brain network organization may allow for greater training responsiveness. On a broader scale, these findings suggest that, particularly in low-performing individuals, global network properties can capture aspects of brain function that are important in understanding individual differences in learning.

Baniqued, PL, Gallen CL, Voss MW, Burzynska AZ, Wong CN, Cooke GE, Duffy K, Fanning J, Ehlers DK, Salerno EA, Aguiñaga S, McAuley E, Kramer AF, D'Esposito M.  2017.  Brain Network Modularity Predicts Exercise-Related Executive Function Gains in Older Adults., 2017. Frontiers in Aging Neuroscience. 9:426. Abstract2017_baniqued.pdf

Recent work suggests that the brain can be conceptualized as a network comprised of groups of sub-networks or modules. The extent of segregation between modules can be quantified with a modularity metric, where networks with high modularity have dense connections within modules and sparser connections between modules. Previous work has shown that higher modularity predicts greater improvements after cognitive training in patients with traumatic brain injury and in healthy older and young adults. It is not known, however, whether modularity can also predict cognitive gains after a physical exercise intervention. Here, we quantified modularity in older adults (N = 128, mean age = 64.74) who underwent one of the following interventions for 6 months (NCT01472744 on ClinicalTrials.gov): (1) aerobic exercise in the form of brisk walking (Walk), (2) aerobic exercise in the form of brisk walking plus nutritional supplement (Walk+), (3) stretching, strengthening and stability (SSS), or (4) dance instruction. After the intervention, the Walk, Walk+ and SSS groups showed gains in cardiorespiratory fitness (CRF), with larger effects in both walking groups compared to the SSS and Dance groups. The Walk, Walk+ and SSS groups also improved in executive function (EF) as measured by reasoning, working memory, and task-switching tests. In the Walk, Walk+, and SSS groups that improved in EF, higher baseline modularity was positively related to EF gains, even after controlling for age, in-scanner motion and baseline EF. No relationship between modularity and EF gains was observed in the Dance group, which did not show training-related gains in CRF or EF control. These results are consistent with previous studies demonstrating that individuals with a more modular brain network organization are more responsive to cognitive training. These findings suggest that the predictive power of modularity may be generalizable across interventions aimed to enhance aspects of cognition and that, especially in low-performing individuals, global network properties can capture individual differences in neuroplasticity.

Kimbrough, A, Lurie DJ, Collazo A, Kreifeldt M, Sidhu H, Macedo GC, D'Esposito M, Contet C, George O.  2020.  Brain-wide functional architecture remodeling by alcohol dependence and abstinence., 2020 Jan 14. Proceedings of the National Academy of Sciences of the United States of America. 117(4):2149-2159. Abstract2020_kimbrough.pdf

Alcohol abuse and alcohol dependence are key factors in the development of alcohol use disorder, which is a pervasive societal problem with substantial economic, medical, and psychiatric consequences. Although our understanding of the neurocircuitry that underlies alcohol use has improved, novel brain regions that are involved in alcohol use and novel biomarkers of alcohol use need to be identified. The present study used a single-cell whole-brain imaging approach to 1) assess whether abstinence from alcohol in an animal model of alcohol dependence alters the functional architecture of brain activity and modularity, 2) validate our current knowledge of the neurocircuitry of alcohol abstinence, and 3) discover brain regions that may be involved in alcohol use. Alcohol abstinence resulted in the whole-brain reorganization of functional architecture in mice and a pronounced decrease in modularity that was not observed in nondependent moderate drinkers. Structuring of the alcohol abstinence network revealed three major brain modules: 1) extended amygdala module, 2) midbrain striatal module, and 3) cortico-hippocampo-thalamic module, reminiscent of the three-stage theory. Many hub brain regions that control this network were identified, including several that have been previously overlooked in alcohol research. These results identify brain targets for future research and demonstrate that alcohol use and dependence remodel brain-wide functional architecture to decrease modularity. Further studies are needed to determine whether the changes in coactivation and modularity that are associated with alcohol abstinence are causal features of alcohol dependence or a consequence of excessive drinking and alcohol exposure.

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(1):290-299. Abstract2007_johnson.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 New England Journal of Medicine. 365(14):1346-1347. Abstract2011_desposito_nejm.pdf

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Curtis, CE, Cole MW, Rao VY, D’Esposito.  2005.  Canceling planned action: an FMRI study of countermanding saccades., 2005 Sep. Cerebral Cortex. 15(9):1281-1289. Abstract2005_curtis_cc.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(1):178-182. Abstract1996_robinson.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(1):37-45. Abstract2004_ranganath.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.

