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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


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


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.

Curtis, CE, Rao VY, D’Esposito.  2004.  Maintenance of spatial and motor codes during oculomotor delayed response tasks., 2004 Apr 21. The Journal of neuroscience : the official journal of the Society for Neuroscience. 24:3944-52. Abstractcurtis_ce_maintenance_of_spatial_and_motor_codes_during_oculomotor_delayed_response_tasks_j_neurosci_2004.pdf

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

Handwerker, DA, Ollinger JM, D’Esposito.  2004.  Variation of BOLD hemodynamic responses across subjects and brain regions and their effects on statistical analyses., 2004 Apr. NeuroImage. 21:1639-51. Abstract2004handwerker.pdf

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

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

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

Postle, BR, Druzgal TJ, D’Esposito.  2003.  Seeking the neural substrates of visual working memory storage., 2003 Sep-Dec. Cortex; a journal devoted to the study of the nervous system and behavior. 39:927-46. Abstractpostlecortex2003.pdf

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

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

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

Schumacher, EH, Elston PA, D’Esposito.  2003.  Neural evidence for representation-specific response selection., 2003 Nov 15. Journal of cognitive neuroscience. 15:1111-21. Abstract2003schumacher.pdf

Response selection is the mental process of choosing representations for appropriate motor behaviors given particular environmental stimuli and one’s current task situation and goals. Many cognitive theories of response selection postulate a unitary process. That is, one central response-selection mechanism chooses appropriate responses in most, if not all, task situations. However, neuroscience research shows that neural processing is often localized based on the type of information processed. Our current experiments investigate whether response selection is unitary or stimulus specific by manipulating response-selection difficulty in two functional magnetic resonance imaging experiments using spatial and nonspatial stimuli. The same participants were used in both experiments. We found spatial response selection involves the right prefrontal cortex, the bilateral premotor cortex, and the dorsal parietal cortical regions (precuneus and superior parietal lobule). Nonspatial response selection, conversely, involves the left prefrontal cortex and the more ventral posterior cortical regions (left middle temporal gyrus, left inferior parietal lobule, and right extrastriate cortex). Our brain activation data suggest a cognitive model for response selection in which different brain networks mediate the choice of appropriate responses for different types of stimuli. This model is consistent with behavioral research suggesting that response-selection processing may be more flexible and adaptive than originally proposed.

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


Postle, BR, D’Esposito.  2003.  Spatial working memory activity of the caudate nucleus is sensitive to frame of reference., 2003 Jun. Cognitive, affective & behavioral neuroscience. 3:133-44. Abstract2004postle.pdf

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

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

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

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

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

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

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

Rypma, B, D’Esposito.  2003.  A subsequent-memory effect in dorsolateral prefrontal cortex., 2003 Apr. Brain research. Cognitive brain research. 16:162-6. Abstractrypma2003.pdf

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

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

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

Ranganath, C, Johnson MK, D’Esposito.  2003.  Prefrontal activity associated with working memory and episodic long-term memory., 2003. Neuropsychologia. 41:378-89. Abstractranganathwmltm.pdf

Many recent neuroimaging studies have highlighted the role of prefrontal regions in the sustained maintenance and manipulation of information over short delays, or working memory (WM). In addition, neuroimaging findings have highlighted the role of prefrontal regions in the formation and retrieval of memories for events, or episodic long-term memory (LTM), but it remains unclear whether these regions are distinct from those that support WM. We used event-related functional magnetic resonance imaging (fMRI) to identify patterns of prefrontal activity associated with encoding and recognition during WM and LTM tasks performed by the same subjects. Results showed that the same bilateral ventrolateral prefrontal regions (at or near Brodmann’s Areas [BA] 6, 44, 45, and 47) and dorsolateral prefrontal regions (BA 9/46) were engaged during encoding and recognition within the context of WM and LTM tasks. In addition, a region situated in the left anterior middle frontal gyrus (BA 10/46) was engaged during the recognition phases of the WM and LTM tasks. These results support the view that the same prefrontal regions implement reflective processes that support both WM and LTM.

