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Bloemendaal, M, van Schouwenburg MR, Miyakawa A, Aarts E, D'Esposito M, Cools R.  2014.  Dopaminergic modulation of distracter-resistance and prefrontal delay period signal., 2014 Oct 11. Psychopharmacology. 232(6):1061-1070. Abstract2014_bloemendaal.pdf

Dopamine has long been implicated in the online maintenance of information across short delays. Specifically, dopamine has been proposed to modulate the strength of working memory representations in the face of intervening distracters. This hypothesis has not been tested in humans. We fill this gap using pharmacological neuroimaging. Healthy young subjects were scanned after intake of the dopamine receptor agonist bromocriptine or placebo (in a within-subject, counterbalanced, and double-blind design). During scanning, subjects performed a delayed match-to-sample task with face stimuli. A face or scene distracter was presented during the delay period (between the cue and the probe). Bromocriptine altered distracter-resistance, such that it impaired performance after face relative to scene distraction. Individual differences in the drug effect on distracter-resistance correlated negatively with drug effects on delay period signal in the prefrontal cortex, as well as on functional connectivity between the prefrontal cortex and the fusiform face area. These results provide evidence for the hypothesis that dopaminergic modulation of the prefrontal cortex alters resistance of working memory representations to distraction. Moreover, we show that the effects of dopamine on the distracter-resistance of these representations are accompanied by modulation of the functional strength of connections between the prefrontal cortex and stimulus-specific posterior cortex.

Cools, R, D'Esposito M.  2009.  Dopaminergic modulation of flexible cognitive control in humans. Dopamine Handbook. , Oxford, UK: Oxford University Press
Wallace, DL, Aarts E, Dang LC, Greer SM, Jagust W, D'Esposito M.  2014.  Dorsal striatal dopamine, food preference, and health perception in humans. PLoS One. 9(5):e96319.2014_wallace.pdf
Nomura, EM, Gratton C, Visser RM, Kayser A, Perez F, D’Esposito.  2010.  Double dissociation of two cognitive control networks in patients with focal brain lesions., 2010 Jun 29. Proceedings of the National Academy of Sciences of the United States of America. 107(26):12017-12022. Abstract2010_nomura.pdf

Neuroimaging studies of cognitive control have identified two distinct networks with dissociable resting state connectivity patterns. This study, in patients with heterogeneous damage to these networks, demonstrates network independence through a double dissociation of lesion location on two different measures of network integrity: functional correlations among network nodes and within-node graph theory network properties. The degree of network damage correlates with a decrease in functional connectivity within that network while sparing the nonlesioned network. Graph theory properties of intact nodes within the damaged network show evidence of dysfunction compared with the undamaged network. The effect of anatomical damage thus extends beyond the lesioned area, but remains within the bounds of the existing network connections. Together this evidence suggests that networks defined by their role in cognitive control processes exhibit independence in resting data.

Peters, J, D'Esposito M.  2020.  The drift diffusion model as the choice rule in inter-temporal and risky choice: A case study in medial orbitofrontal cortex lesion patients and controls., 2020 Apr 20. PLoS Computational Biology. 16(4):e1007615. Abstract2020_peters.pdf

Sequential sampling models such as the drift diffusion model (DDM) have a long tradition in research on perceptual decision-making, but mounting evidence suggests that these models can account for response time (RT) distributions that arise during reinforcement learning and value-based decision-making. Building on this previous work, we implemented the DDM as the choice rule in inter-temporal choice (temporal discounting) and risky choice (probability discounting) using hierarchical Bayesian parameter estimation. We validated our approach in data from nine patients with focal lesions to the ventromedial prefrontal cortex / medial orbitofrontal cortex (vmPFC/mOFC) and nineteen age- and education-matched controls. Model comparison revealed that, for both tasks, the data were best accounted for by a variant of the drift diffusion model including a non-linear mapping from value-differences to trial-wise drift rates. Posterior predictive checks confirmed that this model provided a superior account of the relationship between value and RT. We then applied this modeling framework and 1) reproduced our previous results regarding temporal discounting in vmPFC/mOFC patients and 2) showed in a previously unpublished data set on risky choice that vmPFC/mOFC patients exhibit increased risk-taking relative to controls. Analyses of DDM parameters revealed that patients showed substantially increased non-decision times and reduced response caution during risky choice. In contrast, vmPFC/mOFC damage abolished neither scaling nor asymptote of the drift rate. Relatively intact value processing was also confirmed using DDM mixture models, which revealed that in both groups >98% of trials were better accounted for by a DDM with value modulation than by a null model without value modulation. Our results highlight that novel insights can be gained from applying sequential sampling models in studies of inter-temporal and risky decision-making in cognitive neuroscience.

