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Miller, BT, Verstynen T, Johnson MK, D’Esposito.  2008.  Prefrontal and parietal contributions to refreshing: an rTMS study., 2008 Jan 1. NeuroImage. 39(1):436-440. Abstract2007_miller.pdf

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

Rajah, NM, Ames B, D’Esposito.  2008.  Prefrontal contributions to domain-general executive control processes during temporal context retrieval., 2008 Mar 7. Neuropsychologia. 46(4):1088-1103. Abstract2008_rajah.pdf

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

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

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

D’Esposito, Postle BR, Rypma B.  2000.  Prefrontal cortical contributions to working memory: evidence from event-related fMRI studies., 2000 Jul. Experimental Brain Research. 133(1):3-11. Abstract2000_desposito.pdf

Working memory refers to the short-term retention of information that is no longer accessible in the environment, and the manipulation of this information, for subsequent use in guiding behavior. In this review, we will present data from a series of event-related functional magnetic-resonance-imaging (fMRI) studies of delayed-response tasks that were designed to investigate the role of different regions of the prefrontal cortex (PFC) during different working-memory component processes. From these data, we conclude that: (1) lateral PFC is anatomically organized according to the types of cognitive operations that one performs when attempting to temporarily maintain and manipulate information; and (2) consistent with the picture that has emerged from the monkey electrophysiological literature, human lateral PFC is involved in several encoding- and response-related processes as well as mnemonic and nonmnemonic processes that are engaged during the temporary maintenance of information. Thus, lateral PFC activity cannot be ascribed to the function of a single, unitary cognitive operation.

Yoon, JH, D’Esposito, Carter CS.  2006.  Preserved function of the fusiform face area in schizophrenia as revealed by fMRI., 2006 Dec 1. Psychiatry Research. 148(2-3):205-216. Abstract2006_yoon2.pdf

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

D’Esposito.  1995.  Profile of a neurology residency., 1995 Nov. Archives of Neurology. 52(11):1123-1126. Abstract1995_desposito_an.pdf

The pattern and frequency of patient encounters during the Boston (Mass) University adult neurology residency program (1988 to 1991) for one resident was compared with that in general neurology practice as well as with the frequency of neurologic disorders in the US population. A total of 1332 new patients (85% adult, 15% pediatric) were seen during a 3-year period. This total represented 970 inpatients (73% of all patients) and 362 outpatients (27%). The resident encountered more patients in the hospital (7.5 admissions or 13 consultations per week) and fewer patients in the clinic (2.5 new outpatients per week) than does the average community neurologist (two admissions, 8.7 consultations, and 13.2 new outpatients). The most common diagnosis for an admission encounter was acute ischemic infarct; for a consultation, metabolic encephalopathy; and for an outpatient encounter, radiculopathy. Less prevalent neurologic disorders in the United States (eg, cognitive, demyelinating, movement, and neoplastic disorders) were encountered more frequently in residency than were very prevalent neurologic disorders (eg, headache and trauma). This is the first reported summary of all patients one resident actually encountered during neurology training. The patient encounter profile suggests that this residency training overemphasized acute inpatient care of less prevalent neurologic disorders compared with outpatient care of more prevalent disorders commonly seen in a neurology practice. Accumulation of similar data from other residencies and practicing neurologists can help residency directors assess the changing needs of residents in training and guide curriculum in response to changes in practice patterns.

Leong, YC, Dziembaj R, D'Esposito M.  2021.  Pupil-Linked Arousal Biases Evidence Accumulation Toward Desirable Percepts During Perceptual Decision-Making., 2021 Sep 02. Psychological science. :9567976211004547. Abstract

People's perceptual reports are biased toward percepts they are motivated to see. The arousal system coordinates the body's response to motivationally significant events and is well positioned to regulate motivational effects on perceptual judgments. However, it remains unclear whether arousal would enhance or reduce motivational biases. Here, we measured pupil dilation as a measure of arousal while participants ( = 38) performed a visual categorization task. We used monetary bonuses to motivate participants to perceive one category over another. Even though the reward-maximizing strategy was to perform the task accurately, participants were more likely to report seeing the desirable category. Furthermore, higher arousal levels were associated with making motivationally biased responses. Analyses using computational models suggested that arousal enhanced motivational effects by biasing evidence accumulation in favor of desirable percepts. These results suggest that heightened arousal biases people toward what they want to see and away from an objective representation of the environment.

Cohen, JR, Gallen CL, Jacobs EG, Lee TG, D'Esposito M.  2014.  Quantifying the Reconfiguration of Intrinsic Networks during Working Memory., 2014. PloS one. 9(9):e106636. Abstract2014_cohen.pdf

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

Blumenfeld, RS, Bliss DP, D'Esposito M.  2018.  Quantitative Anatomical Evidence for a Dorsoventral and Rostrocaudal Segregation within the Nonhuman Primate Frontal Cortex., 2017 Oct 24. Journal of Cognitive Neuroscience. 30(3):353-364. Abstract2018_blumenfeld.pdf

The intrinsic white matter connections of the frontal cortex are highly complex, and the organization of these connections is not fully understood. Quantitative graph-theoretical methods, which are not solely reliant on human observation and interpretation, can be powerful tools for describing the organizing network principles of frontal cortex. Here, we examined the network structure of frontal cortical subregions by applying graph-theoretical community detection analyses to a graph of frontal cortex compiled from over 400+ macaque white-matter tracing studies. We find evidence that the lateral frontal cortex can be partitioned into distinct modules roughly organized along the dorsoventral and rostrocaudal axis.

Yamaguchi, S, Hale LA, D’Esposito, Knight RT.  2004.  Rapid prefrontal-hippocampal habituation to novel events., 2004 Jun 9. Journal of Neuroscience. 24(23):5356-5363. Abstract2004_yamaguchi.pdf

Unexpected novel events generate an orienting response that plays an important role in some forms of learning and memory. The orienting response involuntarily captures attention and rapidly habituates as events become familiarized. Although evidence from patients with focal lesions and scalp and intracranial event-related brain potential recordings supports the involvement of a distributed neural network involving association cortex and the limbic system in novelty detection, the key neural substrates and temporal dynamics have not been defined. While subjects performed a bi-field visual-selective attention task with random novel stimuli embedded in either attended or unattended visual fields, we measured rapid changes of regional blood oxygenation level-dependent (BOLD) signal to target and novel stimuli using single-trial analysis of event-related functional magnetic resonance imaging with a 4T scanner. Habituation was quantified by serial BOLD signal changes during the first 10 novel stimuli for each subject. Novel stimuli activated the bilateral superior/middle frontal gyrus, temporal-parietal junction, superior parietal lobe, cingulate gyrus, hippocampus, and fusiform gyrus. The superior/middle frontal gyrus and hippocampus showed significant reduction of BOLD signal during the first few novel stimuli, whereas the signals in the fusiform and cingulate gyrus were constant. Prefrontal and hippocampal responses to attended and unattended novel stimuli were comparably habituated. These results, and previous data from lesion studies, support the view that prefrontal and hippocampal regions are involved in rapid automatic detection and habituation to unexpected environmental events and are key elements of the orienting response in humans.

Scimeca, JM, Kiyonaga A, D'Esposito M.  2018.  Reaffirming the Sensory Recruitment Account of Working Memory., 2018 Mar. Trends in Cognitive Sciences. 22(3):190-192.2018_scimeca.pdf
Buchsbaum, BR, Ye D, D’Esposito.  2011.  Recency Effects in the Inferior Parietal Lobe during Verbal Recognition Memory., 2011. Frontiers in Human Neuroscience. 5:59. Abstract2011_buchsbaum_fihn.pdf

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

Gallen, CL, Turner GR, Adnan A, D'Esposito M.  2016.  Reconfiguration of brain network architecture to support executive control in aging., 2016 Aug. Neurobiology of Aging. 44:42-52. Abstract2016_gallen.pdf

Aging is accompanied by declines in executive control abilities and changes in underlying brain network architecture. Here, we examined brain networks in young and older adults during a task-free resting state and an N-back task and investigated age-related changes in the modular network organization of the brain. Compared with young adults, older adults showed larger changes in network organization between resting state and task. Although young adults exhibited increased connectivity between lateral frontal regions and other network modules during the most difficult task condition, older adults also exhibited this pattern of increased connectivity during less-demanding task conditions. Moreover, the increase in between-module connectivity in older adults was related to faster task performance and greater fractional anisotropy of the superior longitudinal fasciculus. These results demonstrate that older adults who exhibit more pronounced network changes between a resting state and task have better executive control performance and greater structural connectivity of a core frontal-posterior white matter pathway.