D’esposito, M.  2003.  Executive function and frontal systems. Neuropsychiatry. , Baltimore: Williams and Wilkins Abstract


Schumacher, EH, D’Esposito.  2002.  Neural implementation of response selection in humans as revealed by localized effects of stimulus-response compatibility on brain activation., 2002 Nov. Human brain mapping. 17:193-201. Abstractschumacherdespoito2002.pdf

Response selection, which involves choosing representations for appropriate motor behaviors given one’s current situation, is a fundamental mental process central to a wide variety of human performance, yet the neural mechanisms underlying this mental process remain unclear. Research using nonhuman primates implicates ventral prefrontal and lateral premotor cortices in this process. In contrast, human neuroimaging research also highlights the role of dorsal prefrontal, anterior cingulate, and superior parietal cortices in response selection. This inconsistency may stem from the difficulty of isolating response selection within the constraints of cognitive subtraction methodology utilized in neuroimaging. We overcome this limitation by using an experimental procedure designed to selectively influence discrete mental processing stages and analyses that are less reliant on the assumptions of cognitive subtraction. We varied stimulus contrast to affect stimulus encoding and stimulus-response compatibility to affect response selection. Brain activation data suggest processing specific to response selection in superior parietal and dorsal prefrontal cortices, and not ventral prefrontal cortex. Anterior cingulate and lateral premotor cortices may also be involved in response selection, or these regions may mediate other response processes.

Thompson-Schill, SL, Jonides J, Marshuetz C, Smith EE, D’Esposito, Kan IP, Knight RT, Swick D.  2002.  Effects of frontal lobe damage on interference effects in working memory., 2002 Jun. Cognitive, affective & behavioral neuroscience. 2:109-20. Abstractthompsonschill2002.pdf

Working memory is hypothesized to comprise a collection of distinct components or processes, each of which may have a unique neural substrate. Recent neuroimaging studies have isolated a region of the left inferior frontal gyrus that appears to be related specifically to one such component: resolving interference from previous items in working memory. In the present study, we examined working memory in patients with unilateral frontal lobe lesions by using a modified version of an item recognition task in which interference from previous trials was manipulated. In particular, we focused on patient R.C., whose lesion uniquely impinged on the region identified in the neuroimaging studies of interference effects. We measured baseline working memory performance and interference effects in R.C. and other frontal patients and in age-matched control subjects and young control subjects. Comparisons of each of these groups supported the following conclusions. Normal aging is associated with changes to both working memory and interference effects. Patients with frontal damage exhibited further declines in working memory but normal interference effects, with the exception of R.C., who exhibited a pronounced interference effect on both response time and accuracy. We propose that the left inferior frontal gyrus subserves a general, nonmnemonic function of selecting relevant information in the face of competing alternatives and that this function may be required by some working memory tasks.

Rypma, B, Berger JS, D’Esposito.  2002.  The influence of working-memory demand and subject performance on prefrontal cortical activity., 2002 Jul 1. Journal of cognitive neuroscience. 14:721-31. Abstractrypma2002.pdf

Brain imaging and behavioral studies of working memory (WM) converge to suggest that the ventrolateral prefrontal cortex (PFC) mediates a capacity-limited storage buffer and that the dorsolateral PFC mediates memory organization processes that support supracapacity memory storage. Previous research from our laboratory has shown that the extent to which such memory organization processes are required depends on both task factors (i.e., memory load) and subject factors (i.e., response speed). Task factors exert their effects mainly during WM encoding while subject factors exert their effects mainly during WM retrieval. In this study, we sought to test the generalizability of these phenomena under more difficult memory-demand conditions than have been used previously. During scanning, subjects performed a WM task in which they were required to maintain between 1 and 8 letters over a brief delay. Neural activity was measured during encoding, maintenance, and retrieval task periods using event-related functional magnetic resonance imaging. With increasing memory load, there were reaction time increases and accuracy rate decreases, ventrolateral PFC activation decreases during encoding, and dorsolateral PFC activation increases during maintenance and retrieval. These results suggest that the ventrolateral PFC mediates WM storage and that the dorsolateral PFC mediates strategic memory organization processes that facilitate supracapacity WM storage. Additionally, high-performing subjects showed overall less activation than low-performing subjects, but activation increases with increasing memory load in the lateral PFC during maintenance and retrieval. Low-performing subjects showed overall more activation than high-performing subjects, but minimal activation increases in the dorsolateral PFC with increasing memory load. These results suggest that individual differences in both neural efficiency and cognitive strategy underlie individual differences in the quality of subjects’ WM performance.

