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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Cools, R, Sheridan M, Jacobs E, D’Esposito.  2007.  Impulsive personality predicts dopamine-dependent changes in frontostriatal activity during component processes of working memory., 2007 May 16. The Journal of neuroscience : the official journal of the Society for Neuroscience. 27:5506-14. Abstract2007cools.pdf

Dopaminergic drugs affect a variety of cognitive processes, but the direction and extent of effects vary across individuals and tasks. Paradoxical effects are observed, by which the same drug causes cognitive enhancing as well as adverse effects. Here, we demonstrate that individual differences in impulsive personality account for the contrasting effects of dopaminergic drugs on working memory and associated frontostriatal activity. We observed that the dopamine D2 receptor agonist bromocriptine improved the flexible updating (switching) of relevant information in working memory in high-impulsive subjects, but not in low-impulsive subjects. These behavioral effects in high-impulsive subjects accompanied dissociable effects on frontostriatal activity. Bromocriptine modulated the striatum during switching but not during distraction from relevant information in working memory. Conversely, the lateral frontal cortex was modulated by bromocriptine during distraction but not during switching. The present results provide a key link between dopamine D2 receptor function, impulsivity, and frontostriatal activity during component processes of working memory.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Gibbs, SE, D’Esposito.  2006.  A functional magnetic resonance imaging study of the effects of pergolide, a dopamine receptor agonist, on component processes of working memory., 2006 Apr 28. Neuroscience. 139:359-71. Abstract2006gibbsfmristudyoftheeffectsofpergolide.pdf

Working memory is an important cognitive process dependent on a network of prefrontal and posterior cortical regions. In this study we tested the effects of the mixed D1-D2 dopamine receptor agonist pergolide on component processes of human working memory using functional magnetic resonance imaging (fMRI). An event-related trial design allowed separation of the effects on encoding, maintenance, and retrieval processes. Subjects were tested with spatial and object memoranda to investigate modality-specific effects of dopaminergic stimulation. We also measured baseline working memory capacity as previous studies have shown that effects of dopamine agonists vary with working memory span. Pergolide improved reaction time for high-span subjects and impaired reaction time for low-span subjects. This span-dependent change in behavior was accompanied by span-dependent changes in delay-related activity in the premotor cortex. We also found evidence for modality-specific effects of pergolide only during the response period. Pergolide increased activity for spatial memoranda and decreased activity for object memoranda in task-related regions including the prefrontal and parietal cortices.

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

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

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

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

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

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

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

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

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

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

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 : a journal of neurology. 128:1964-83. Abstractrajahdesposito2005_brain.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.

Sun, FT, Miller LM, D’Esposito.  2005.  Measuring temporal dynamics of functional networks using phase spectrum of fMRI data., 2005 Oct 15. NeuroImage. 28:227-37. Abstractsun2005_measuring_temporal_dynamics_of_functional_networks_using_phase_spectrum_of_fmri_data.pdf

We present a novel method to measure relative latencies between functionally connected regions using phase-delay of functional magnetic resonance imaging data. Derived from the phase component of coherency, this quantity estimates the linear delay between two time-series. In conjunction with coherence, derived from the magnitude component of coherency, phase-delay can be used to examine the temporal properties of functional networks. In this paper, we apply coherence and phase-delay methods to fMRI data in order to investigate dynamics of the motor network during task and rest periods. Using the supplementary motor area (SMA) as a reference region, we calculated relative latencies between the SMA and other regions within the motor network including the dorsal premotor cortex (PMd), primary motor cortex (M1), and posterior parietal cortex (PPC). During both the task and rest periods, we measured significant delays that were consistent across subjects. Specifically, we found significant delays between the SMA and the bilateral PMd, bilateral M1, and bilateral PPC during the task condition. During the rest condition, we found that the temporal dynamics of the network changed relative to the task period. No significant delays were measured between the SMA and the left PM and left M1; however, the right PM, right M1, and bilateral PPC were significantly delayed with respect to the SMA. Additionally, we observed significant map-wise differences in the dynamics of the network at task compared to the network at rest. These differences were observed in the interaction between the SMA and the left M1, left superior frontal gyrus, and left middle frontal gyrus. These temporal measurements are important in determining how regions within a network interact and provide valuable information about the sequence of cognitive processes within a network.