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, Alexander M, Fischer R, McGlinchey-Berroth R, O’Connor M.  1996.  Recovery of memory and executive function following anterior communicating artery aneurysm rupture., 1996 Nov. Journal of the International Neuropsychological Society. 2(6):565-570. Abstract1996_desposito_jins.pdf

We studied the recovery of memory and executive function in 10 patients following anterior communicating artery aneurysm (ACoA) rupture and repair. Patients were tested at 2 consecutive points in time following surgery (approximately at 2 and 3 months). At the first testing, the patients divided into 2 groups based on the severity of impairment on executive measures. Both groups had severe anterograde amnesia, but only patients with severe executive impairments had retrograde amnesia with a temporal gradient. At second testing, both groups had persistent severe anterograde amnesia. The dysexecutive group showed significant improvement in executive deficits and in retrograde amnesia, with attenuation of the temporal gradient. Patients with more severe executive impairments had more extensive bilateral frontal lesions than other patients. These results suggest that the cognitive profile following ACoA rupture changes with time. Time postonset following aneurysm rupture and lesion site are both critical for defining the neuropsychological profile, and determining the underlying cognitive mechanisms in this neurological disorder.

Handwerker, DA, Gazzaley A, Inglis BA, D’Esposito.  2007.  Reducing vascular variability of fMRI data across aging populations using a breathholding task., 2007 Sep. Human Brain Mapping. 28(9):846-859. Abstract2007_handwerker.pdf

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

Rajah, NM, D’Esposito.  2005.  Region-specific changes in prefrontal function with age: a review of PET and fMRI studies on working and episodic memory., 2005 Sep. Brain. 128(9):1964-1983. Abstract2005_rajah.pdf

Several neuroimaging studies of cognitive ageing have found that age-related deficits in working memory (WM) and episodic memory abilities are related to changes in prefrontal cortex (PFC) function. Reviews of these neuroimaging studies have generally concluded that with age there is a reduction in the hemispheric specialization of cognitive function in the frontal lobes that may either be due to dedifferentiation of function, deficits in function and/or functional reorganization and compensation. Moreover, previous reviews have considered the PFC as homogeneous in function and have not taken into account the possibility that region specific changes in PFC function may occur with age. In the current review we performed a qualitative meta-analytic review of all the functional magnetic resonance imaging ageing studies and positron emission tomography ageing studies of WM and episodic memory that report PFC activation, to determine if any region-specific changes occur. The results indicated that in normal ageing distinct PFC regions exhibit different patterns of functional change, suggesting that age-related changes in PFC function are not homogeneous in nature. Specifically, we hypothesize that normal ageing is related to the differentiation of cortical function in a bilateral ventral PFC and deficits in function in right dorsal and anterior PFC. As a result of these changes, functional compensation in left dorsal and anterior PFC may occur. We hope that future studies will be conducted to either confirm or counter these hypotheses.

Landau, SM, Garavan H, Schumacher EH, D’Esposito.  2007.  Regional specificity and practice: dynamic changes in object and spatial working memory., 2007 Nov 14. Brain Research. 1180:78-89. Abstract2007_landau.pdf

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

Novakovic-Agopian, T, Chen AJ-W, Rome S, Abrams G, Castelli H, Rossi A, McKim R, Hills N, D'Esposito M.  2011.  Rehabilitation of executive functioning with training in attention regulation applied to individually defined goals: a pilot study bridging theory, assessment, and treatment., 2011 Sep-Oct. Journal of Head Trauma Rehabilitation. 26(5):325-338. Abstract2011_novakovic.pdf

To assess feasibility and effects of training in goal-oriented attentional self-regulation for patients with brain injury and chronic executive dysfunction.

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
Buchsbaum, BR, D’Esposito.  2009.  Repetition suppression and reactivation in auditory-verbal short-term recognition memory., 2009 Jun. Cerebral Cortex. 19(6):1474-1485. Abstract2008_buchsbaum_cc.pdf

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

Zarahn, E, Aguirre GK, D’Esposito.  2000.  Replication and further studies of neural mechanisms of spatial mnemonic processing in humans., 2000 Jan. Brain Research: Cognitive Brain Research. 9(1):1-17. Abstract2000_zarahn.pdf

Changes in neuronal firing rates during periods of time when subjects are required to remember information (retention delays) have been reported in non-human primates. In humans, tests for such functional changes using hemodynamic markers of neural activity have typically relied on cognitive subtraction. However, the temporal resolution of fMRI allows a more direct test than that afforded by cognitive subtraction of the idea that certain brain regions may increase their neural activity during retention delays in humans. Using a method that exploits this temporal resolution, increased functional activity attributable to a retention delay for spatial information in regions proximate to/within the right frontal eye field and the right superior parietal lobule were detected (in four out of four and three out of four subjects, respectively; this is an internal replication of the results of [E. Zarahn, G.K. Aguirre, M. D’Esposito, Temporal isolation of the neural correlates of spatial mnemonic processing with fMRI, Cognit. Brain Res., 7 (1999) 255-268. ]). Second, a model in which ventral and not dorsal prefrontal cortex in humans is involved in simply maintaining spatial information was tested. The results disputed this model as increases in fMRI signal attributable to the retention delay were detected more frequently in dorsal than ventral prefrontal cortex. Third, a model which posited that the intensity of neural activity is causally related to the accuracy of spatial mnemonic representation was tested by comparing retention delay signal between correct and incorrect trials. The results did not support this model in any of the regions tested.

Nee, DE, D'Esposito M.  2018.  The Representational Basis of Working Memory., 2016 Sep 28. Current Topics in Behavioral Neurosciences. 37:213-230. Abstract2018_nee.pdf

Working memory refers to a system involved in the online maintenance and manipulation of information in the absence of external input. Due to the importance of working memory in higher-level cognition, a wealth of neuroscience studies has investigated its neural basis. These studies have often led to conflicting viewpoints regarding the importance of the prefrontal cortex (PFC) and posterior sensory cortices. Here, we review evidence for each position. We suggest that the relative contributions of the PFC and sensory cortices to working memory can be understood with respect to processing demands. We argue that procedures that minimize processing demands lead to increased importance of sensory representations, while procedures that permit transformational processing lead to representational abstraction that relies on the PFC. We suggest that abstract PFC representations support top-down control over posterior representations while also providing bottom-up inputs into higher-level cognitive processing. Although a number of contemporary studies have studied working memory while using procedures that minimize the role of the PFC, we argue that consideration of the PFC is critical for our understanding of working memory and higher-level cognition more generally.

Cools, R, Altamirano LJ, D’Esposito.  2006.  Reversal learning in Parkinson’s disease depends on medication status and outcome valence., 2006. Neuropsychologia. 44(10):1663-1673. Abstract2006_altamirano.pdf

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

Sreenivasan, KK, Curtis CE, D'Esposito M.  2014.  Revising the role of persistent neural activity in working memory. Trends in Cognitive Science. 18(2):82-89.2014_sreenivasan.pdf
Krawczyk, DC, Gazzaley A, D’Esposito.  2007.  Reward modulation of prefrontal and visual association cortex during an incentive working memory task., 2007 Apr 13. Brain Research. 1141:168-177. Abstract2007_krawczyk.pdf

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

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


Thompson-Schill, SL, D’Esposito, Aguirre GK, Farah MJ.  1997.  Role of left inferior prefrontal cortex in retrieval of semantic knowledge: a reevaluation., 1997 Dec 23. Proceedings of the National Academy of Sciences of the United States of America. 94(26):14792-14797. Abstract1997_thompsonschill.pdf

A number of neuroimaging findings have been interpreted as evidence that the left inferior frontal gyrus (IFG) subserves retrieval of semantic knowledge. We provide a fundamentally different interpretation, that it is not retrieval of semantic knowledge per se that is associated with left IFG activity but rather selection of information among competing alternatives from semantic memory. Selection demands were varied across three semantic tasks in a single group of subjects. Functional magnetic resonance imaging signal in overlapping regions of left IFG was dependent on selection demands in all three tasks. In addition, the degree of semantic processing was varied independently of selection demands in one of the tasks. The absence of left IFG activity for this comparison counters the argument that the effects of selection can be attributed solely to variations in degree of semantic retrieval. Our findings suggest that it is selection, not retrieval, of semantic knowledge that drives activity in the left IFG.