Rissman, J, Gazzaley A, D’Esposito.  2008.  Dynamic adjustments in prefrontal, hippocampal, and inferior temporal interactions with increasing visual working memory load., 2008 Jul. Cerebral Cortex. 18(7):1618-1629. Abstract2008_rissman.pdf

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

Lee, TG, D'Esposito M.  2012.  The Dynamic Nature of Top-Down Signals Originating from Prefrontal Cortex: A Combined fMRI-TMS Study., 2012 Oct 31. Journal of Neuroscience. 32(44):15458-15466. Abstract2012_lee.pdf

The prefrontal cortex (PFC) is proposed to be the source of top-down signals that can modulate extrastriate visual processing in accordance with behavioral goals, yet little direct causal evidence for this hypothesis exists. Using theta burst transcranial magnetic stimulation, we disrupted PFC function in human participants before performing a working memory task during fMRI scanning. PFC disruption decreased the tuning of extrastriate cortex responses, coinciding with decrements in working memory performance. We also found that activity in the homologous PFC region in the nonstimulated hemisphere predicted performance following disruption. Specifically, those participants with greater homologous PFC activity and greater connectivity between this region and extrastriate cortex were the most resistant to PFC disruption. These findings provide evidence for a compensatory mechanism following insults to the brain, and insight into the dynamic nature of top-down signals originating from the PFC.

Lorenc, ES, Lee TG, Chen AJ-W, D'Esposito M.  2015.  The Effect of Disruption of Prefrontal Cortical Function with Transcranial Magnetic Stimulation on Visual Working Memory., 2015. Frontiers in Systems Neuroscience. 9:169. Abstract2015_lorenc.pdf

It is proposed that feedback signals from the prefrontal cortex (PFC) to extrastriate cortex are essential for goal-directed processing, maintenance, and selection of information in visual working memory (VWM). In a previous study, we found that disruption of PFC function with transcranial magnetic stimulation (TMS) in healthy individuals impaired behavioral performance on a face/scene matching task and decreased category-specific tuning in extrastriate cortex as measured with functional magnetic resonance imaging (fMRI). In this study, we investigated the effect of disruption of left inferior frontal gyrus (IFG) function on the fidelity of neural representations of two distinct information codes: (1) the stimulus category and (2) the goal-relevance of viewed stimuli. During fMRI scanning, subjects were presented face and scene images in pseudo-random order and instructed to remember either faces or scenes. Within both anatomical and functional regions of interest (ROIs), a multi-voxel pattern classifier was used to quantitatively assess the fidelity of activity patterns representing stimulus category: whether a face or a scene was presented on each trial, and goal relevance, whether the presented image was task relevant (i.e., a face is relevant in a "Remember Faces" block, but irrelevant in a "Remember Scenes" block). We found a reduction in the fidelity of the stimulus category code in visual cortex after left IFG disruption, providing causal evidence that lateral PFC modulates object category codes in visual cortex during VWM. In addition, we found that IFG disruption caused a reduction in the fidelity of the goal relevance code in a distributed set of brain regions. These results suggest that the IFG is involved in determining the task-relevance of visual input and communicating that information to a network of regions involved in further processing during VWM. Finally, we found that participants who exhibited greater fidelity of the goal relevance code in the non-disrupted right IFG after TMS performed the task with the highest accuracy.

Rissman, J, Gazzaley A, D’Esposito.  2009.  The effect of non-visual working memory load on top-down modulation of visual processing., 2009 Jun. Neuropsychologia. 47(7):1637-1646. Abstract2009_rissman.pdf

While a core function of the working memory (WM) system is the active maintenance of behaviorally relevant sensory representations, it is also critical that distracting stimuli are appropriately ignored. We used functional magnetic resonance imaging to examine the role of domain-general WM resources in the top-down attentional modulation of task-relevant and irrelevant visual representations. In our dual-task paradigm, each trial began with the auditory presentation of six random (high load) or sequentially ordered (low load) digits. Next, two relevant visual stimuli (e.g., faces), presented amongst two temporally interspersed visual distractors (e.g., scenes), were to be encoded and maintained across a 7-s delay interval, after which memory for the relevant images and digits was probed. When taxed by high load digit maintenance, participants exhibited impaired performance on the visual WM task and a selective failure to attenuate the neural processing of task-irrelevant scene stimuli. The over-processing of distractor scenes under high load was indexed by elevated encoding activity in a scene-selective region-of-interest relative to low load and passive viewing control conditions, as well as by improved long-term recognition memory for these items. In contrast, the load manipulation did not affect participants’ ability to upregulate activity in this region when scenes were task-relevant. These results highlight the critical role of domain-general WM resources in the goal-directed regulation of distractor processing. Moreover, the consequences of increased WM load in young adults closely resemble the effects of cognitive aging on distractor filtering [Gazzaley, A., Cooney, J. W., Rissman, J., & D’Esposito, M. (2005). Top-down suppression deficit underlies working memory impairment in normal aging. Nature Neuroscience 8, 1298-1300], suggesting the possibility of a common underlying mechanism.