Miller, LM, Sun FT, Curtis CE, D’Esposito.  2005.  Functional interactions between oculomotor regions during prosaccades and antisaccades., 2005 Oct. Human brain mapping. 26:119-27. Abstractmiller2005_functional_interactions_between_oculomotor_regions_during_saccades_and_antisaccades.pdf

Human behavior reflects a continual negotiation of automatic and directed actions. The oculomotor network is a well-characterized neural system in which to study this balance of behavioral control. For instance, saccades made toward and away from a flashed visual stimulus (prosaccades and antisaccades, respectively) are known to engage different cognitive processes. Brain regions important for such controlled execution include the presupplementary motor area (pre-SMA), frontal eye fields (FEF), and intraparietal sulcus (IPS). Recent work has emphasized various elements of this network but has not explored the functional interactions among regions. We used event-related fMRI to image human brain activity during performance of an interleaved pro/antisaccade task. Since traditional univariate statistics cannot address issues of functional connectivity, a multivariate technique is necessary. Coherence between fMRI time series of the pre-SMA with the FEF and IPS was used to measure functional interactions. The FEF, but not IPS, showed significant differential coherence between pro- and antisaccade trials with pre-SMA. These results suggest that the pre-SMA coordinates with FEF to maintain a controlled, preparatory set for task-appropriate oculomotor execution.

Gazzaley, A, Cooney JW, Rissman J, D’Esposito.  2005.  Top-down suppression deficit underlies working memory impairment in normal aging., 2005 Oct. Nature neuroscience. 8:1298-300. Abstractgazzaley_natneuro_2005.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.

Miller, BT, D’Esposito.  2005.  Searching for "the top" in top-down control., 2005 Nov 23. Neuron. 48:535-8. Abstractmiller2005_searching_for_the_top_in_top-down_control.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.

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

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

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

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

Postle, BR, Desposito M, Corkin S.  2005.  Effects of verbal and nonverbal interference on spatial and object visual working memory., 2005 Mar. Memory & cognition. 33:203-12. Abstract2005postle.pdf

We tested the hypothesis that a verbal coding mechanism is necessarily engaged by object, but not spatial, visual working memory tasks. We employed a dual-task procedure that paired n-back working memory tasks with domain-specific distractor trials inserted into each interstimulus interval of the n-back tasks. In two experiments, object n-back performance demonstrated greater sensitivity to verbal distraction, whereas spatial n-back performance demonstrated greater sensitivity to motion distraction. Visual object and spatial working memory may differ fundamentally in that the mnemonic representation of featural characteristics of objects incorporates a verbal (perhaps semantic) code, whereas the mnemonic representation of the location of objects does not. Thus, the processes supporting working memory for these two types of information may differ in more ways than those dictated by the "what/where" organization of the visual system, a fact more easily reconciled with a component process than a memory systems account of working memory function.

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. 17:507-17. Abstractgazzaley_jocn_2005.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.

Miller, LM, D’Esposito.  2005.  Perceptual fusion and stimulus coincidence in the cross-modal integration of speech., 2005 Jun 22. The Journal of neuroscience : the official journal of the Society for Neuroscience. 25:5884-93. Abstractmiller2005_preceptual_fusion_and_stimulus_coincidence_in_the_cross-modal_integration_of_speech.pdf

Human speech perception is profoundly influenced by vision. Watching a speaker’s mouth movements significantly improves comprehension, both for normal listeners in noisy environments and especially for the hearing impaired. A number of brain regions have been implicated in audiovisual speech tasks, but little evidence distinguishes them functionally. In an event-related functional magnetic resonance imaging study, we differentiate neural systems that evaluate cross-modal coincidence of the physical stimuli from those that mediate perceptual binding. Regions consistently involved in perceptual fusion per se included Heschl’s gyrus, superior temporal sulcus, middle intraparietal sulcus, and inferior frontal gyrus. Successful fusion elicited activity biased toward the left hemisphere, although failed cross-modal binding recruited regions in both hemispheres. A broad network of other areas, including the superior colliculus, anterior insula, and anterior intraparietal sulcus, were more involved with evaluating the spatiotemporal correspondence of speech stimuli, regardless of a subject’s perception. All of these showed greater activity to temporally offset stimuli than to audiovisually synchronous stimuli. Our results demonstrate how elements of the cross-modal speech integration network differ in their sensitivity to physical reality versus perceptual experience.