Menon, V, D'Esposito M.  2021.  The role of PFC networks in cognitive control and executive function., 2021 Aug 18. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology. Abstract

Systems neuroscience approaches with a focus on large-scale brain organization and network analysis are advancing foundational knowledge of how cognitive control processes are implemented in the brain. Over the past decade, technological and computational innovations in the study of brain connectivity have led to advances in our understanding of how brain networks function, inspiring new conceptualizations of the role of prefrontal cortex (PFC) networks in the coordination of cognitive control. In this review, we describe six key PFC networks involved in cognitive control and elucidate key principles relevant for understanding how these networks implement cognitive control. Implementation of cognitive control in a constantly changing environment depends on the dynamic and flexible organization of PFC networks. In this context, we describe major empirical and theoretical models that have emerged in recent years and describe how their functional architecture and dynamic organization supports flexible cognitive control. We take an overarching view of advances made in the past few decades and consider fundamental issues regarding PFC network function, global brain dynamics, and cognition that still need to be resolved. We conclude by clarifying important future directions for research on cognitive control and their implications for advancing our understanding of PFC networks in brain disorders.

D’Esposito, Ballard D, Zarahn E, Aguirre GK.  2000.  The role of prefrontal cortex in sensory memory and motor preparation: an event-related fMRI study., 2000 May. NeuroImage. 11(5):400-408. Abstract2000_ballard.pdf

Delayed-response tasks are behavioral paradigms in which subjects must remember stimulus attributes across a delay to subsequently perform the appropriate motor response. Quintana and Fuster (1992), reported that there exist subpopulations of neurons in monkey lateral prefrontal cortex (PFC) whose firing rates during the delay are tuned to either sensorial attributes of the stimulus (i.e., involved in sensory memory) or the direction of a postdelay motor response associated with the stimulus (i.e., involved in motor preparation). We studied human subjects with an event-related fMRI method that would allow us to test the hypothesis that there are regions within the PFC that are recruited during both motor preparation and sensory memory. Subjects performed a delayed-response task with two types of trials that either (1) allowed subjects to prepare during a delay period for a specific motor response or (2) required that subjects maintain a sensory attribute (specifically, color) during a delay period for correct performance postdelay. It was assumed that during the delay periods, the delayed-response trials would engage motor preparation while delayed-match trials would engage sensory memory. Behavioral data supported this assumption. Imaging results support the hypothesis that the PFC is involved in both motor preparation and sensory memory. Furthermore, no selectivity (in terms of intensity of neural representation on the spatial scale of the voxel size <5 mm(3)) for motor preparation over sensory memory (or vice-versa) was detected within the PFC. This latter result fails to support a gross anatomical segregation within the PFC with respect to involvement in these two cognitive processes.

D'Esposito, M, Postle BR, Rypma B.  2002.  The role of the lateral prefrontal cortex in working memory: evidence from event-related fMRI studies. International Congress Series. 1232:21-27.
Rypma, B, D’Esposito.  1999.  The roles of prefrontal brain regions in components of working memory: effects of memory load and individual differences., 1999 May 25. Proceedings of the National Academy of Sciences of the United States of America. 96(11):6558-6563. Abstract1999_rypma_pnas.pdf

Using an event-related functional MRI design, we explored the relative roles of dorsal and ventral prefrontal cortex (PFC) regions during specific components (Encoding, Delay, Response) of a working memory task under different memory-load conditions. In a group analysis, effects of increased memory load were observed only in dorsal PFC in the encoding period. Activity was lateralized to the right hemisphere in the high but not the low memory-load condition. Individual analyses revealed variability in activation patterns across subjects. Regression analyses indicated that one source of variability was subjects’ memory retrieval rate. It was observed that dorsal PFC plays a differentially greater role in information retrieval for slower subjects, possibly because of inefficient retrieval processes or a reduced quality of mnemonic representations. This study supports the idea that dorsal and ventral PFC play different roles in component processes of working memory.

Bahlmann, J, Blumenfeld RS, D'Esposito M.  2014.  The Rostro-Caudal Axis of Frontal Cortex Is Sensitive to the Domain of Stimulus Information., 2014 Jan 22. Cerebral Cortex . 25(7):1815-1826. Abstract2014_bahlmann.pdf

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

Chiong, W, Wilson SM, D'Esposito M, Kayser AS, Grossman SN, Poorzand P, Seeley WW, Miller BL, Rankin KP.  2013.  The salience network causally influences default mode network activity during moral reasoning., 2013 Apr 9. Brain. 136(6):1929-1941. Abstract2013_chiong.pdf

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

Buchsbaum, BR, D’Esposito.  2008.  The search for the phonological store: from loop to convolution., 2008 May. Journal of Cognitive Neuroscience. 20(5):762-778. Abstract2008_buchsbaum_jocn.pdf

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

Miller, BT, D’Esposito.  2005.  Searching for "the top" in top-down control., 2005 Nov 23. Neuron. 48(4):535-538. Abstract2005_bmiller.pdf

Although numerous theoretical models implicate the prefrontal cortex (PFC) as a source of top-down control signals, empirical support is limited. In this review, we highlight direct evidence for this view of PFC function and discuss several lines of other supportive findings. Most evidence to-date is only suggestive due to methodological challenges in tracking the spatiotemporal dynamics of cortical networks. However, we discuss several promising approaches that could further our understanding of the role of the PFC in goal-directed behavior.

Postle, BR, Druzgal TJ, D’Esposito.  2003.  Seeking the neural substrates of visual working memory storage., 2003 Sep-Dec. Cortex. 39(4-5):927-946. Abstract2003_postle_cortex.pdf

It is widely assumed that the prefrontal cortex (PFC) is a critical site of working memory storage in monkeys and humans. Recent reviews of the human lesion literature and recent neuroimaging results, however, challenge this view. To test these alternatives, we used event-related fMRI to trace the retention of working memory representation of target faces across three delay periods that were interposed between the presentation of each of four stimuli. Across subjects, only posterior fusiform gyrus demonstrated reliable retention of target-specific activity across all delay periods. Our results suggest that no part of frontal cortex, including PFC, stores mnemonic representation of faces reliably across distracted delay periods. Rather, working memory storage of faces is mediated by a domain-specific network in posterior cortex.

Cohen, JR, D'Esposito M.  2016.  The Segregation and Integration of Distinct Brain Networks and Their Relationship to Cognition., 2016 Nov 30. Journal of Neuroscience. 36(48):12083-12094. Abstract2016_cohen.pdf

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

Yoon, JH, Hoffman J, D’Esposito.  2007.  Segregation of function in the lateral prefrontal cortex during visual object working memory., 2007 Dec 12. Brain Research. 1184:217-225. Abstract2007_yoon.pdf

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

Curtis, CE, D’Esposito.  2006.  Selection and maintenance of saccade goals in the human frontal eye fields., 2006 Jun. Journal of Neurophysiology. 95(6):3923-3927. Abstract2006_curtis.pdf

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

Schumacher, EH, Cole MW, D’Esposito.  2007.  Selection and maintenance of stimulus-response rules during preparation and performance of a spatial choice-reaction task., 2007 Mar 9. Brain Research. 1136(1):77-87. Abstract2007_schumacher.pdf

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

Grossman, M, Robinson K, Biassou N, White-Devine T, D’Esposito.  1998.  Semantic memory in Alzheimer’s disease: representativeness, ontologic category, and material., 1998 Jan. Neuropsychology. 12(1):34-42. Abstract1998_grossman_np.pdf

Alzheimer’s disease (AD) patients with semantic memory difficulty and AD patients with relatively preserved semantic memory named pictures and judged the category membership of words and pictures of natural kinds and manufactured artifacts that varied in their representativeness. Only semantically impaired patients were insensitive to representativeness in their category judgments. AD subgroup judgments did not differ for natural kinds compared to manufactured artifacts nor for words compared to pictures. AD subgroup differences could not be explained by dementia severity, memory, reading, and visuoperception. The similarity process for relating coordinate members of a taxonomic category contributes to the normal appreciation of word and picture meaning, and this process is compromised in AD patients with semantic difficulty.