D’Esposito, Zarahn E, Aguirre GK, Rypma B.  1999.  The effect of normal aging on the coupling of neural activity to the bold hemodynamic response., 1999 Jul. NeuroImage. 10(1):6-14. Abstract1999_desposito_ni.pdf

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

D’Esposito, Zarahn E, Aguirre GK, Shin RK, Auerbach P, Detre JA.  1997.  The effect of pacing of experimental stimuli on observed functional MRI activity., 1997 Aug. NeuroImage. 6(2):113-121. Abstract1997_desposito_ni.pdf

Neuroimaging activation studies typically observe signals during two or more periods of differing cognitive activity which are then analyzed by a subtraction to test for localized neuroanatomical dissociations between cognitive tasks. Significant activity found between task conditions is frequently assumed to reflect a novel cognitive process present in one task and not the other. We present a conceptual framework that considers the neural mechanisms underlying such observed neuroimaging changes. We propose that neuroimaging experiments which present stimuli at a fixed pace (where each trial takes the same amount of time) will be sensitive to changes in both duration and intensity of neural processing. In contrast, the signal observed during a self-paced design is derived from neural processing averaged over the reaction time and hence could be less sensitive to differences in duration of neural processing. As an empirical demonstration of these ideas, we studied normal subjects using echoplanar functional MRI during two visuospatial tasks (matching of either ROTATED or NONROTATED stimuli) performed using FIXED and SELF-PACED designs. In both pacing designs, reaction times were greater in the ROTATED than NONROTATED task, interpreted as a greater duration of neural processing during the ROTATED compared to the NONROTATED task. In the FIXED-PACED design, significantly greater signal was present within a parieto-occipital cortical region during the ROTATED task compared to the NONROTATED task. This difference was not observed during the SELF-PACED design. This result illustrates the importance of considering trial pacing in the interpretation of functional neuroimaging activation studies.

Fegen, D, Buchsbaum BR, D'Esposito M.  2014.  The effect of rehearsal rate and memory load on verbal working memory., 2014 Oct 23. NeuroImage. 105C:120-131. Abstract2014_fegen.pdf

While many neuroimaging studies have investigated verbal working memory (WM) by manipulating memory load, the subvocal rehearsal rate at these various memory loads has generally been left uncontrolled. Therefore, the goal of this study was to investigate how mnemonic load and the rate of subvocal rehearsal modulate patterns of activity in the core neural circuits underlying verbal working memory. Using fMRI in healthy subjects, we orthogonally manipulated subvocal rehearsal rate and memory load in a verbal WM task with long 45-s delay periods. We found that middle frontal gyrus (MFG) and superior parietal lobule (SPL) exhibited memory load effects primarily early in the delay period and did not exhibit rehearsal rate effects. In contrast, we found that inferior frontal gyrus (IFG), premotor cortex (PM) and Sylvian-parietal-temporal region (area Spt) exhibited approximately linear memory load and rehearsal rate effects, with rehearsal rate effects lasting through the entire delay period. These results indicate that IFG, PM and area Spt comprise the core articulatory rehearsal areas involved in verbal WM, while MFG and SPL are recruited in a general supervisory role once a memory load threshold in the core rehearsal network has been exceeded.

Gratton, C, Lee T, Nomura EM, D'Esposito M.  2013.  The effect of theta-burst TMS on cognitive control networks. Frontiers in Systems Neuroscience. 7:124.2013_gratton.pdf
Kimberg, DY, D’Esposito, Farah MJ.  1997.  Effects of bromocriptine on human subjects depend on working memory capacity., 1997 Nov 10. Neuroreport. 8(16):3581-3585. Abstract1997_kimberg.pdf

Pharmacological manipulation of brain dopamine concentration affects visuospatial working memory in humans and in animals, the latter effects localized to the prefrontal cortex. However, the effects of dopamine agonists on humans are poorly understood. We hypothesized that bromocriptine would have an effect on cognitive functions associated with the prefrontal cortex via its effects on cortical dopamine receptors and on subcortical receptors in areas that project to the neocortex. We found that the effect of bromocriptine on young normal subjects depended on the subjects’ working memory capacity. High-capacity subjects performed more poorly on the drug, while low-capacity subjects improved. These results demonstrate an empirical link between a dopamine-mediated working memory system and higher cognitive function in humans.

Furman, DJ, White RL, Naskolnakorn JR, Ye S, Kayser AS, D'Esposito M.  2020.  Effects of dopaminergic drugs on cognitive control processes vary by genotype. Journal of Cognitive Neuroscience. 32(5):804-821.2020_furman.pdf
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.

Blumenfeld, RS, Lee T, D'Esposito M.  2013.  The effects of lateral prefrontal transcranial magnetic stimulation on item memory encoding., 2013 Dec 4. Neuropsychologia. 53:197-202. Abstract2013_blumenfeld.pdf

