Export 407 results:
Sort by: Author Title Type [ Year  (Asc)]
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


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(4):246-257. Abstract2001_kimberg.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.

Druzgal, TJ, D’Esposito.  2001.  A neural network reflecting decisions about human faces., 2001 Dec 6. Neuron. 32(5):947-955. Abstract2001_druzgal_neuron.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.

Druzgal, TJ, D’Esposito.  2001.  Activity in fusiform face area modulated as a function of working memory load., 2001 Jan. Brain research: Cognitive Brain Research. 10(3):355-364. Abstract2001_druzgal.pdf

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

Kounios, J, Smith RW, Yang W, Bachman P, D’Esposito.  2001.  Cognitive association formation in human memory revealed by spatiotemporal brain imaging., 2001 Jan. Neuron. 29(1):297-306. Abstract2001_kounios.pdf

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

Postle, BR, Berger JS, Goldstein JH, Curtis CE, D’Esposito.  2001.  Behavioral and neurophysiological correlates of episodic coding, proactive interference, and list length effects in a running span verbal working memory task., 2001 Mar. Cognitive, Affective & Behavioral Neuroscience. 1(1):10-21. Abstract2001_postle.pdf

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

Ranganath, C, D’Esposito.  2001.  Medial temporal lobe activity associated with active maintenance of novel information., 2001 Sep 13. Neuron. 31(5):865-873. Abstract2001_ranganath.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.

D'Esposito, M.  2002.  Dopamine in cerebral aging: the key to memory. Servier International, France.
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


Ranganath, C, Lokendra S, D'Esposito M.  2002.  A new view of the medial temporal lobes and the structure of memory. , Berkeley, CA: International Computer Science Institute2002_ranganath.pdf
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


D'Esposito, M, Postle BR, Rypma B.  2002.  The role of the lateral prefrontal cortex in working memory: evidence from event-related fMRI studies. International Congress Series. 1232:21-27.
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(2):145-159. Abstract2002_polk.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.

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(5):721-731. Abstract2002_rypma.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.

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(2):109-120. Abstract2002_thompsonschill.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.

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(3):193-201. Abstract2002_schumacher.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.

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


Kimberg, DY, D’Esposito.  2003.  Cognitive effects of the dopamine receptor agonist pergolide., 2003. Neuropsychologia. 41(8):1020-1027. Abstract2003_kimberg.pdf

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

Ranganath, C, Johnson MK, D’Esposito.  2003.  Prefrontal activity associated with working memory and episodic long-term memory., 2003. Neuropsychologia. 41(3):378-389. Abstract2003_ranganath.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.

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

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

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

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

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(6):771-784. Abstract2003_druzgal.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.

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. 2003(4):PE2. Abstract2003_gazzaley.pdf

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.

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

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

D’Esposito, Deouell LY, Gazzaley A.  2003.  Alterations in the BOLD fMRI signal with ageing and disease: a challenge for neuroimaging., 2003 Nov. Nature Reviews: Neuroscience. 4(11):863-872. Abstract2003_desposito.pdf


Schumacher, EH, Elston PA, D’Esposito.  2003.  Neural evidence for representation-specific response selection., 2003 Nov 15. Journal of Cognitive Neuroscience. 15(8):1111-1121. Abstract2003_schumacher.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.

Curtis, CE, D’Esposito.  2003.  Persistent activity in the prefrontal cortex during working memory., 2003 Sep. Trends in Cognitive Sciences. 7(9):415-423. Abstract2003_curtis_tcs.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.

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

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

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(1):2-13. Abstract2004_ranganath_neuro.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.

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

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

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. Journal of Neuroscience. 24(16):3917-3925. Abstract2004_ranganath_jn2004.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. Journal of Neuroscience. 24(16):3944-3952. Abstract2004_curtis_jn.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.

Curtis, CE, D’Esposito.  2004.  The effects of prefrontal lesions on working memory performance and theory., 2004 Dec. Cognitive, Affective & Behavioral Neuroscience. 4(4):528-539. Abstract2004_curtis.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(4):580-599. Abstract2004_gazzaley.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.

Sun, FT, Miller LM, D’Esposito.  2004.  Measuring interregional functional connectivity using coherence and partial coherence analyses of fMRI data., 2004 Feb. NeuroImage. 21(2):647-658. Abstract2004_sun.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.