Polk, TA, Stallcup M, Aguirre GK, Alsop D, D’Esposito, Detre JA, Farah MJ.  2002.  Neural specialization for letter recognition., 2002 Feb 15. Journal of cognitive neuroscience. 14:145-59. Abstractpolk2002.pdf

Functional magnetic resonance imaging (fMRI) was used to estimate neural activity while subjects viewed strings of consonants, digits, and shapes. An area on or near the left fusiform gyrus was found that responded significantly more to letters than digits. Similar results were obtained when consonants were used whose visual features were matched with the digits and when an active matching task was used, suggesting that the results cannot be easily attributed to artifacts of the stimuli or task. These results demonstrate that neural specialization in the human brain can extend to a category of stimuli that is culturally defined and that is acquired many years postnatally.

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


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


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


Ranganath, C, D’Esposito.  2001.  Medial temporal lobe activity associated with active maintenance of novel information., 2001 Sep 13. Neuron. 31:865-73. Abstractranganath2001.pdf

Using event-related functional magnetic resonance imaging, we investigated the role of medial temporal regions during active maintenance of information over short delays or working memory. In experiment 1, we observed sustained bilateral hippocampal activation during maintenance of novel faces across a short delay period but not during face encoding or recognition. In contrast, we observed transient right parahippocampal activation during encoding and recognition but not during maintenance. We replicated these findings in experiment 2 and further determined that anterior hippocampal activation was greater during maintenance of novel than familiar faces. Our results reveal the importance of medial temporal lobe regions for the active maintenance of novel information in the absence of perceptual stimulation.

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

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

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

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

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

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

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

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

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

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

Rypma, B, D'Esposito M.  2001.  Age-related changes in brain-behavior relationships: evidence from event-related functional MRI studies. Ageing and Executive Control. , Hove, UK: Psychology Press
Johnson, MK, Hayes SM, D'Esposito M, Raye CL.  2001.  Confabulation. Handbook of Neuropsychology (2nd edition, volume 2). , Amsterdam: Elsevier Abstract


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


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

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

Mitchell, KJ, Johnson MK, Raye CL, D’Esposito.  2000.  fMRI evidence of age-related hippocampal dysfunction in feature binding in working memory., 2000 Sep. Brain research. Cognitive brain research. 10:197-206. Abstractmitchhippo.pdf

Richly detailed memories for particular events depend on processes that bind individual features of experience together. Previous cognitive behavioral research indicates that older adults have more difficulty than young adults in conditions requiring feature binding. We used functional magnetic resonance imaging (fMRI) during a working memory task to identify neural substrates of this age-related deficit in feature binding. For young, but not older, adults there was greater activation in left anterior hippocampus on combination trials (remember objects together with their locations) than on trials in which participants were told to remember only which objects or only which locations occurred. The results provide neuroimaging evidence for an age-related hippocampal dysfunction in feature binding in working memory.

Kimberg, DY, Aguirre GK, D’Esposito.  2000.  Modulation of task-related neural activity in task-switching: an fMRI study., 2000 Sep. Brain research. Cognitive brain research. 10:189-96. Abstractmodulation.pdf

Task-switching paradigms, in which subjects are typically asked to switch between different S-R mappings, can be considered operationalizations of executive control. Such paradigms are therefore potentially useful in investigating the neural bases of control functions. Here, we present the results of an fMRI study intended to examine two separable components of task-switching: preparation, and the residual shift cost identified by Rogers and Monsell [13]. In analyses restricted to functionally identified regions of interest, we found robust evidence of greater activity for switch trials, compared to repeat trials. This pattern was present both at the time of stimulus presentation and prior to the switch trial. In analyses of the entire brain, we were able to identify one area in the superior parietal lobule that was active during switching but was not part of the apparent network of task-related regions. We conclude that switch trials are neurally distinct from repeat trials in eliciting generally greater neural activity both before and during the performance of a trial.