McGlinchey-Berroth, R, Milberg W, Verfaellie M, Grande L, D’Esposito, Alexander M.  1996.  Semantic processing and orthographic specificity in hemispatial neglect. Journal of Cognitive Neuroscience. 8(3):291-304. Abstract1996_mcglinchey_jocn.pdf


Buchsbaum, BR, D'Esposito M.  2019.  A sensorimotor view of verbal working memory., 2018 Nov 20. Cortex. 112:134-148. Abstract2019_buchsbaum.pdf

The divide-and-conquer approach to the study of human cognition has succeeded in focusing researchers' efforts on behavioral phenomena that fall under well-defined categories such as attention, perception, language, memory, emotion, and motor control. The result has been the development of coherent bodies of work in each area replete with successful explanatory theories and a rich collection of paradigms, tasks, and analytic techniques. There has been a renewed in recent years in combining and integrating ideas across these domains, as well as in incorporating neuroscientific data, as a way to build more powerful and general models of cognition. Here we review the history and current state of integration between verbal short-term memory (VeSTM) and language, two domains of study that have significant areas of overlap but have not been fully integrated. We review evidence from cognitive neuroscience that has generally shown VeSTM to greatly depend on the network of brain regions that are known to form the core sensory-motor basis of human language. Whereas classic psychological models of VeSTM posit the existence of dedicated short-term storage buffers, we suggest that temporary verbal memory emerges from the coordinated interplay of a fronto-temporal sensory-motor circuit that has evolved to support the perception and production of speech. Phonological rehearsal in the service of temporary maintenance is achieved by feedforward and feedback pathways connecting the auditory- and motor-speech systems via a sensorymotor interface component situated in the Sylvian-parietal-temporal region (Spt). Reciprocal connectivity between the frontal and temporal speech systems enables the kind of "round-tripping" of dual speech codes long hypothesized by cognitive models such as Baddeley and Hitch's "phonological loop".

Grossman, M, Robinson KM, Onishi K, Thompson H, Cohen J, D’Esposito.  1995.  Sentence comprehension in multiple sclerosis., 1995 Oct. Acta Neurologica Scandinavica. 92(4):324-331. Abstract1995_grossman.pdf

INTRODUCTION: Explanations of sentence processing difficulty in aphasia have implicated slowed information processing speed. We tested this hypothesis by evaluating sentence comprehension in multiple sclerosis (MS), and relating comprehension performance to measures of information processing speed. MATERIAL & METHODS: Twenty right-handed, high school-educated, non-demented, native English speakers with clinically definite MS and 16 age- and education-matched control subjects were examined on 3 different sentence comprehension measures that stress grammatical appreciation. Performance was related to quantitative assessments of mental information processing speed. RESULTS: Group-wide analyses demonstrated a trend toward sentence comprehension difficulty in MS. Analyses of individual patient profiles identified a subgroup of MS patients who were consistently impaired to a significant extent across all sentence comprehension tasks. Their sentence comprehension difficulty was associated with selectively compromised mental information processing speed. CONCLUSION: Sentence comprehension difficulty in MS is associated with slowed information processing speed. This finding supports the claim that information processing speed contributes to sentence processing.

Landau, SM, D’Esposito.  2006.  Sequence learning in pianists and nonpianists: an fMRI study of motor expertise., 2006 Sep. Cognitive, Affective & Behavioral Neuroscience. 6(3):246-259. Abstract2006_landau.pdf

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

Bliss, DP, Sun JJ, D'Esposito M.  2018.  Serial dependence is absent at the time of perception but grows in visual working memory. Scientific Reports. 7(1):14739.2018_bliss.pdf
Armstrong, C, Onishi K, Robinson K, D’Esposito, Thompson H, Rostami A, Grossman M.  1996.  Serial position and temporal cue effects in multiple sclerosis: two subtypes of defective memory mechanisms., 1996 Sep. Neuropsychologia. 34(9):853-862. Abstract1996_armstrong.pdf

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

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
Toker, D, Sommer FT, D'Esposito M.  2020.  A simple method for detecting chaos in nature., 2020. Communications Biology. 3:11. Abstract2020_toker.pdf

Chaos, or exponential sensitivity to small perturbations, appears everywhere in nature. Moreover, chaos is predicted to play diverse functional roles in living systems. A method for detecting chaos from empirical measurements should therefore be a key component of the biologist's toolkit. But, classic chaos-detection tools are highly sensitive to measurement noise and break down for common edge cases, making it difficult to detect chaos in domains, like biology, where measurements are noisy. However, newer tools promise to overcome these limitations. Here, we combine several such tools into an automated processing pipeline, and show that our pipeline can detect the presence (or absence) of chaos in noisy recordings, even for difficult edge cases. As a first-pass application of our pipeline, we show that heart rate variability is not chaotic as some have proposed, and instead reflects a stochastic process in both health and disease. Our tool is easy-to-use and freely available.

Cole, MA, Muir JJ, Gans JJ, Shin LM, D'Esposito M, Harel BT, Schembri A.  2015.  Simultaneous Treatment of Neurocognitive and Psychiatric Symptoms in Veterans with Post-Traumatic Stress Disorder and History of Mild Traumatic Brain Injury: A Pilot Study of Mindfulness-Based Stress Reduction., 2015 Sep. Military Medicine. 180(9):956-963. Abstract2015_cole.pdf

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

Miller, BT, D'Esposito M.  2012.  Spatial and temporal dynamics of cortical networks engaged in memory encoding and retrieval., 2012. Frontiers in Human Neuroscience. 6:109. Abstract2012_miller.pdf

Memory operations such as encoding and retrieval require the coordinated interplay of cortical regions with distinct functional contributions. The mechanistic nature of these interactions, however, remains unspecified. During the performance of a face memory task during fMRI scanning, we measured the magnitude (a measure of the strength of coupling between areas) and phase (a measure of the relative timing across areas) of coherence between regions of interest and the rest of the brain. The fusiform face area (FFA) showed robust coherence with a distributed network of subregions in the prefrontal cortex (PFC), posterior parietal cortex (PPC), precuneus, and hippocampus across both memory operations. While these findings reveal significant overlap in the cortical networks underlying mnemonic encoding and retrieval, coherence phase analyses revealed context-dependent differences in cortical dynamics. During both encoding and retrieval, PFC and PPC exhibited earlier activity than in the FFA and hippocampus. Also, during retrieval, PFC activity preceded PPC activity. These findings are consistent with prior physiology studies suggesting an early contribution of PFC and PPC in mnemonic control. Together, these findings contribute to the growing literature exploring the spatio-temporal dynamics of basic memory operations.

Postle, BR, D’Esposito.  2003.  Spatial working memory activity of the caudate nucleus is sensitive to frame of reference., 2003 Jun. Cognitive, Affective & Behavioral Neuroscience. 3(2):133-144. Abstract2003_postle.pdf

We used event-related fMRI to test the hypothesis that the caudate nucleus is preferentially recruited by a spatial working memory task employing egocentrically defined stimuli, which are amenable to transformation into a motor code, as contrasted with allocentrically defined stimuli, which are not. Our results revealed greater delay-epoch activity in egocentric than in allocentric trials in the caudate nucleus and trends in the same direction in the putamen and the lateral premotor cortex (PMC). Response-related activity was greater for egocentric trials in the lateral PMC. We propose that the neostriatum, possibly interacting with the PMC, may contribute to the sensory-motor transformation necessary to establish a prospective motor code (e.g., the representation of a saccade or a grasp). In addition, the PMC may participate in decision-making processes, prompted by the onset of the probe stimulus, that employ this prospective motor information. This model accounts for the empirical evidence that motor distraction disrupts spatial working memory performance.