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

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

Ranganath, C, DeGutis J, D’Esposito.  2004.  Category-specific modulation of inferior temporal activity during working memory encoding and maintenance., 2004 Jun. Brain Research: Cognitive Brain Research. 20(1):37-45. Abstract2004_ranganath.pdf

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

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

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

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(1):211-221. Abstract2004_landau.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.

Rissman, J, Gazzaley A, D’Esposito.  2004.  Measuring functional connectivity during distinct stages of a cognitive task., 2004 Oct. NeuroImage. 23(2):752-763. 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.

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 Abstract2005_desposito_neurorehab.pdf


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

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

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(2):175-182. Abstract2005_ranganath.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.

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. 41(4):582-594. Abstract2005_rypma.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(4):644-653. Abstract2005_gibbs_pp.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.

Mitchell, JM, Fields HL, D’Esposito, Boettiger CA.  2005.  Impulsive responding in alcoholics., 2005 Dec. Alcoholism. Clinical and Experimental Research. 29(12):2158-2169. Abstract2005_mitchell.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(4):797-814. Abstract2005_ochsner.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.

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(2):212-221. Abstract2005_gibbs.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.

Miller, LM, D’Esposito.  2005.  Perceptual fusion and stimulus coincidence in the cross-modal integration of speech., 2005 Jun 22. Journal of Neuroscience. 25(25):5884-5893. Abstract2005_miller_jocn.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.

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(2):203-212. Abstract2005_postle.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(3):507-517. Abstract2005_gazzaley_jocn.pdf

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

Boettiger, CA, D’Esposito.  2005.  Frontal networks for learning and executing arbitrary stimulus-response associations., 2005 Mar 9. Journal of Neuroscience. 25(10):2723-2732. Abstract2005_boettiger.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.

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(1):177-183. Abstract2005_curtis.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.

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

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

Miller, LM, Sun FT, Curtis CE, D’Esposito.  2005.  Functional interactions between oculomotor regions during prosaccades and antisaccades., 2005 Oct. Human Brain Mapping. 26(2):119-127. Abstract2005_miller.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(10):1298-1300. Abstract2005_gazzaley.pdf

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

Sun, FT, Miller LM, D’Esposito.  2005.  Measuring temporal dynamics of functional networks using phase spectrum of fMRI data., 2005 Oct 15. NeuroImage. 28(1):227-237. Abstract2005_sun.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.

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

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

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

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

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


Millman, J, D'Esposito M.  2006.  Data and Analysis Management for Functional Magnetic Resonance Imaging Studies. 2nd International Advanced Database Conference. :24-28.: US Education Service
D’esposito, M.  2006.  Functional MRI: cognitive neuroscience applications. Functional MRI. , Berlin: Springer-Verlag Abstract2006_despo_cogfmri.pdf


Gazzaley, A, D'Esposito M.  2006.  Unifying the prefrontal cortex: executive control, neural networks and top-down modulation. The Human Frontal Lobes (2nd Edition). , New York: Guilford Publications Abstract2006_gazzaley_topdown.pdf


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


D’Esposito, Chen AJ-W.  2006.  Neural mechanisms of prefrontal cortical function: implications for cognitive rehabilitation., 2006. Progress in Brain Research. 157:123-139. Abstract2006_despo.pdf

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

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

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

Gibbs, SE, D’Esposito.  2006.  A functional magnetic resonance imaging study of the effects of pergolide, a dopamine receptor agonist, on component processes of working memory., 2006 Apr 28. Neuroscience. 139(1):359-371. Abstract2006_gibbs.pdf

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

Hooker, CI, Germine LT, Knight RT, D’Esposito.  2006.  Amygdala response to facial expressions reflects emotional learning., 2006 Aug 30. Journal of Neuroscience. 26(35):8915-8922. Abstract2006_hooker.pdf

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

Cools, R, Ivry R, D’Esposito.  2006.  The human striatum is necessary for responding to changes in stimulus relevance., 2006 Dec. Journal of Cognitive Neuroscience. 18(12):1973-1983. Abstract2006_cools.pdf