Previous neuroimaging research has established that the left ventrolateral prefrontal cortex (VLPFC) is involved in long-term memory (LTM) encoding for individual items. Dorsolateral prefrontal cortex (DLPFC) is implicated less frequently, and one theory that has gained support to explain this discrepancy is that DLPFC is involved in forming item-item relational but not item LTM. Given that neuroimaging results are correlational, complimentary methods such as repetitive transcranial magnetic stimulation (TMS) have been used to test causal hypotheses generated from imaging data. Most TMS studies of LTM encoding have found that disruption of lateral PFC activity impairs subsequent memory. However these studies have lacked methods to precisely localize and directly compare TMS effects from frontal subregions implicated by the neuroimaging literature. Here, we target specific subregions of lateral PFC with TMS to test the prediction from the item/relational framework that temporary disruption of VLPFC during encoding will impair subsequent memory whereas TMS to DLPFC during item encoding will not. Frontal TMS was administered prior to a LTM encoding task in which participants were presented with a list of individual nouns and asked to judge whether each noun was concrete or abstract. After a 40min delay period, item recognition memory was tested. Results indicate that VLPFC and DLPFC TMS have differential effects on subsequent item memory. VLPFC TMS reliably disrupted subsequent item memory whereas DLPFC TMS led to numerical enhancement in item memory, relative to TMS to a control region.

Peters, J, D'Esposito M.  2016.  Effects of Medial Orbitofrontal Cortex Lesions on Self-Control in Intertemporal Choice., 2016 Aug 31. Current Biology. 26(19):2625-2628. Abstract2016_peters.pdf

Many decisions involve a trade-off between the temporal proximity of a reward and its magnitude. A range of clinical conditions are associated with poor self-control during such intertemporal choices, such that smaller rewards that are received sooner are preferred over larger rewards that are received later to a greater extent [1, 2]. According to a prominent neural model of self-control [3-6], subjective reward values are represented in the medial orbitofrontal cortex (mOFC) at the time of choice [7-9]. Successful self-control in this model is then thought to depend on a modulation of these mOFC value representations via the lateral prefrontal cortex (lPFC) [3, 6]. Here we directly tested three key predictions of this model in patients with lesions to the mOFC (n = 9) and matched controls (n = 19). First, we show that mOFC lesions disrupt choice-free valuation ratings. This finding provides causal evidence for a role of the mOFC in reward valuation and contrasts with the effects of lPFC disruption [6]. Second, we show that mOFC damage indeed decreases self-control during intertemporal choice, replicating previous findings [10]. Third, extending these previous observations, we show that the effect of mOFC damage on intertemporal choice depends on the actual self-control demands of the task. Our findings thus provide causal evidence for a role of mOFC in reward valuation and are compatible with the idea that mOFC damage affects self-control specifically under conditions that might normally require a modulation of mOFC value representations, e.g., by the lPFC.

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.

Thompson-Schill, SL, D’Esposito, Kan IP.  1999.  Effects of repetition and competition on activity in left prefrontal cortex during word generation., 1999 Jul. Neuron. 23(3):513-522. Abstract1999_thompsonschill_neuron.pdf

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

Cameron, IGM, Wallace DL, Al-Zughoul A, Kayser AS, D'Esposito M.  2018.  Effects of tolcapone and bromocriptine on cognitive stability and flexibility., 2018 Feb 09. Psychopharmacology. 235(4):1295-1305. Abstract2018_cameron.pdf

The prefrontal cortex (PFC) and basal ganglia (BG) have been associated with cognitive stability and cognitive flexibility, respectively. We hypothesized that increasing PFC dopamine tone by administering tolcapone (a catechol-O-methyltransferase (COMT) inhibitor) to human subjects should promote stability; conversely, increasing BG dopamine tone by administering bromocriptine (a D2 receptor agonist) should promote flexibility.

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.

Sheridan, MA, Hinshaw S, D’Esposito.  2007.  Efficiency of the prefrontal cortex during working memory in attention-deficit/hyperactivity disorder., 2007 Oct. Journal of the American Academy of Child and Adolescent Psychiatry. 46(10):1357-1366. Abstract2007_sheridan.pdf

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

Zarahn, E, Aguirre GK, D’Esposito.  1997.  Empirical analyses of BOLD fMRI statistics. I. Spatially unsmoothed data collected under null-hypothesis conditions., 1997 Apr. NeuroImage. 5(3):179-197. Abstract1997_zarahn2.pdf

Temporal autocorrelation, spatial coherency, and their effects on voxel-wise parametric statistics were examined in BOLD fMRI null-hypothesis, or "noise," datasets. Seventeen normal, young subjects were scanned using BOLD fMRI while not performing any time-locked experimental behavior. Temporal autocorrelation in these datasets was described well by a 1/frequency relationship. Voxel-wise statistical analysis of these noise datasets which assumed independence (i.e., ignored temporal autocorrelation) rejected the null hypothesis at a higher rate than specified by the nominal alpha. Temporal smoothing in conjunction with the use of a modified general linear model (Worsley and Friston, 1995, NeuroImage 2: 173-182) brought the false-positive rate closer to the nominal alpha. It was also found that the noise fMRI datasets contain spatially coherent time signals. This observed spatial coherence could not be fully explained by a continuously differentiable spatial autocovariance function and was much greater for lower temporal frequencies. Its presence made voxel-wise test statistics in a given noise dataset dependent, and thus shifted their distributions to the right or left of 0. Inclusion of a "global signal" covariate in the general linear model reduced this dependence and consequently stabilized (i.e., reduced the variance of) dataset false-positive rates.