Ranganath, C, Johnson MK, D’Esposito.  2000.  Left anterior prefrontal activation increases with demands to recall specific perceptual information., 2000 Nov 15. The Journal of neuroscience : the official journal of the Society for Neuroscience. 20:RC108. Abstractranganath2000.pdf

Results from neuroimaging studies have led to competing theories regarding the contributions of prefrontal regions to memory formation and retrieval. To investigate this issue, we used event-related functional magnetic resonance imaging to assess prefrontal activation during encoding and retrieval of pictures of objects. Responses to studied and unstudied objects at retrieval were compared between two tests with differing demands for the specificity of information to be retrieved (source vs old-new recognition). Results showed that bilateral ventral [Brodmann’s areas (BA) 44, 45, and 47] and right dorsal (BA 9) prefrontal regions were activated during both encoding and retrieval, but activity in these regions was not reliably modulated by the specificity of information to be retrieved. A region in left anterior prefrontal cortex (BA 10/46) was reliably activated during retrieval trials, and activation in this region increased with demands to retrieve perceptually detailed information about studied objects. Our results show that left anterior prefrontal cortex is engaged during the monitoring and evaluation of specific memory characteristics at retrieval-a process critical for accurate episodic remembering.

Rypma, B, D’Esposito.  2000.  Isolating the neural mechanisms of age-related changes in human working memory., 2000 May. Nature neuroscience. 3:509-15. Abstractisolating.pdf

Working memory (WM), the process by which information is coded into memory, actively maintained and subsequently retrieved, declines with age. To test the hypothesis that age-related changes in prefrontal cortex (PFC) may mediate this WM decline, we used functional MRI to investigate age differences in PFC activity during separate WM task components (encoding, maintenance, retrieval). We found greater PFC activity in younger than older adults only in dorsolateral PFC during memory retrieval. Fast younger subjects showed less dorsolateral PFC activation during retrieval than slow younger subjects, whereas older adults showed the opposite pattern. Thus age-related changes in dorsolateral PFC and not ventrolateral PFC account for WM decline with normal aging.

D’Esposito, Ballard D, Zarahn E, Aguirre GK.  2000.  The role of prefrontal cortex in sensory memory and motor preparation: an event-related fMRI study., 2000 May. NeuroImage. 11:400-8. Abstractballard.pdf

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

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

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

D’Esposito, Postle BR, Rypma B.  2000.  Prefrontal cortical contributions to working memory: evidence from event-related fMRI studies., 2000 Jul. Experimental brain research. Experimentelle Hirnforschung. Expérimentation cérébrale. 133:3-11. Abstractdespo2000.pdf

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

Zarahn, E, Aguirre GK, D’Esposito.  2000.  Replication and further studies of neural mechanisms of spatial mnemonic processing in humans., 2000 Jan. Brain research. Cognitive brain research. 9:1-17. Abstract2000zarahn.pdf

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

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

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

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

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

D’Esposito.  2000.  Functional neuroimaging of cognition., 2000. Seminars in neurology. 20:487-98. Abstract

Neuroimaging has, in many respects, revolutionized the study of behavioral neurology and cognitive neuroscience. Early studies of brain-behavior relationships relied on a precise neurological examination as the basis for hypothesizing the site of brain damage that was responsible for a given behavioral syndrome. The advent of structural brain imaging, first with computed tomography (CT) and later with magnetic resonance imaging (MRI), paved the way for more precise anatomical localization of the cognitive deficits that are manifest after brain injury. In recent years, functional neuroimaging, broadly defined as techniques that provide measures of brain activity, has further increased our ability to study the neural basis of behavior. The modern era of functional brain imaging was introduced with the use of positron emission tomography (PET). In more recent years, functional magnetic resonance imaging (fMRI) has rapidly emerged as an extremely powerful technique with many advantages over PET for studying cognition. Thus, the principles underlying fMRI studies of cognition are the focus of this review.