Miller, BT, Deouell LY, Dam C, Knight RT, D’Esposito.  2008.  Spatio-temporal dynamics of neural mechanisms underlying component operations in working memory., 2008 Apr 24. Brain Research. 1206:61-75. Abstract2008_miller2.pdf

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

Fuhrmann Alpert, G, Sun FT, Handwerker DA, D’Esposito, Knight RT.  2007.  Spatio-temporal information analysis of event-related BOLD responses., 2007 Feb 15. NeuroImage. 34(4):1545-1561. Abstract2007_fuhrmann.pdf

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

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


Sheridan, MA, Hinshaw S, D’Esposito.  2010.  Stimulant medication and prefrontal functional connectivity during working memory in ADHD: a preliminary report., 2010 Jul. Journal of Attention Disorders. 14(1):69-78. Abstract2010_sheridan.pdf

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

Aguirre, GK, Singh R, D’Esposito.  1999.  Stimulus inversion and the responses of face and object-sensitive cortical areas., 1999 Jan 18. Neuroreport. 10(1):189-194. Abstract1999_aguirre_neuro.pdf

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

Cools, R, Frank MJ, Gibbs SE, Miyakawa A, Jagust W, D’Esposito.  2009.  Striatal dopamine predicts outcome-specific reversal learning and its sensitivity to dopaminergic drug administration., 2009 Feb 4. Journal of Neuroscience. 29(5):1538-1543. Abstract2009_cools.pdf

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

D’Esposito, Alexander M.  1995.  Subcortical aphasia: distinct profiles following left putaminal hemorrhage., 1995 Jan. Neurology. 45(1):38-41. Abstract1995_desposito_neurology.pdf

Numerous reports of aphasia after subcortical lesions have produced incomplete agreement about basic clinico-anatomic correlations. Some disagreement has arisen from methodologic differences. To control for some of the common differences, we analyzed 13 patients with left putaminal hemorrhage controlled for location–subcortical but not thalamic, and for time postonset–studied in both acute and postacute epochs. There was no apparent correlation between lesion site and acute language profiles. During the postacute epoch, there were several distinct correlations between lesion site (postacute decreased CT density) and specific aphasia dimensions–nonfluency, impaired comprehension, and perhaps impaired repetition. Our correlations were compatible with comparably controlled cases in the literature. A corollary result of this study is that patients fluent during the early epoch are likely to have a better outcome, and those initially nonfluent have a poor prognosis for language recovery.

Rypma, B, D’Esposito.  2003.  A subsequent-memory effect in dorsolateral prefrontal cortex., 2003 Apr. Brain Research: Cognitive Brain Research. 16(2):162-166. Abstract2003_rypma.pdf

The importance of brain regions for long-term memory encoding has been examined by comparison of encoding-related neural activity on trials in which successful recollection subsequently occurred to the encoding-related activity on trials in which successful recollection did not occur. We applied similar analyses to event-related functional magnetic resonance imaging (fMRI) data to explore the relative roles of dorsolateral and ventrolateral prefrontal cortex (PFC) regions during specific components of a working-memory (WM) maintenance task. The results of this study indicated that increases in dorsolateral PFC activity during encoding was related to subsequent retrieval-success. These results lend support to the hypothesis that ventrolateral PFC mediates a limited-capacity WM buffer that supports rehearsal maintenance functions while dorsolateral PFC mediates WM organization functions that accommodate the capacity limits of WM maintenance.

Curtis, CE, D’Esposito.  2003.  Success and failure suppressing reflexive behavior., 2003 Apr 1. Journal of Cognitive Neuroscience. 15(3):409-418. Abstract2003_curtis.pdf

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

Schumacher, EH, Hendricks MJ, D’Esposito.  2005.  Sustained involvement of a frontal-parietal network for spatial response selection with practice of a spatial choice-reaction task., 2005. Neuropsychologia. 43(10):1444-1455. Abstract2005_schumacher.pdf

With practice, performance on a task typically becomes faster, more accurate, and less prone to interference from competing tasks. Some theories of this performance change suggest it reflects a qualitative reorganization of the cognitive processing required for successful task performance. Other theories suggest this change in performance reflects a more quantitative change in the amount of processing required to perform the task. Neuroimaging research results provide some support for both of these broad theories. This inconsistency may reflect the complex nature of the effect of practice on cognitive and neural processing. Our current experiment addresses this issue by investigating the effect of practice of a relatively easy perceptual-motor task on the frontal-parietal brain network for a specific cognitive process (viz. spatial response selection). Participants were scanned during three functional magnetic resonance imaging sessions on separate days within 4 days while they performed a relatively easy spatial perceptual-motor task. We found sustained activity with practice in right dorsal prefrontal cortex; and sustained but decreasing activity in bilateral dorsal premotor, left superior parietal, and precuneus cortices, supporting a quantitative decrease in difficulty of response selection with practice. Conversely, we found a qualitative change in activity with practice in left dorsal prefrontal cortex. This brain region is outside the response selection network for this task and showed activity only during novel task performance. These results suggest that practice produces both qualitative and quantitative changes in processing. The particular effect of practice depends on the cognitive process in question.

Bliss, DP, D'Esposito M.  2017.  Synaptic augmentation in a cortical circuit model reproduces serial dependence in visual working memory., 2017. PloS one. 12(12):e0188927. Abstract2017_bliss.pdf

Recent work has established that visual working memory is subject to serial dependence: current information in memory blends with that from the recent past as a function of their similarity. This tuned temporal smoothing likely promotes the stability of memory in the face of noise and occlusion. Serial dependence accumulates over several seconds in memory and deteriorates with increased separation between trials. While this phenomenon has been extensively characterized in behavior, its neural mechanism is unknown. In the present study, we investigate the circuit-level origins of serial dependence in a biophysical model of cortex. We explore two distinct kinds of mechanisms: stable persistent activity during the memory delay period and dynamic "activity-silent" synaptic plasticity. We find that networks endowed with both strong reverberation to support persistent activity and dynamic synapses can closely reproduce behavioral serial dependence. Specifically, elevated activity drives synaptic augmentation, which biases activity on the subsequent trial, giving rise to a spatiotemporally tuned shift in the population response. Our hybrid neural model is a theoretical advance beyond abstract mathematical characterizations, offers testable hypotheses for physiological research, and demonstrates the power of biological insights to provide a quantitative explanation of human behavior.

Zarahn, E, Aguirre GK, D’Esposito.  1999.  Temporal isolation of the neural correlates of spatial mnemonic processing with fMRI., 1999 Jan. Brain Research: Cognitive Brain Research. 7(3):255-268. Abstract1999_zarahn.pdf

The use of cognitive subtraction to study the neural substrates of the maintenance component of spatial working memory in humans relies upon the assumptions of the pure insertion of cognitive processes and a linear transform of neural activity to neuroimaging signal. Here, functional changes attributable to the memory requiring phase (referred to as the retention delay) of a spatial working memory task were temporally discriminated from those attributable to other behavioral subcomponents within trials using an experimental design that is argued to obviate these assumptions, as well as permit a joint test of their validity. The hypothesis that the assumptions of cognitive subtraction (as applied to neuroimaging) hold in general was not supported. Functional changes attributable to the retention delay were detected in the dorsolateral prefrontal cortex as well as in other cortical regions in a subset of the subjects, and in the right frontal eye field and right superior parietal lobule of all subjects (n=5). These results support models in which these regions are involved in maintaining spatial representations in humans. In addition, nearly all regions that evidenced such functional changes during the retention delay also evidenced functional changes during behaviors that did not require spatial working memory. This result tends to dispute models which posit the existence of gross neuroanatomical regions involved in solely mnemonic function.