Aguirre, GK, Zarahn E, D’Esposito.  1997.  Empirical analyses of BOLD fMRI statistics. II. Spatially smoothed data collected under null-hypothesis and experimental conditions., 1997 Apr. NeuroImage. 5(3):199-212. Abstract1997_aguirre_ni.pdf

In the companion to this paper (E. Zarahn, G. K. Aguirre, and M. D’Esposito, 1997, NeuroImage, 179-197), we describe an implementation of a general linear model for autocorrelated observations in which the voxel-wise false-positive rates in fMRI "noise" datasets were stabilized and brought close to theoretical values. Here, implementations of the model are tested for use with statistical parametric mapping analysis of spatially smoothed fMRI data. Analyses using varying models of intrinsic temporal autocorrelation and either including or excluding a global signal covariate were conducted upon human subject data collected under null hypothesis as well as under experimental conditions. We found that smoothing with an empirically derived impulse response function (IRF), combined with a model of the intrinsic temporal autocorrelation in spatially smoothed fMRI data, resulted in a map-wise false-positive rate which did not exceed a 5% level when a nominal alpha = 0.05 tabular threshold was applied. Use of other models of intrinsic temporal autocorrelation resulted in map-wise false-positive rates that significantly exceeded this level. fMRI data collected while subjects performed a behavioral task were used to examine (a) task-dependent global signal changes and (b) the dependence of sensitivity on the temporal smoothing kernel and inclusion/exclusion of a global signal covariate. The global signal changes within an fMRI dataset were shown to be influenced by the performance of a behavioral task. However, the inclusion of this measure as a covariate did not have an adverse affect upon our measure of sensitivity. Finally, use of an empirically derived estimate of the IRF of the system was shown to result in greater map-wise sensitivity for signal changes than the use of a broader (in time) Poisson (parameter = 8 s) kernel.

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.

Cools, R, Miyakawa A, Sheridan M, D’Esposito.  2010.  Enhanced frontal function in Parkinson’s disease., 2010 Jan. Brain. 133(1):225-233. Abstract2010_cools.pdf

We investigated the role of dopamine in working memory by examining effects of withdrawing dopaminergic medication in patients with Parkinson’s disease. Resistance to distraction during a delayed response task was abnormally enhanced in Parkinson’s disease patients OFF medication relative to controls. Conversely, performance on a backward digit span test was impaired in these same Parkinson’s disease patients OFF medication. Dopaminergic medication reinstated susceptibility to distraction and backward digit span performance, so that performance of Parkinson’s disease patients ON medication did not differ from that of controls. We hypothesize that the enhanced distractor resistance and impaired backward digit span in Parkinson’s disease reflects low dopamine levels in the striatum, and perhaps upregulated frontal dopamine levels. Dopaminergic medication may reinstate distractibility by normalizing the balance between striatal and prefrontal dopamine transmission.

Aguirre, GK, D’Esposito.  1997.  Environmental knowledge is subserved by separable dorsal/ventral neural areas., 1997 Apr 1. Journal of Neuroscience . 17(7):2512-2518. Abstract1997_aguirre_jn.pdf

Environmental psychology models propose that knowledge of large-scale space is stored as distinct landmark (place appearance) and survey (place position) information. Studies of brain-damaged patients suffering from "topographical disorientation" tentatively support this proposal. In order to determine if the components of psychologically derived models of environmental representation are realized as distinct functional, neuroanatomical regions, a functional magnetic resonance imaging (fMRI) study of environmental knowledge was performed. During scanning, subjects made judgments regarding the appearance and position of familiar locations within a virtual reality environment. The fMRI data were analyzed in a manner that has been empirically demonstrated to rigorously control type I error and provide optimum sensitivity, allowing meaningful results in the single subject. A direct comparison of the survey position and landmark appearance conditions revealed a dorsal/ventral dissociation in three of four subjects. These results are discussed in the context of the observed forms of topographical disorientation and are found to be in good agreement with the human lesion studies. This experiment confirms that environmental knowledge is not represented by a unitary system but is instead functionally distributed across the neocortex.

Armstrong, C, Lewis T, D’Esposito, Freundlich B.  1997.  Eosinophilia-myalgia syndrome: selective cognitive impairment, longitudinal effects, and neuroimaging findings., 1997 Nov. Journal of Neurology, Neurosurgery, and Psychiatry. 63(5):633-641. Abstract1997_armstrong.pdf

OBJECTIVE: To identify the specific nature of the neurocognitive impairments of eosinophilia-myalgia syndrome (EMS) in an unselected population, and to present longitudinal patterns. METHODS: A consecutive sample of 23 patients with EMS and 18 age and education matched control subjects were assessed on a comprehensive neuropsychological battery. Longitudinal results were gathered from six patients. RESULTS: Neurocognitive impairments were found which represent a subset of deficits reported in previous group and case study reports. Deficits were limited to complex visual memory, conceptual set shifting, and attention, which suggest a selective dysexecutive syndrome. The motor slowing and verbal memory deficits previously reported were not found. Although depression, fatigue, sleep deprivation, and pain were significant symptoms, they were unassociated with deficits with the exception of an association of depression with one deficit. There was no pattern of overall decline over time in a subset of the group, although considerable heterogeneity in the longitudinal patterns of neurocognitive tests was found. Abnormalities of white matter appeared in the MRI of eight of 12 patients. CONCLUSIONS: The neurocognitive and neuroimaging findings contribute to the evidence which indicates that the neural substrate of EMS is white matter damage.