Tambini, A, D'Esposito M.  2020.  Causal Contribution of Awake Post-encoding Processes to Episodic Memory Consolidation., 2020 Jul 17. Current Biology. S0960-9822(20):30915-5. Abstract2020_tambini.pdf

Stable representations of past experience are thought to depend on processes that unfold after events are initially encoded into memory. Post-encoding reactivation and hippocampal-cortical interactions are leading candidate mechanisms thought to support memory retention and stabilization across hippocampal-cortical networks. Although putative consolidation mechanisms have been observed during sleep and periods of awake rest, the direct causal contribution of awake consolidation mechanisms to later behavior is unclear, especially in humans. Moreover, it has been argued that observations of putative consolidation processes are epiphenomenal and not causally important, yet there are few tools to test the functional contribution of these mechanisms in humans. Here, we combined transcranial magnetic stimulation (TMS) and fMRI to test the role of awake consolidation processes by targeting hippocampal interactions with lateral occipital cortex (LOC). We applied theta-burst TMS to LOC (and a control site) to interfere with an extended window (approximately 30-50 min) after memory encoding. Behaviorally, post-encoding TMS to LOC selectively impaired associative memory retention compared to multiple control conditions. In the control TMS condition, we replicated prior reports of post-encoding reactivation and memory-related hippocampal-LOC interactions during periods of awake rest using fMRI. However, post-encoding LOC TMS reduced these processes, such that post-encoding reactivation in LOC and memory-related hippocampal-LOC functional connectivity were no longer present. By targeting and manipulating post-encoding neural processes, these findings highlight the direct contribution of awake time periods to episodic memory consolidation. This combined TMS-fMRI approach provides an opportunity for causal manipulations of human memory consolidation.

Riddle, J, Scimeca JM, Cellier D, Dhanani S, D'Esposito M.  2020.  Causal Evidence for a Role of Theta and Alpha Oscillations in the Control of Working Memory., 2020 Apr 06. Current Biology. 30(9):1748-1754. Abstract2020_riddle_cb.pdf

Working memory (WM) relies on the prioritization of relevant information and suppression of irrelevant information [1, 2]. Prioritizing relevant information has been linked to theta frequency neural oscillations in lateral prefrontal cortex and suppressing irrelevant information has been linked to alpha oscillations in occipito-parietal cortex [3,11]. Here, we used a retrospective-cue WM paradigm to manipulate prioritization and suppression task demands designed to drive theta oscillations in prefrontal cortex and alpha oscillations in parietal cortex, respectively. To causally test the role of these neural oscillations, we applied rhythmic transcranial magnetic stimulation (TMS) in either theta or alpha frequency to prefrontal and parietal regions identified using functional MRI. The effect of rhythmic TMS on WM performance was dependent on whether the TMS frequency matched or mismatched the expected underlying task-driven oscillations of the targeted region. Functional MRI in the targeted regions predicted subsequent TMS effects across subjects supporting a model by which theta oscillations are excitatory to neural activity, and alpha oscillations are inhibitory. Together, these results causally establish dissociable roles for prefrontal theta oscillations and parietal alpha oscillations in the control of internally maintained WM representations.

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. 113(21):6059-6064. Abstract2016_rahnev.pdf

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:e28040. Abstract2017_nee.pdf

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.

Riddle, J, Hwang K, Cellier D, Dhanani S, D'Esposito M.  2019.  Causal Evidence for the Role of Neuronal Oscillations in Top-Down and Bottom-Up Attention., 2019 Feb 06. Journal of Cognitive Neuroscience. 31(5):768-779. Abstract2019_riddle.pdf

Beta and gamma frequency neuronal oscillations have been implicated in top-down and bottom-up attention. In this study, we used rhythmic TMS to modulate ongoing beta and gamma frequency neuronal oscillations in frontal and parietal cortex, while human participants performed a visual search task that manipulates bottom-up and top-down attention (single feature and conjunction search). Both task conditions will engage bottom-up attention processes, whereas the conjunction search condition will require more top-down attention. Gamma frequency TMS to superior precentral sulcus (sPCS) slowed saccadic RTs during both task conditions and induced a response bias to the contralateral visual field. In contrary, beta frequency TMS to sPCS and intraparietal sulcus decreased search accuracy only during the conjunction search condition that engaged more top-down attention. Furthermore, beta frequency TMS increased trial errors specifically when the target was in the ipsilateral visual field for the conjunction search condition. These results indicate that beta frequency TMS to sPCS and intraparietal sulcus disrupted top-down attention, whereas gamma frequency TMS to sPCS disrupted bottom-up, stimulus-driven attention processes. These findings provide causal evidence suggesting that beta and gamma oscillations have distinct functional roles for 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(6):985-996. Abstract2007_deouell.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(5):904-914. Abstract2008_silver.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. Journal of Neuroscience. 37(16):4405-4415. Abstract2017_gratton.pdf

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. Abstract1996_grossman_nnbn.pdfWebsite

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D’Esposito, Alexander M.  1995.  The clinical profiles, recovery and rehabilitation of memory disorders. Neurorehabilitation. 5(2):141-159. Abstract1995_despo_nr.pdf

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Blumenfeld, RS, Bliss DP, Perez F, D'Esposito M.  2014.  CoCoTools: Open-source Software for Building Connectomes Using the CoCoMac Anatomical Database., 2013 Oct 11. Journal of Cognitive Neuroscience. 26(4):722-745. Abstract2014_blumenfeld.pdf

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. 9(24):R939-R941. Abstract1999_desposito_cb.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(1):297-306. Abstract2001_kounios.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(8):1020-1027. Abstract2003_kimberg.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. 6(6):185-192. Abstract1997_kimberg_cd.pdfWebsite

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D'Esposito, M, Postle BR.  2014.  The Cognitive Neuroscience of Working Memory., 2014 Sep 19. Annual Review of Psychology. 66:115-142. Abstract2014_desposito.pdf

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 http://www.annualreviews.org/catalog/pubdates.aspx for revised estimates.