Van Vleet, TM, Chen A, Vernon A, Novakovic-Agopian T, D'Esposito MT.  2014.  Tonic and phasic alertness training: a novel treatment for executive control dysfunction following mild traumatic brain injury., 2014 Jul 1. Neurocase. 21(4):489-498. Abstract2014_vanvleet.pdf

Many individuals with traumatic brain injury (TBI) suffer difficulty regulating fundamental aspects of attention (focus, sustained attention) and may also exhibit hypo- or hyper-states of alertness. Deficits in the state of attention may underlie or exacerbate higher order executive dysfunction. Recent studies indicate that computerized cognitive training targeting attentional control and alertness can ameliorate attention deficits evident in patients with TBI or acquired brain injury. The current study examined whether improvements in attentional state following training can also influence performance on higher-order executive function and mood in individuals with mild TBI (mTBI). The current study examined five patients with executive control deficits as a result of mTBI, with or without persistent anxiety. Three patients engaged in ~5 hours of an executive control training task targeting inhibitory control and sustained attention; two additional patients were re-tested following the same period of time. Performance on standard neuropsychological measures of attention, executive function, and mood were evaluated pre- and post-training. The results indicate that tonic and phasic alertness training may improve higher-order executive function and mood regulation in individuals with TBI.

Bentin, S, DeGutis J, D’Esposito, Robertson LC.  2007.  Too many trees to see the forest: performance, event-related potential, and functional magnetic resonance imaging manifestations of integrative congenital prosopagnosia., 2007 Jan. Journal of Cognitive Neuroscience. 19(1):132-146. Abstract2007_bentin.pdf

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

Gazzaley, A, Cooney JW, McEvoy K, Knight RT, D’Esposito.  2005.  Top-down enhancement and suppression of the magnitude and speed of neural activity., 2005 Mar. Journal of Cognitive Neuroscience. 17(3):507-517. Abstract2005_gazzaley_jocn.pdf

Top-down modulation underlies our ability to selectively attend to relevant stimuli and to ignore irrelevant stimuli. Theories addressing neural mechanisms of top-down modulation are driven by studies that reveal increased magnitude of neural activity in response to directed attention, but are limited by a lack of data reporting modulation of neural processing speed, as well as comparisons with a perceptual (passive view) baseline necessary to evaluate the presence of enhancement and suppression. Utilizing functional MRI (fMRI) and event-related potential recordings (ERPs), we provide converging evidence that both the magnitude of neural activity and the speed of neural processing are modulated by top-down influences. Furthermore, both enhancement and suppression occur relative to a perceptual baseline depending on task instruction. These findings reveal the fine degree of influence that goal-directed attention exerts upon activity within the visual association cortex. We further document capacity limitations in top-down enhancement corresponding with working memory performance deficits.

Lauritzen, TZ, D’Esposito, Heeger DJ, Silver MA.  2009.  Top-down flow of visual spatial attention signals from parietal to occipital cortex., 2009. Journal of Vision. 9(13):18.1-18.14. Abstract2009_lauritzen.pdf

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

Gazzaley, A, D’Esposito.  2007.  Top-down modulation and normal aging., 2007 Feb. Annals of the New York Academy of Sciences. 1097:67-83. Abstract2007_gazzaley.pdf

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

Sneve, MH, Magnussen S, Alnæs D, Endestad T, D'Esposito M.  2013.  Top-Down Modulation from Inferior Frontal Junction to FEFs and Intraparietal Sulcus during Short-term Memory for Visual Features., 2013 May 22. Journal of Cognitive Neuroscience. 25(11):1944-1956. Abstract2013_sneve.pdf

Visual STM of simple features is achieved through interactions between retinotopic visual cortex and a set of frontal and parietal regions. In the present fMRI study, we have investigated effective connectivity between central nodes in this network during the different task epochs of a modified delayed orientation discrimination task. Our univariate analyses demonstrate that the inferior frontal junction (IFJ) is preferentially involved in memory encoding, whereas activity in the putative FEFs and anterior intraparietal sulcus (aIPS) remains elevated throughout periods of memory maintenance. We have earlier reported, using the same task, that areas in visual cortex sustain information about task-relevant stimulus properties during delay intervals [Sneve, M. H., Alnæs, D., Endestad, T., Greenlee, M. W., & Magnussen, S. Visual short-term memory: Activity supporting encoding and maintenance in retinotopic visual cortex. Neuroimage, 63, 166-178, 2012]. To elucidate the temporal dynamics of the IFJ-FEF-aIPS-visual cortex network during memory operations, we estimated Granger causality effects between these regions with fMRI data representing memory encoding/maintenance as well as during memory retrieval. We also investigated a set of control conditions involving active processing of stimuli not associated with a memory task and passive viewing. In line with the developing understanding of IFJ as a region critical for control processes with a possible initiating role in visual STM operations, we observed influence from IFJ to FEF and aIPS during memory encoding. Furthermore, FEF predicted activity in a set of higher-order visual areas during memory retrieval, a finding consistent with its suggested role in top-down biasing of sensory cortex.

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


Gazzaley, A, Cooney JW, Rissman J, D’Esposito.  2005.  Top-down suppression deficit underlies working memory impairment in normal aging., 2005 Oct. Nature Neuroscience. 8(10):1298-1300. Abstract2005_gazzaley.pdf

In this study, we assess the impact of normal aging on top-down modulation, a cognitive control mechanism that supports both attention and memory by the suppression and enhancement of sensory processing in accordance with task goals. Using fMRI (functional magnetic resonance imaging), we show that healthy older adults demonstrated a prominent deficit in the suppression of cortical activity associated with task-irrelevant representations, whereas enhancement of task-relevant activity was preserved. Moreover, this suppression-specific attention deficit correlated with impaired working memory performance.

Aguirre, GK, D’Esposito.  1999.  Topographical disorientation: a synthesis and taxonomy., 1999 Sep. Brain. 122(9):1613-1628. Abstract1999_aguirre.pdf

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

Novakovic-Agopian, T, Kornblith ES, Abrams G, Burciaga-Rosales J, Loya F, D'Esposito M, Chen AJ-W.  2018.  Training in Goal-Oriented Attentional Self-Regulation Improves Executive Functioning in Veterans with Chronic TBI., 2018 May 02. Journal of Neurotrauma. 35(23):2784-2795. Abstract2018_novakovic.pdf

Deficits in executive control functions are some of the most common and disabling consequences of both military and civilian brain injury. However, effective interventions are scant. The goal of this study was to assess whether cognitive rehabilitation training that was successfully applied in chronic civilian brain injury would be effective for military Veterans with TBI. In a prior study, participants with chronic acquired brain injury significantly improved after training in goal-oriented attentional self-regulation (GOALS) on measures of attention/executive function, functional task performance, and goal-directed control over neural processing on fMRI. The objective of this study was to assess effects of GOALS training in Veterans with chronic TBI. 33 Veterans with chronic TBI and executive difficulties in their daily life completed either five weeks of manualized Goal-Oriented Attentional Self-Regulation (GOALS) training or Brain-Health Education (BHE) matched in time and intensity. Evaluator-blinded assessments at baseline and post training included neuropsychological and complex functional task performance and self-report measures of emotional regulation. After GOALS, but not BHE training, participants significantly improved from baseline on primary outcome measures of: Overall Complex Attention/Executive Function composite neuropsychological performance score [F = 7.10, p =.01; partial 2 = .19], and on overall complex functional task performance (Goal Processing Scale Overall Performance) [F=6.92, p=.01, partial 2 =.20]. Additionally, post-GOALS participants indicated significant improvement on emotional regulation self-report measures [POMS Confusion Score F=6.05, p=.02, partial2=.20]. Training in attentional self-regulation applied to participant defined goals may improve cognitive functioning in Veterans with chronic TBI. Attention regulation training may not only impact executive control functioning in real world complex tasks, but may also improve emotional regulation and functioning. Implications for treatment of Veterans with TBI are discussed.