Jacobs, E, D’Esposito.  2011.  Estrogen shapes dopamine-dependent cognitive processes: implications for women’s health., 2011 Apr 6. Journal of Neuroscience. 31(14):5286-5293. Abstract2011_jacobs.pdf

The prefrontal cortex (PFC) is exquisitely sensitive to its neurochemical environment. Minor fluctuations in cortical dopamine (DA) can profoundly alter working memory, a PFC-dependent cognitive function that supports an array of essential human behaviors. Dopamine’s action in the PFC follows an inverted U-shaped curve, where an optimal DA level results in maximal function and insufficient or excessive DA impairs PFC function. In animals, 17β-estradiol (the major estrogen in most mammals, referred to henceforth as estradiol) has been shown to enhance DA activity, yet no human study has adequately addressed whether estradiol’s impact on cognition occurs by way of modulating specific neurochemical systems. Here we examined the effects of endogenous fluctuations in estradiol on working memory in healthy young women as a function of baseline PFC DA [indexed by catechol-O-methyltransferase (COMT) Val(158)Met genotype and, at a finer scale, COMT enzyme activity]. The results demonstrate that estradiol status impacts working memory function and, crucially, the direction of the effect depends on indices of baseline DA. Moreover, consistent with a DA cortical efficiency hypothesis, functional MRI revealed that inferred optimal DA was associated with reduced PFC activity sustained across task blocks and selectively enhanced PFC activity on trials with the greatest demand for cognitive control. The magnitude of PFC activity during high control trials was predictive of an individual’s performance. These findings show that although estrogen, considered in isolation, may have unpredictable effects on cognitive performance, its influence is clarified when considered within a larger neuromodulatory framework. Given the clinical prevalence of dopaminergic drugs, understanding the relationship between estrogen and DA is essential for advancing women’s health.

Cookson, SL, D'Esposito M.  2022.  Evaluating the reliability, validity, and utility of overlapping networks: Implications for network theories of cognition., 2022 Nov 01. Human brain mapping. Abstract

Brain network definitions typically assume nonoverlap or minimal overlap, ignoring regions' connections to multiple networks. However, new methods are emerging that emphasize network overlap. Here, we investigated the reliability and validity of one assignment method, the mixed membership algorithm, and explored its potential utility for identifying gaps in existing network models of cognition. We first assessed between-sample reliability of overlapping assignments with a split-half design; a bootstrapped Dice similarity analysis demonstrated good agreement between the networks from the two subgroups. Next, we assessed whether overlapping networks captured expected nonoverlapping topographies; overlapping networks captured portions of one to three nonoverlapping topographies, which aligned with canonical network definitions. Following this, a relative entropy analysis showed that a majority of regions participated in more than one network, as is seen biologically, and many regions did not show preferential connection to any one network. Finally, we explored overlapping network membership in regions of the dual-networks model of cognitive control, showing that almost every region was a member of multiple networks. Thus, the mixed membership algorithm produces consistent and biologically plausible networks, which presumably will allow for the development of more complete network models of cognition.

Cookson, SL, D'Esposito M.  2022.  Evaluating the reliability, validity, and utility of overlapping networks: Implications for network theories of cognition., 2022 Nov 01. Human brain mapping. Abstract

Brain network definitions typically assume nonoverlap or minimal overlap, ignoring regions' connections to multiple networks. However, new methods are emerging that emphasize network overlap. Here, we investigated the reliability and validity of one assignment method, the mixed membership algorithm, and explored its potential utility for identifying gaps in existing network models of cognition. We first assessed between-sample reliability of overlapping assignments with a split-half design; a bootstrapped Dice similarity analysis demonstrated good agreement between the networks from the two subgroups. Next, we assessed whether overlapping networks captured expected nonoverlapping topographies; overlapping networks captured portions of one to three nonoverlapping topographies, which aligned with canonical network definitions. Following this, a relative entropy analysis showed that a majority of regions participated in more than one network, as is seen biologically, and many regions did not show preferential connection to any one network. Finally, we explored overlapping network membership in regions of the dual-networks model of cognitive control, showing that almost every region was a member of multiple networks. Thus, the mixed membership algorithm produces consistent and biologically plausible networks, which presumably will allow for the development of more complete network models of cognition.