Gibbs, SE, D’Esposito.  2005.  Individual capacity differences predict working memory performance and prefrontal activity following dopamine receptor stimulation., 2005 Jun. Cognitive, affective & behavioral neuroscience. 5:212-21. Abstractgibbs2005_individual_capacity_differences_predict_working_memory_performance_and_prefrontal_activity_following_dopamine_receptor_stimulation.pdf

Dopamine receptors are abundant in the prefrontal cortex (PFC), a critical region involved in working memory. This pharmacological fMRI study tested the relationships between dopamine, PFC function, and individual differences in working memory capacity. Subjects performed a verbal delayed-recognition task after taking either the dopamine receptor agonist bromocriptine or a placebo. Behavioral effects of bromocriptine treatment depended on subjects’ working memory spans, with the greatest behavioral benefit for lower span subjects. After bromocriptine, PFC activity was positively correlated with a measure of cognitive efficiency (RT slope) during the probe period of the task. Less efficient subjects with slower memory retrieval rates had greater PFC activity, whereas more efficient subjects had less activity. After placebo, these measures were uncorrelated. These results support the role of dopamine in verbal working memory and suggest that dopamine may modulate the efficiency of retrieval of items from the contents of working memory. Individual differences in PFC dopamine receptor concentration may thus underlie the behavioral effects of dopamine stimulation on working memory function.

Mitchell, JM, Fields HL, D’Esposito, Boettiger CA.  2005.  Impulsive responding in alcoholics., 2005 Dec. Alcoholism, clinical and experimental research. 29:2158-69. Abstract2005mitchell.pdf

{BACKGROUND: Impaired decision-making is one diagnostic characteristic of alcoholism. Quantifying decision-making with rapid and robust laboratory-based measures is thus desirable for the testing of novel treatments for alcoholism. Previous research has demonstrated the utility of delay discounting (DD) tasks for quantifying differences in decision-making in substance abusers and normal controls. In DD paradigms subjects choose between a small, immediate reward and a larger, delayed reward. METHODS: We used a novel computerized DD task to demonstrate that abstinent alcoholics (AA

Ochsner, KN, Beer JS, Robertson ER, Cooper JC, Gabrieli JDE, Kihsltrom JF, D’Esposito.  2005.  The neural correlates of direct and reflected self-knowledge., 2005 Dec. NeuroImage. 28:797-814. Abstractochsner2005_the_neural_correlates_of_direct_and_reflected_self-knowledge.pdf

Socrates said that in order to lead a balanced life one must, "know thyself." In two fMRI experiments, the present study examined the mechanisms mediating two ways in which the self can be known: through direct appraisals (i.e., an individual’s own self-beliefs) and reflected appraisals (i.e., an individual’s perception of how others view him or her). Experiment 1 examined the common and distinct neural bases of direct appraisals of the self, close others, and normative judgments of trait desirability. All three judgment types activated medial prefrontal cortex (MPFC) to a similar degree. Experiment 2 examined the common and distinct neural bases of (1) direct appraisals of self, a close other or a non-close other, and (2) reflected appraisals made from the perspective of a close or a non-close other. Consistent with Experiment 1, all judgment types activated MPFC. Direct appraisals of the self as compared to others more strongly recruited MPFC and right rostrolateral PFC. Direct appraisals as compared to reflected appraisals recruited regions associated with a first-person perspective (posterior cingulate), whereas reflected as compared to direct appraisals recruited regions associated with emotion and memory (insula, orbitofrontal, and temporal cortex). These results support models suggesting that MPFC mediates meta-cognitive processes that may be recruited for direct and reflected self appraisals depending upon the demands of a specific task.

Rypma, B, Berger JS, Genova HM, Rebbechi D, D’Esposito.  2005.  Dissociating age-related changes in cognitive strategy and neural efficiency using event-related fMRI., 2005 Aug. Cortex; a journal devoted to the study of the nervous system and behavior. 41:582-94. Abstract2005rypma.pdf

We used event-related fMRI to measure brain activity while younger and older adults performed an item-recognition task in which the memory-set size varied between 1 and 8 letters. Each trial was composed of a 4-second encoding period in which subjects viewed random letter strings, a 12-second retention period and a 2-second retrieval period in which subjects decided whether a single probe letter was or was not part of the memory set. For both groups, reaction time increased and accuracy decreased with increasing memory set-size. There were minimal age-related differences in activation patterns with increasing memory set-size in prefrontal cortex (PFC). Regression analyses of individual subjects’ performance and cortical activity indicated that speed and accuracy accounted for considerable variance in dorsal and ventral PFC activity during encoding and retrieval. These results suggest that younger and older adults utilize similar working memory (WM) strategies to accommodate increasing memory demand. They support a model of cognitive slowing in which processing rate is related to neural efficiency.