Chen, AJ-W, Novakovic-Agopian T, Nycum TJ, Song S, Turner GR, Hills N, Rome S, Abrams GM, D’Esposito.  2011.  Training of goal-directed attention regulation enhances control over neural processing for individuals with brain injury., 2011 May. Brain. 134(5):1541-1554. Abstract2011_chen.pdf

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

Chen, AJ-W, D’Esposito.  2010.  Traumatic brain injury: from bench to bedside [corrected] to society., 2010 Apr 15. Neuron. 66(1):11-14. Abstract2010_chen.pdf

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

Zarahn, E, Aguirre GK, D’Esposito.  1997.  A trial-based experimental design for fMRI., 1997 Aug. NeuroImage. 6(2):122-138. Abstract1997_zarahn.pdf

An experimental design for functional MRI (fMRI) is presented whose conceptual units of analysis are behavioral trials, in contrast to blocks of trials. This type of design is referred to as a trial-based (TB) fMRI design. It is explained how TB designs can afford the ability to: (1) randomize the presentation of behavioral trials and (2) utilize intertrial variance in uncontrolled behavioral measures to examine their functional correlates. A particular type of TB design that involves modeling trial-evoked fMRI responses with one or more shifted impulse response functions is described. This design is capable of discriminating functional changes occurring during temporally separated behavioral subcomponents within trials. An example of such a design is implemented and its statistical specificity, functional sensitivity, and functional specificity are tested.

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


Postle, BR, Zarahn E, D’Esposito.  2000.  Using event-related fMRI to assess delay-period activity during performance of spatial and nonspatial working memory tasks., 2000 Feb. Brain Research Protocols. 5(1):57-66. Abstract2000_postle.pdf

Event-related experimental design and analysis techniques for functional magnetic resonance imaging (fMRI) take advantage of the intrinsic temporal resolution of fMRI to permit investigation of complex human behaviors on the time scale over which they can occur. The protocol described in this report permits the effective isolation and assessment of variance in the fMRI signal that is attributable solely to the delay portion of delayed-response tasks. It permits, therefore, evaluation of the purely mnemonic portions of working memory tasks without requiring the "cognitive subtraction" of nonmnemonic components of such tasks, such as visual processing and motor output. Features of this event-related fMRI technique include the empirical derivation of an impulse response function (IRF) from each subject participating in the experiment, single-subject and random effects group analyses, use of t-values of dependent measures, and the use of regions of interest (ROI) to improve the sensitivity of a priori contrasts. This report provides a detailed exposition of the research methodology of our event-related fMRI technique, the rationale behind many of its critical features, and examples of its application to two empirical datasets.

Miller, JA, D'Esposito M, Weiner KS.  2021.  Using Tertiary Sulci to Map the "Cognitive Globe" of Prefrontal Cortex., 2021 Mar 03. Journal of cognitive neuroscience. :1-18. Abstract

Stuss considered the human prefrontal cortex (pFC) as a "cognitive globe" [Stuss, D. T., & Benson, D. F. Neuropsychological studies of the frontal lobes. , , 3-28, 1984] on which functions of the frontal lobe could be mapped. Here, we discuss classic and recent findings regarding the evolution, development, function, and cognitive role of shallow indentations or tertiary sulci in pFC, with the goal of using tertiary sulci to map the "cognitive globe" of pFC. First, we discuss lateral pFC (LPFC) tertiary sulci in classical anatomy and modern neuroimaging, as well as their development, with a focus on those within the middle frontal gyrus. Second, we discuss tertiary sulci in comparative neuroanatomy, focusing on primates. Third, we summarize recent findings showing the utility of tertiary sulci for understanding structural-functional relationships with functional network insights in ventromedial pFC and LPFC. Fourth, we revisit and update unresolved theoretical perspectives considered by C. Vogt and O. Vogt (Allgemeinere ergebnisse unserer hirnforschung. , , 279-462, 1919) and F. Sanides (Structure and function of the human frontal lobe. , , 209-219, 1964) that tertiary sulci serve as landmarks for cortical gradients. Together, the consideration of these classic and recent findings indicate that tertiary sulci are situated in a unique position within the complexity of the "cognitive globe" of pFC: They are the smallest and shallowest of sulci in pFC, yet can offer insights that bridge spatial scales (microns to networks), modalities (functional connectivity to behavior), and species. As such, the map of tertiary sulci within each individual participant serves as a coordinate system specific to that individual on which functions may be further mapped. We conclude with new theoretical and methodological questions that, if answered in future research, will likely lead to mechanistic insight regarding the structure and function of human LPFC.

Miller, JA, D'Esposito M, Weiner KS.  2021.  Using Tertiary Sulci to Map the "Cognitive Globe" of Prefrontal Cortex., 2021 Aug 01. Journal of cognitive neuroscience. 33(9):1698-1715. Abstract

Stuss considered the human PFC as a "cognitive globe" [Stuss, D. T., & Benson, D. F. Neuropsychological studies of the frontal lobes. Psychological Bulletin, 95, 3-28, 1984] on which functions of the frontal lobe could be mapped. Here, we discuss classic and recent findings regarding the evolution, development, function, and cognitive role of shallow indentations or tertiary sulci in PFC, with the goal of using tertiary sulci to map the "cognitive globe" of PFC. First, we discuss lateral PFC (LPFC) tertiary sulci in classical anatomy and modern neuroimaging, as well as their development, with a focus on those within the middle frontal gyrus. Second, we discuss tertiary sulci in comparative neuroanatomy, focusing on primates. Third, we summarize recent findings showing the utility of tertiary sulci for understanding structural-functional relationships with functional network insights in ventromedial PFC and LPFC. Fourth, we revisit and update unresolved theoretical perspectives considered by C. Vogt and O. Vogt (Allgemeinere ergebnisse unserer hirnforschung. Journal für Psychologie und Neurologie, 25, 279-462, 1919) and F. Sanides (Structure and function of the human frontal lobe. Neuropsychologia, 2, 209-219, 1964) that tertiary sulci serve as landmarks for cortical gradients. Together, the consideration of these classic and recent findings indicate that tertiary sulci are situated in a unique position within the complexity of the "cognitive globe" of PFC: They are the smallest and shallowest of sulci in PFC, yet can offer insights that bridge spatial scales (microns to networks), modalities (functional connectivity to behavior), and species. As such, the map of tertiary sulci within each individual participant serves as a coordinate system specific to that individual on which functions may be further mapped. We conclude with new theoretical and methodological questions that, if answered in future research, will likely lead to mechanistic insight regarding the structure and function of human LPFC.

Aguirre, GK, Zarahn E, D’Esposito.  1998.  The variability of human, BOLD hemodynamic responses., 1998 Nov. NeuroImage. 8(4):360-369. Abstract1998_aguirre.pdf

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

Handwerker, DA, Ollinger JM, D’Esposito.  2004.  Variation of BOLD hemodynamic responses across subjects and brain regions and their effects on statistical analyses., 2004 Apr. NeuroImage. 21(4):1639-1651. Abstract2004_handwerker.pdf

Estimates of hemodynamic response functions (HRF) are often integral parts of event-related fMRI analyses. Although HRFs vary across individuals and brain regions, few studies have investigated how variations affect the results of statistical analyses using the general linear model (GLM). In this study, we empirically estimated HRFs from primary motor and visual cortices and frontal and supplementary eye fields (SEF) in 20 subjects. We observed more variability across subjects than regions and correlated variation of time-to-peak values across several pairs of regions. Simulations examined the effects of observed variability on statistical results and ways different experimental designs and statistical models can limit these effects. Widely spaced and rapid event-related experimental designs with two sampling rates were tested. Statistical models compared an empirically derived HRF to a canonical HRF and included the first derivative of the HRF in the GLM. Small differences between the estimated and true HRFs did not cause false negatives, but larger differences within an observed range of variation, such as a 2.5-s time-to-onset misestimate, led to false negatives. Although small errors minimally affected detection of activity, time-to-onset misestimates as small as 1 s influenced model parameter estimation and therefore random effects analyses across subjects. Experiment and analysis design methods such as decreasing the sampling rate or including the HRF’s temporal derivative in the GLM improved results, but did not eliminate errors caused by HRF misestimates. These results highlight the benefits of determining the best possible HRF estimate and potential negative consequences of assuming HRF consistency across subjects or brain regions.