D’Esposito, Zarahn E, Aguirre GK.  1999.  Event-related functional MRI: implications for cognitive psychology., 1999 Jan. Psychological Bulletin. 125(1):155-164. Abstract1999_desposito_pb.pdf

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

Sreenivasan, KK, Gratton C, Vytlacil J, D'Esposito M.  2014.  Evidence for working memory storage operations in perceptual cortex., 2014 Jan 17. Cognitive, Affective & Behavioral Neuroscience. 14(1):117–128. Abstract2014_sreenivasan_cban.pdf

Isolating the short-term storage component of working memory (WM) from the myriad of associated executive processes has been an enduring challenge. Recent efforts have identified patterns of activity in visual regions that contain information about items being held in WM. However, it remains unclear (1) whether these representations withstand intervening sensory input and (2) how communication between multimodal association cortex and the unimodal perceptual regions supporting WM representations is involved in WM storage. We present evidence that the features of a face held in WM are stored within face-processing regions, that these representations persist across subsequent sensory input, and that information about the match between sensory input and a memory representation is relayed forward from perceptual to prefrontal regions. Participants were presented with a series of probe faces and indicated whether each probe matched a target face held in WM. We parametrically varied the feature similarity between the probe and target faces. Activity within face-processing regions scaled linearly with the degree of feature similarity between the probe face and the features of the target face, suggesting that the features of the target face were stored in these regions. Furthermore, directed connectivity measures revealed that the direction of information flow that was optimal for performance was from sensory regions that stored the features of the target face to dorsal prefrontal regions, supporting the notion that sensory input is compared to representations stored within perceptual regions and is subsequently relayed forward. Together, these findings indicate that WM storage operations are carried out within perceptual cortex.

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


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


Ween, JE, Alexander M, D’Esposito, Roberts M.  1996.  Factors predictive of stroke outcome in a rehabilitation setting., 1996 Aug. Neurology. 47(2):388-392. Abstract1996_ween.pdf

Accurate outcome prediction following stroke is important for proper delivery of poststroke care. It has been difficult to determine specific factors that provide reliable and accurate predictions of outcome, particularly for patients with intermediate deficit severities. Age and severity of deficit have repeatedly been found to be most reliable, but only as rough estimates and for patients at either extreme of the disability spectrum. This paper reports a prospective study of consecutive rehabilitation admissions (N = 536) to determine the influence of preselected factors. Outcome was analyzed in terms of functional improvement and disposition. Patients younger than 55 years or with an admission Functional Independence Measure (FIM) greater than 80 almost universally went home. Admission FIMs less than 40 were associated with nearly certain nursing home discharge. The comprehensive FIM score was a stronger predictor of outcome than motor impairment in isolation. An admission FIM of 60 or greater was associated with a higher probability of functional improvement during rehabilitation. Small-vessel strokes had the best outcome. Intracerebral hemorrhages improved more than ischemic strokes but more slowly. Right hemisphere lesions did worse than left. Comorbidities influenced outcome only when several conditions accumulated. The absence of a committed caregiver at home increased the risk of nursing home discharge. Suggestions for rehabilitation triage are given.

Lorenc, ES, Sreenivasan KK, Nee DE, Vandenbroucke ARE, D'Esposito M.  2018.  Flexible coding of visual working memory representations during distraction., 2018 May 08. Journal of Neuroscience. 38(23):5267-5276. Abstract2018_lorenc.pdf

Visual working memory (VWM) recruits a broad network of brain regions, including prefrontal, parietal, and visual cortices. Recent evidence supports a "sensory recruitment" model of VWM, whereby precise visual details are maintained in the same stimulus-selective regions responsible for perception. A key question in evaluating the sensory recruitment model is how VWM representations persist through distracting visual input, given that the early visual areas that putatively represent VWM content are susceptible to interference from visual stimulation.To address this question, we employed an fMRI inverted encoding model approach to quantitatively assess the effect of distractors on VWM representations in early visual cortex and the intraparietal sulcus (IPS), another region previously implicated in the storage of VWM information. This approach allowed us to reconstruct VWM representations for orientation, both before and after visual interference, and to examine whether oriented distractors systematically biased these representations. In our human participants (both male and female), we found that orientation information was maintained simultaneously in early visual areas and IPS in anticipation of possible distraction, and these representations persisted in the absence of distraction. Importantly, early visual representations were susceptible to interference; VWM orientations reconstructed from visual cortex were significantly biased toward distractors, corresponding to a small attractive bias in behavior. In contrast, IPS representations did not show such a bias. These results provide quantitative insight into the effect of interference on VWM representations, and suggest a dynamic tradeoff between visual and parietal regions that allows flexible adaptation to task demands in service of VWM.Despite considerable evidence that stimulus-selective visual regions maintain precise visual information in working memory, it remains unclear how these representations persist through subsequent input. Here, we used quantitative model-based fMRI analyses to reconstruct the contents of working memory and examine the effects of distracting input. While representations in the early visual areas were systematically biased by distractors, those in the intraparietal sulcus appeared distractor-resistant. In contrast, early visual representations were most reliable in the absence of distraction. These results demonstrate the dynamic, adaptive nature of visual working memory processes, and provide quantitative insight into the ways in which representations can be affected by interference. Further, they suggest that current models of working memory should be revised to incorporate this flexibility.