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

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

Raye, CL, Johnson MK, Mitchell KJ, Nolde SF, D’Esposito.  2000.  fMRI investigations of left and right PFC contributions to episodic remembering. Psychobiology. Abstract2000raye.pdf


Kimberg, DY, D'Esposito M.  2000.  Frontal lobes II: cognitive issues. Patient-Based Approaches to Cognitive Neuroscience. : Kluwer Academic Publishers Abstract


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


D'Esposito, M, Postle BR.  2000.  Neural correlates of component processes of working memory: evidence from neuropsychological and pharmacological studies. Control of Cognitive Processes: Attention & Performance XVIII. Abstract


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


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

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

Postle, BR, Berger JS, D’Esposito.  1999.  Functional neuroanatomical double dissociation of mnemonic and executive control processes contributing to working memory performance., 1999 Oct 26. Proceedings of the National Academy of Sciences of the United States of America. 96:12959-64. Abstractdoubledissociation.pdf

We used event-related functional MRI to investigate the neural bases of two categories of mental processes believed to contribute to performance of an alphabetization working memory task: memory storage and memory manipulation. Our delayed-response tasks required memory for the identity and position-in-the-display of items in two- or five-letter memory sets (to identify load-sensitive regions) or memory for the identity and relative position-in-the-alphabet of items in five-letter memory sets (to identify manipulation-sensitive regions). Results revealed voxels in the left perisylvian cortex of five of five subjects showing load sensitivity (as contrasted with alphabetization-sensitive voxels in this region in only one subject) and voxels of dorsolateral prefrontal cortex in all subjects showing alphabetization sensitivity (as contrasted with load-sensitive voxels in this region in two subjects). This double dissociation was reliable at the group level. These data are consistent with the hypothesis that the nonmnemonic executive control processes that can contribute to working memory function are primarily prefrontal cortex-mediated whereas mnemonic processes necessary for working memory storage are primarily posteriorly mediated. More broadly, they support the view that working memory is a faculty that arises from the coordinated interaction of computationally and neuroanatomically dissociable processes.

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

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

D’Esposito, Postle BR, Ballard D, Lease J.  1999.  Maintenance versus manipulation of information held in working memory: an event-related fMRI study., 1999 Oct. Brain and cognition. 41:66-86. Abstractmaintenance.pdf

One model of the functional organization of lateral prefrontal cortex (PFC) in primates posits that this region is organized in a dorsal/ventral fashion subserving spatial and object working memory, respectively. Alternatively, it has been proposed that a dorsal/ventral subdivision of lateral PFC instead reflects the type of processing performed upon information held in working memory. We tested this hypothesis using an event-related fMRI method that can discriminate among functional changes occurring during temporally separated behavioral subcomponents of a single trial. Subjects performed a delayed-response task with two types of trials in which they were required to: (1) retain a sequence of letters across the delay period (maintenance) or (2) reorder the sequence into alphabetical order across the delay period (manipulation). In each subject, activity during the delay period was found in both dorsolateral and ventrolateral PFC in both types of trials. However, dorsolateral PFC activity was greater in manipulation trials. These findings are consistent with the processing model of the functional organization of working memory in PFC.

Postle, BR, D’Esposito.  1999.  "What"-Then-Where" in visual working memory: an event-related fMRI study., 1999 Nov. Journal of cognitive neuroscience. 11:585-97. Abstractwhat.pdf

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

Rypma, B, D’Esposito.  1999.  The roles of prefrontal brain regions in components of working memory: effects of memory load and individual differences., 1999 May 25. Proceedings of the National Academy of Sciences of the United States of America. 96:6558-63. Abstractroles.pdf

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

D’Esposito, Postle BR, Jonides J, Smith EE.  1999.  The neural substrate and temporal dynamics of interference effects in working memory as revealed by event-related functional MRI., 1999 Jun 22. Proceedings of the National Academy of Sciences of the United States of America. 96:7514-9. Abstractsubstrate.pdf

Research on the prefrontal cortex (PFC) of monkeys and humans indicates that this region supports a heterogeneous repertoire of mental processes that contribute to many complex behaviors, such as working memory. Anatomical evidence for some of these processes derives from functional neuroimaging experiments using blocked experimental designs, which average signal across all components of many trials and therefore cannot dissociate distinct processes with different time courses. Using event-related functional MRI, we were able to isolate temporally the neural correlates of processes contributing to the target presentation, delay, and probe portions of an item-recognition task. Two types of trials were of greatest interest: those with Recent Negative probes that matched an item from the target set of the previous, but not the present, two trials, and those with Nonrecent Negative probes that did not match a target item from either the present or the two previous trials. There was no difference between the two trial types in target presentation (i.e., encoding) or delay-period (i.e., active maintenance) PFC activation, but there was significantly greater activation for Recent Negatives than Nonrecent Negative activation associated with the probe period within left ventrolateral PFC. These findings characterize spatially and temporally a proactive interference effect that may reflect the operation of a PFC-mediated response-inhibition mechanism that contributes to working memory performance.