Launer, LJ, Lewis CE, Schreiner PJ, Sidney S, Battapady H, Jacobs DR, Lim KO, D'Esposito M, Zhang Q, Reis J, Davatzikos C, Bryan NR.  2015.  Vascular Factors and Multiple Measures of Early Brain Health: CARDIA Brain MRI Study., 2015. PloS one. 10(3):e0122138. Abstract2015_launer.pdf

To identify early changes in brain structure and function that are associated with cardiovascular risk factors (CVRF).

Haight, TJ, Bryan NR, Erus G, Davatzikos C, Jacobs DR, D'Esposito M, Lewis CE, Launer LJ.  2015.  Vascular risk factors, cerebrovascular reactivity, and the default-mode brain network., 2015 Apr 23. NeuroImage. 115:7-16. Abstract2015_haight.pdf

Cumulating evidence from epidemiologic studies implicates cardiovascular health and cerebrovascular function in several brain diseases in late life. We examined vascular risk factors with respect to a cerebrovascular measure of brain functioning in subjects in mid-life, which could represent a marker of brain changes in later life. Breath-hold functional MRI (fMRI) was performed in 541 women and men (mean age 50.4 years) from the Coronary Artery Risk Development in Young Adults (CARDIA) Brain MRI sub-study. Cerebrovascular reactivity (CVR) was quantified as percentage change in blood-oxygen level dependent (BOLD) signal in activated voxels, which was mapped to a common brain template and log-transformed. Mean CVR was calculated for anatomic regions underlying the default-mode network (DMN) - a network implicated in AD and other brain disorders - in addition to areas considered to be relatively spared in the disease (e.g. occipital lobe), which were utilized as reference regions. Mean CVR was significantly reduced in the posterior cingulate/precuneus (β = -0.063, 95% CI: -0.106, -0.020), anterior cingulate (β = -0.055, 95% CI: -0.101, -0.010), and medial frontal lobe (β = -0.050, 95% CI: -0.092, -0.008) relative to mean CVR in the occipital lobe, after adjustment for age, sex, race, education, and smoking status, in subjects with pre-hypertension/hypertension compared to normotensive subjects. By contrast, mean CVR was lower, but not significantly, in the inferior parietal lobe (β = -0.024, 95% CI: -0.062, 0.014) and the hippocampus (β = -0.006, 95% CI: -0.062, 0.050) relative to mean CVR in the occipital lobe. Similar results were observed in subjects with diabetes and dyslipidemia compared to those without these conditions, though the differences were non-significant. Reduced CVR may represent diminished vascular functionality for the DMN for individuals with prehypertension/ hypertension in mid-life, and may serve as a preclinical marker for brain dysfunction in later life.

White-Devine, T, Grossman M, Robinson K, Onishi K, Biassou N.  1996.  Verb confrontation naming and word-picture matching in Alzheimer’s disease. Neuropsychology. 10(4):495-503. Abstract1996_whitedevine.pdfWebsite


Thompson-Schill, SL, Swick D, Farah MJ, D’Esposito, Kan IP, Knight RT.  1998.  Verb generation in patients with focal frontal lesions: a neuropsychological test of neuroimaging findings., 1998 Dec 22. Proceedings of the National Academy of Sciences of the United States of America. 95(26):15855-15860. Abstract1998_thompsonschill.pdf

What are the neural bases of semantic memory? Traditional beliefs that the temporal lobes subserve the retrieval of semantic knowledge, arising from lesion studies, have been recently called into question by functional neuroimaging studies finding correlations between semantic retrieval and activity in left prefrontal cortex. Has neuroimaging taught us something new about the neural bases of cognition that older methods could not reveal or has it merely identified brain activity that is correlated with but not causally related to the process of semantic retrieval? We examined the ability of patients with focal frontal lesions to perform a task commonly used in neuroimaging experiments, the generation of semantically appropriate action words for concrete nouns, and found evidence of the necessity of the left inferior frontal gyrus for certain components of the verb generation task. Notably, these components did not include semantic retrieval per se.

Postle, BR, D’Esposito.  1999.  "What"-Then-Where" in visual working memory: an event-related fMRI study., 1999 Nov. Journal of Cognitive Neuroscience. 11(6):585-597. Abstract1999_postle_jocn.pdf

Behavioral studies indicate that spatial and object working memory are computed by dissociable subsystems. We investigated the neural bases of this dissociation with a whole-brain fMRI design and analysis technique that permitted direct assessment of delay-period activity, uncontaminated by other components of the trial. The task employed a "what"-then-"where" design, with an object and a spatial delay period incorporated in each trial; within-trial order of delay conditions was balanced across each scan. Our experiment failed to find evidence, at the single-subject level and at the group level, for anatomical segregation of spatial and object working memory function in the frontal cortex. Delay-period activity in the caudate nucleus revealed a sensitivity to position in the trial in the spatial, but not the object, condition. In posterior regions, spatial delay-period activity was associated with preferential recruitment of extrastriate areas falling within Brodmann’s area 19 and, less reliably, the superior parietal lobule. Object-specific delay-period activity was found predominantly in ventral regions of the posterior cortex and demonstrated more topographic variability across subjects than did spatial working memory activity.

Sreenivasan, KK, D'Esposito M.  2019.  The what, where and how of delay activity., 2019 May 13. Nature Reviews: Neuroscience. 20(8):466-481. Abstract2019_sreenivasan.pdf

Working memory is characterized by neural activity that persists during the retention interval of delay tasks. Despite the ubiquity of this delay activity across tasks, species and experimental techniques, our understanding of this phenomenon remains incomplete. Although initially there was a narrow focus on sustained activation in a small number of brain regions, methodological and analytical advances have allowed researchers to uncover previously unobserved forms of delay activity various parts of the brain. In light of these new findings, this Review reconsiders what delay activity is, where in the brain it is found, what roles it serves and how it may be generated.

Postle, BR, Awh E, Jonides J, Smith EE, D’Esposito.  2004.  The where and how of attention-based rehearsal in spatial working memory., 2004 Jul. Brain Research. Cognitive Brain Research. 20(2):194-205. Abstract2004_postle.pdf

Rehearsal in human spatial working memory is accomplished, in part, via covert shifts of spatial selective attention to memorized locations ("attention-based rehearsal"). We addressed two outstanding questions about attention-based rehearsal: the topography of the attention-based rehearsal effect, and the mechanism by which it operates. Using event-related fMRI and a procedure that randomized the presentation of trials with delay epochs that were either filled with a flickering checkerboard or unfilled, we localized the effect to extrastriate areas 18 and 19, and confirmed its absence in striate cortex. Delay-epoch activity in these extrastriate regions, as well as in superior parietal lobule and intraparietal sulcus, was also lateralized on unfilled trials, suggesting that attention-based rehearsal produces a baseline shift in areas representing the to-be-remembered location in space. No frontal regions (including frontal eye fields) demonstrated lateralized activity consistent with a role in attention-based rehearsal.

Haight, T, Nick Bryan R, Erus G, Hsieh M-K, Davatzikos C, Nasrallah I, D'Esposito M, Jacobs DR, Lewis C, Schreiner P, Sidney S, Meirelles O, Launer LJ.  2018.  White matter microstructure, white matter lesions, and hypertension: An examination of early surrogate markers of vascular-related brain change in midlife., 2018. NeuroImage: Clinical. 18:753-761. Abstract2018_haight.pdf

We examined imaging surrogates of white matter microstructural abnormalities which may precede white matter lesions (WML) and represent a relevant marker of cerebrovascular injury in adults in midlife.

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


Curtis, CE, D'Esposito M.  2006.  Working Memory. Handbook of Functional Neuroimaging of Cognition (2nd Edition). , Cambridge: MIT Press Abstract2006_curtis.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
Nee, DE, D'Esposito M.  2015.  Working Memory. Brain Mapping: An Encyclopedic Reference. : Academic Press: Elsevier