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

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

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

Yoon, JH, Curtis CE, D’Esposito.  2006.  Differential effects of distraction during working memory on delay-period activity in the prefrontal cortex and the visual association cortex., 2006 Feb 15. NeuroImage. 29(4):1117-1126. Abstract2006_yoon.pdf

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

Fiebach, CJ, Rissman J, D’Esposito.  2006.  Modulation of inferotemporal cortex activation during verbal working memory maintenance., 2006 Jul 20. Neuron. 51(2):251-261. Abstract2006_fiebach.pdf

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

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

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

D’Esposito, Cooney JW, Gazzaley A, Gibbs SE, Postle BR.  2006.  Is the prefrontal cortex necessary for delay task performance? Evidence from lesion and FMRI data., 2006 Mar Journal of the International Neuropsychological Society. 12(2):248-260. Abstract2006_desposito.pdf

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

Chen, AJ-W, Abrams GM, D’Esposito.  2006.  Functional reintegration of prefrontal neural networks for enhancing recovery after brain injury., 2006 Mar-Apr. Journal of Head Trauma Rehabilitation. 21(2):107-118. Abstract2006_chen.pdf

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

Beer, JS, Knight RT, D’Esposito.  2006.  Controlling the integration of emotion and cognition: the role of frontal cortex in distinguishing helpful from hurtful emotional information., 2006 May. Psychological Science. 17(5):448-453. Abstract2006_beer.pdf

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

Stelzel, C, Schumacher EH, Schubert T, D’Esposito.  2006.  The neural effect of stimulus-response modality compatibility on dual-task performance: an fMRI study., 2006 Nov. Psychological Research. 70(6):514-525. Abstract2006_stelzel.pdf

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

Rypma, B, Berger JS, Prabhakaran V, Bly BM, Kimberg DY, Biswal BB, D’Esposito.  2006.  Neural correlates of cognitive efficiency., 2006 Nov 15. NeuroImage. 33(3):969-979. Abstract2006_rypma.pdf

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

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

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

D'Esposito, M.  2007.  Attention! How your brain manages its need to heed. Scientific American.
Gazzaley, A, D'Esposito M.  2007.  Considerations for the application of BOLD fMRI to neurological impaired populations. Functional Neuroimaging of Neurological Disorders. , New York: Guilford Publications Abstract2007_gazzaley4.pdf


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


Krawczyk, DC, Gazzaley A, D’Esposito.  2007.  Reward modulation of prefrontal and visual association cortex during an incentive working memory task., 2007 Apr 13. Brain Research. 1141:168-177. Abstract2007_krawczyk.pdf

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

Johnson, MR, Mitchell KJ, Raye CL, D’Esposito, Johnson MK.  2007.  A brief thought can modulate activity in extrastriate visual areas: Top-down effects of refreshing just-seen visual stimuli., 2007 Aug 1. NeuroImage. 37(1):290-299. Abstract2007_johnson.pdf

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

Badre, D, D’Esposito.  2007.  Functional magnetic resonance imaging evidence for a hierarchical organization of the prefrontal cortex., 2007 Dec. Journal of Cognitive Neuroscience. 19(12):2082-2099. Abstract2007_badre.pdf

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

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

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

Boettiger, CA, Mitchell JM, Tavares VC, Robertson M, Joslyn G, D’Esposito, Fields HL.  2007.  Immediate reward bias in humans: fronto-parietal networks and a role for the catechol-O-methyltransferase 158(Val/Val) genotype., 2007 Dec 26. Journal of Neuroscience. 27(52):14383-14391. Abstract2007_boettiger.pdf

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

Mitchell, JM, Tavares VC, Fields HL, D’Esposito, Boettiger CA.  2007.  Endogenous opioid blockade and impulsive responding in alcoholics and healthy controls., 2007 Feb. Neuropsychopharmacology. 32(2):439-449. Abstract2007_mitchell.pdf

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

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

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

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

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

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

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

Logie, RH, D’Esposito.  2007.  Working memory in the brain., 2007 Jan. Cortex. 43(1):1-4. Abstract2007_logie.pdf


Hester, R, D’Esposito, Cole MW, Garavan H.  2007.  Neural mechanisms for response selection: comparing selection of responses and items from working memory., 2007 Jan 1. NeuroImage. 34(1):446-454. Abstract2007_hester.pdf

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

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

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