Thompson-Schill, SL, Aguirre GK, D’Esposito, Farah MJ.  1999.  A neural basis for category and modality specificity of semantic knowledge., 1999 Jun. Neuropsychologia. 37:671-6. Abstractschillneuralbasis.pdf

Prevalent theories hold that semantic memory is organized by sensorimotor modality (e.g., visual knowledge, motor knowledge). While some neuroimaging studies support this idea, it cannot account for the category specific (e.g., living things) knowledge impairments seen in some brain damaged patients that cut across modalities. In this article we test an alternative model of how damage to interactive, modality-specific neural regions might give rise to these categorical impairments. Functional MRI was used to examine a cortical area with a known modality-specific function during the retrieval of visual and non-visual knowledge about living and non-living things. The specific predictions of our model regarding the signal observed in this area were confirmed, supporting the notion that semantic memory is functionally segregated into anatomically discrete, but highly interactive, modality-specific regions.

Postle, BR, D’Esposito.  1999.  Dissociation of human caudate nucleus activity in spatial and nonspatial working memory: an event-related fMRI study., 1999 Jul 16. Brain research. Cognitive brain research. 8:107-15. Abstractdissociation.pdf

We employed a novel event-related fMRI design and analysis technique to explore caudate nucleus contributions to spatial and nonspatial working memory. The spatial condition of a delayed-response task revealed greater mnemonic activation in four of six subjects when the delay period preceded immediately a probe stimulus requiring an overt motor response, as contrasted with a probe requiring no response. This effect was not seen in frontal or parietal cortical areas, and was seen in the caudate nucleus in a formally identical object condition in just one of six subjects. We hypothesized that this pattern of activity represented spatially dependent motor preparation. A second experiment confirmed this hypothesis: delay-period activity of the caudate nucleus showed greater time dependence in a task that featured spatial and motoric memory demands than in a comparable nonspatial task that featured the same response contingencies. These results suggest an important subcortical locus of the dissociation between spatial and nonspatial working memory, and a role for the human caudate nucleus in the integration of spatially coded mnemonic information with motor preparation to guide behavior.

D’Esposito, Zarahn E, Aguirre GK, Rypma B.  1999.  The effect of normal aging on the coupling of neural activity to the bold hemodynamic response., 1999 Jul. NeuroImage. 10:6-14. Abstractagingeffect.pdf

The use of functional neuroimaging to test hypotheses regarding age-related changes in the neural substrates of cognitive processes relies on assumptions regarding the coupling of neural activity to neuroimaging signal. Differences in neuroimaging signal response between young and elderly subjects can be mapped directly to differences in neural response only if such coupling does not change with age. Here we examined spatial and temporal characteristics of the BOLD fMRI hemodynamic response in primary sensorimotor cortex in young and elderly subjects during the performance of a simple reaction time task. We found that 75% of elderly subjects (n = 20) exhibited a detectable voxel-wise relationship with the behavioral paradigm in this region as compared to 100% young subjects (n = 32). The median number of suprathreshold voxels in the young subjects was greater than four times that of the elderly subjects. Young subjects had a slightly greater signal:noise per voxel than the elderly subjects that was attributed to a greater level of noise per voxel in the elderly subjects. The evidence did not support the idea that the greater head motion observed in the elderly was the cause of this greater voxel-wise noise. There were no significant differences between groups in either the shape of the hemodynamic response or in its the within-group variability, although the former evidenced a near significant trend. The overall finding that some aspects of the hemodynamic coupling between neural activity and BOLD fMRI signal change with age cautions against simple interpretations of the results of imaging studies that compare young and elderly subjects.