Gibbs, SE, D’Esposito.  2005.  A functional MRI study of the effects of bromocriptine, a dopamine receptor agonist, on component processes of working memory., 2005 Aug. Psychopharmacology. 180:644-53. Abstractgibbs2005_a_functional_mri_study_ofthe_effects_of_bromocriptine_a_dopamine_receptor_agonist_on_component_processes_of_working_memory.pdf

RATIONALE: Dopamine is abundant in the prefrontal cortex and striatum, regions implicated in working memory processes. Monkey studies suggest that subpopulations of prefrontal neurons are sensitive to component processes of working memory, and that dopaminergic actions at D1 and D2 receptors differentially affect these neurons. However, it is not known to what extent the effects of dopaminergic stimulation may differ in human subjects across the processing stages of working memory, and whether these effects are found throughout the network of task-related brain regions. OBJECTIVE: In this study we tested the effects of the D2 dopamine agonist bromocriptine during the performance of a delayed recognition task using functional magnetic resonance imaging (fMRI). METHODS: We measured blood oxygenation level dependent (BOLD) signals as subjects performed a spatial and object delayed recognition task. Subjects were scanned twice, once following 1.25 mg of bromocriptine and once following lactose placebo in a randomized double-blind design. Using an event-related design allowed for separate investigation of encoding, delay, and response period effects of dopaminergic stimulation. RESULTS: A group analysis revealed that bromocriptine treatment decreased activity in the task network at encoding and increased activity at response. There was no clear pattern of change in the delay period network. Across subjects, these BOLD signal changes were accompanied by reductions in accuracy and increases in response time during delayed recognition for spatial and object information. CONCLUSIONS: Decreased activity during encoding suggests that hyperdopaminergic stimulation may have reduced stimulus encoding processes, contributing to impaired performance.

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

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

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. 43:1444-55. Abstractschumacher2005_sustained_involvement_of_a_frontal-parietal_network_for_spatial_response_selection_with_practice_of_a_spatial_choice-reaction_task.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.

Gazzaley, A, D'Esposito M.  2005.  BOLD fMRI and cognitive aging. Cognitive Neuroscience of Aging. : Oxford University Press Abstract

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

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2004
Rissman, J, Gazzaley A, D’Esposito.  2004.  Measuring functional connectivity during distinct stages of a cognitive task., 2004 Oct. NeuroImage. 23:752-63. Abstract2004_rissman.pdf

The inherently multivariate nature of functional brain imaging data affords the unique opportunity to explore how anatomically disparate brain areas interact during cognitive tasks. We introduce a new method for characterizing inter-regional interactions using event-related functional magnetic resonance imaging (fMRI) data. This method’s principle advantage over existing analytical techniques is its ability to model the functional connectivity between brain regions during distinct stages of a cognitive task. The method is implemented by using separate covariates to model the activity evoked during each stage of each individual trial in the context of the general linear model (GLM). The resulting parameter estimates (beta values) are sorted according to the stage from which they were derived to form a set of stage-specific beta series. Regions whose beta series are correlated during a given stage are inferred to be functionally interacting during that stage. To validate the assumption that correlated fluctuations in trial-to-trial beta values imply functional connectivity, we applied the method to an event-related fMRI data set in which subjects performed two sequence-tapping tasks. In concordance with previous electrophysiological and fMRI coherence studies, we found that the task requiring greater bimanual coordination induced stronger correlations between motor regions of the two hemispheres. The method was then applied to an event-related fMRI data set in which subjects performed a delayed recognition task. Distinct functional connectivity maps were generated during the component stages of this task, illustrating how important and novel observations of neural networks within the isolated stages of a cognitive task can be obtained.

Landau, SM, Schumacher EH, Garavan H, Druzgal TJ, D’Esposito.  2004.  A functional MRI study of the influence of practice on component processes of working memory., 2004 May. NeuroImage. 22:211-21. Abstract2004landau.pdf

Previous neuroimaging studies have shown that neural activity changes with task practice. The types of changes reported have been inconsistent, however, and the neural mechanisms involved remain unclear. In this study, we investigated the influence of practice on different component processes of working memory (WM) using a face WM task. Event-related functional magnetic resonance imaging (fMRI) methodology allowed us to examine signal changes from early to late in the scanning session within different task stages (i.e., encoding, delay, retrieval), as well as to determine the influence of different levels of WM load on neural activity. We found practice-related decreases in fMRI signal and effects of memory load occurring primarily during encoding. This suggests that practice improves encoding efficiency, especially at higher memory loads. The decreases in fMRI signal we observed were not accompanied by improved behavioral performance; in fact, error rate increased for high WM load trials, indicating that practice-related changes in activation may occur during a scanning session without behavioral evidence of learning. Our results suggest that practice influences particular component processes of WM differently, and that the efficiency of these processes may not be captured by performance measures alone.