Thompson-Schill, SL, D’Esposito, Kan IP.  1999.  Effects of repetition and competition on activity in left prefrontal cortex during word generation., 1999 Jul. Neuron. 23:513-22. Abstractthompsonschill1999.pdf

Neuroimaging studies have revealed an association between word generation and activity in the left inferior frontal gyrus (IFG) that is attentuated with item repetition. The experiment reported here examined the effects of repeated word generation, under conditions in which completion was either decreased or increased, on activity measured during whole-brain echoplanar functional magnetic resonance imaging. Activity in left IFG decreased during repetition conditions that reduced competition but increased during repetition conditions that increased competition; this pattern was contrasted to repetition effects observed in other cortical areas, specifically regions of left temporal cortex. The increase in left IFG activity, which is not predicted by a simple semantic retrieval account of prefrontal function, is consistent with the hypothesis that left IFG subserves the selection of semantic knowledge among competing alternatives.

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

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

D’Esposito, Zarahn E, Aguirre GK.  1999.  Event-related functional MRI: implications for cognitive psychology., 1999 Jan. Psychological bulletin. 125:155-64. Abstractdesposito1999.pdf

Functional magnetic resonance imaging (fMRI) has rapidly emerged as a powerful technique in cognitive neuroscience. We describe and critique a new class of imaging experimental designs called event-related fMRI that exploit the temporal resolution of fMRI by modeling fMRI signal changes associated with behavioral trials as opposed to blocks of behavioral trials. Advantages of this method over block designs include the ability to (a) randomize trial presentations, (b) test for functional correlates of behavioral measures with greater power, (c) directly examine the neural correlates of temporally dissociable components of behavioral trials (e.g., the delay period of a working memory task), and (d) test for differences in the onset time of neural activity evoked by different trial types. Consequently, event-related fMRI has the potential to address a number of cognitive psychology questions with a degree of inferential and statistical power not previously available.

Zarahn, E, Aguirre GK, D’Esposito.  1999.  Temporal isolation of the neural correlates of spatial mnemonic processing with fMRI., 1999 Jan. Brain research. Cognitive brain research. 7:255-68. Abstract1999zarahn.pdf

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

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

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

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


Nolde, SF, Johnson MK, D’Esposito.  1998.  Left prefrontal activation during episodic remembering: an event-related fMRI study., 1998 Oct 26. Neuroreport. 9:3509-14. Abstractnolde.pdf

The major current theory relating brain mechanisms in prefrontal cortex (PFC) to memory for discrete events (episodic memory) emphasizes the role of right PFC during retrieval. Using event-related fMRI, we found both right and left PFC activity during episodic remembering, but only the left PFC activity was related to the amount of episodic detail required at test. We suggest that right PFC subserves relatively simple, heuristic, cognitive processes and that left PFC is recruited for more reflectively demanding, systematic, processes. Episodic remembering often requires such systematic processes and, under those circumstances, recruits left, as well as right, PFC.

D’Esposito, Ballard D, Aguirre GK, Zarahn E.  1998.  Human prefrontal cortex is not specific for working memory: a functional MRI study., 1998 Oct. NeuroImage. 8:274-82. Abstract

Lesion studies in monkeys have provided evidence that lateral prefrontal cortex is necessary for working memory, the cognitive processes involved in the temporary maintenance and manipulation of information. Monkey electrophysiological studies, however, have also observed prefrontal neuronal activity associated with cognitive processes that are nonmnemonic. We tested the hypothesis that the same regions of human prefrontal cortex that demonstrate activity during working memory tasks would also demonstrate activity during tasks without working memory demands. During echoplanar fMRI imaging, subjects performed a three-condition experiment (working memory task, nonworking memory task, rest). In the working memory task, subjects observed serially presented stimuli and determined if each stimulus was the same as that presented two stimuli back. The nonworking memory task in Experiment 1 required subjects to identify a single predetermined stimulus; in Experiment 2, subjects were required to make a button press to every stimulus. In all subjects in both experiments, the working memory task exhibited greater prefrontal cortical activity compared to either nonworking memory task. In these same prefrontal regions, greater activation was also observed during both nonworking memory tasks compared to rest. We conclude that human lateral prefrontal cortex supports processes in addition to working memory. Thus, reverse inference of the form "if prefrontal cortex is active, working memory is engaged" is not supported.

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


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

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

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

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