Yamaguchi, S, Hale LA, D’Esposito, Knight RT.  2004.  Rapid prefrontal-hippocampal habituation to novel events., 2004 Jun 9. The Journal of neuroscience : the official journal of the Society for Neuroscience. 24:5356-63. Abstractyamaguchi_etal_jn_2004.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.

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

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

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. 20:194-205. Abstractpostle_etal_cbr_2004.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.

Sun, FT, Miller LM, D’Esposito.  2004.  Measuring interregional functional connectivity using coherence and partial coherence analyses of fMRI data., 2004 Feb. NeuroImage. 21:647-58. Abstractsunni2004.pdf

Understanding functional connectivity within the brain is crucial to understanding neural function; even the simplest cognitive operations are supported by highly distributed neural circuits. We developed a novel method to measure task-related functional interactions between neural regions by applying coherence and partial coherence analyses to functional magnetic resonance imaging (fMRI) data. Coherence and partial coherence are spectral measures that estimate the linear time-invariant (LTI) relationship between time series. They can be used to generate maps of task-specific connectivity associated with seed regions of interest (ROIs). These maps may then be compared across tasks, revealing nodes with task-related changes of connectivity to the seed ROI. To validate the method, we applied it to an event-related fMRI data set acquired while subjects performed two sequence tapping tasks, one of which required more bimanual coordination. Areas showing increased functional connectivity with both tasks were the same as those showing increased activity. Furthermore, though there were no significant differences in mean activity between the two tasks, significant increases in interhemispheric coherence were found between the primary motor (M1) and premotor (PM) regions for the task requiring more bimanual coordination. This increase in interhemispheric connectivity is supported by other brain imaging techniques as well as patient studies.

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

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

Gazzaley, A, Rissman J, D’Esposito.  2004.  Functional connectivity during working memory maintenance., 2004 Dec. Cognitive, affective & behavioral neuroscience. 4:580-99. Abstract2004gazzaley.pdf

Neurophysiological experiments with monkeys have demonstrated that working memory (WM) is associated with persistent neural activity in multiple brain regions, such as the prefrontal cortex (PFC), the parietal cortex, and posterior unimodal association areas. WM maintenance is believed to require the coordination of these brain regions, which do not function in isolation but, rather, interact to maintain visual percepts that are no longer present in the environment. However, single-unit physiology studies and traditional univariate analyses of functional brain imaging data cannot evaluate interactions between distant brain regions, and so evidence of regional integration during WM maintenance is largely indirect. In this study, we utilized a recently developed multivariate analysis method that allows us to explore functional connectivity between brain regions during the distinct stages of a delayed face recognition task. To characterize the neural network mediating the on-line maintenance of faces, the fusiform face area (FFA) was defined as a seed and was then used to generate whole-brain correlation maps. A random effects analysis of the correlation data revealed a network of brain regions exhibiting significant correlations with the FFA seed during the WM delay period. This maintenance network included the dorsolateral and ventrolateral PFC, the premotor cortex, the intraparietal sulcus, the caudate nucleus, the thalamus, the hippocampus, and occipitotemporal regions. These findings support the notion that the coordinated functional interaction between nodes of a widely distributed network underlies the active maintenance of a perceptual representation.

Ranganath, C, Cohen MX, Dam C, D’Esposito.  2004.  Inferior temporal, prefrontal, and hippocampal contributions to visual working memory maintenance and associative memory retrieval., 2004 Apr 21. The Journal of neuroscience : the official journal of the Society for Neuroscience. 24:3917-25. Abstractranganathjn2004.pdf

Higher order cognition depends on the ability to recall information from memory and hold it in mind to guide future behavior. To specify the neural mechanisms underlying these processes, we used event-related functional magnetic resonance imaging to compare brain activity during the performance of a visual associative memory task and a visual working memory task. Activity within category-selective subregions of inferior temporal cortex reflected the type of information that was actively maintained during both the associative memory and working memory tasks. In addition, activity in the anterior prefrontal cortex and hippocampus was specifically enhanced during associative memory retrieval. These data are consistent with the view that the active maintenance of visual information is supported by activation of object representations in inferior temporal cortex, but that goal-directed associative memory retrieval additionally depends on top-down signals from the anterior prefrontal cortex and medial temporal lobes.