Mitchell, KJ, Johnson MK, Raye CL, D’Esposito.  2000.  fMRI evidence of age-related hippocampal dysfunction in feature binding in working memory., 2000 Sep. Brain Research: Cognitive Brain Research. 10(1-2):197-206. Abstract2000_mitch_br.pdf

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

Raye, CL, Johnson MK, Mitchell KJ, Nolde SF, D’Esposito.  2000.  fMRI investigations of left and right PFC contributions to episodic remembering. Psychobiology. 28(2):197-206. Abstract2000_raye.pdf


Gratton, C, Nomura EM, Pérez F, D’esposito M.  2012.  Focal Brain Lesions to Critical Locations Cause Widespread Disruption of the Modular Organization of the Brain., 2012 Mar 8. Journal of Cognitive Neuroscience. 24(6):1275-1285. Abstract2012_gratton1.pdf

Although it is generally assumed that brain damage predominantly affects only the function of the damaged region, here we show that focal damage to critical locations causes disruption of network organization throughout the brain. Using resting state fMRI, we assessed whole-brain network structure in patients with focal brain lesions. Only damage to those brain regions important for communication between subnetworks (e.g., "connectors")-but not to those brain regions important for communication within sub-networks (e.g., "hubs")-led to decreases in modularity, a measure of the integrity of network organization. Critically, this network dysfunction extended into the structurally intact hemisphere. Thus, focal brain damage can have a widespread, nonlocal impact on brain network organization when there is damage to regions important for the communication between networks. These findings fundamentally revise our understanding of the remote effects of focal brain damage and may explain numerous puzzling cases of functional deficits that are observed following brain injury.

Iyer, KK, Hwang K, Hearne LJ, Muller E, D'Esposito M, Shine JM, Cocchi L.  2022.  Focal neural perturbations reshape low-dimensional trajectories of brain activity supporting cognitive performance., 2022 01 10. Nature communications. 13(1):4. Abstract

The emergence of distributed patterns of neural activity supporting brain functions and behavior can be understood by study of the brain's low-dimensional topology. Functional neuroimaging demonstrates that brain activity linked to adaptive behavior is constrained to low-dimensional manifolds. In human participants, we tested whether these low-dimensional constraints preserve working memory performance following local neuronal perturbations. We combined multi-session functional magnetic resonance imaging, non-invasive transcranial magnetic stimulation (TMS), and methods translated from the fields of complex systems and computational biology to assess the functional link between changes in local neural activity and the reshaping of task-related low dimensional trajectories of brain activity. We show that specific reconfigurations of low-dimensional trajectories of brain activity sustain effective working memory performance following TMS manipulation of local activity on, but not off, the space traversed by these trajectories. We highlight an association between the multi-scale changes in brain activity underpinning cognitive function.

Grossman, M, Mickanin J, Onishi K, Robinson KM, D’Esposito.  1996.  Freehand drawing impairments in probable Alzheimer’s disease., 1996 May. Journal of the International Neuropsychological Society. 2(3):226-235. Abstract1996_grossman_jins.pdf

We evaluated freehand picture production of familiar objects in patients with probable Alzheimer’s disease. The overall recognizability of their drawings was significantly compromised. Error analyses revealed the production of category violations and the frequent inclusion of incorrect features in a picture that were borrowed from semantically related objects, suggesting difficulty distinguishing between items with overlapping features sets in semantic memory. Analyses of individual patient drawing profiles also revealed that some patients are disproportionately compromised in expressing a particular perceptual feature, implicating difficulty at the level of perceptual processing. Regression analyses demonstrated the contribution of limited visual attentional resources. We conclude that impaired freehand drawing in probable Alzheimer’s disease is multifactorial in nature.

D'Esposito, M.  2008.  From cognitive to neural models of working memory. Mental Processes in the Human Brain. , Oxford, UK: Oxford University Press
D’Esposito.  2007.  From cognitive to neural models of working memory., 2007 May 29. Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences. 362(1481):761-772. Abstract2007_despo.pdf

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

Badre, D, Kayser A, D’Esposito.  2010.  Frontal cortex and the discovery of abstract action rules., 2010 Apr 29. Neuron. 66(2):315-326. Abstract2010_badre.pdf

Although we often encounter circumstances with which we have no prior experience, we rapidly learn how to behave in these novel situations. Such adaptive behavior relies on abstract behavioral rules that are generalizable, rather than concrete rules mapping specific cues to specific responses. Although the frontal cortex is known to support concrete rule learning, less well understood are the neural mechanisms supporting the acquisition of abstract rules. Here, we use a reinforcement learning paradigm to demonstrate that more anterior regions along the rostro-caudal axis of frontal cortex support rule learning at higher levels of abstraction. Moreover, these results indicate that when humans confront new rule learning problems, this rostro-caudal division of labor supports the search for relationships between context and action at multiple levels of abstraction simultaneously.

Gazzaley, A, Lee TG, D'Esposito M.  2017.  The Frontal Lobes and Executive Control. The Human Frontal Lobes, 3rd Edition. , New York: Guilford Publications
Kimberg, DY, D'Esposito M.  2000.  Frontal lobes II: cognitive issues. Patient-Based Approaches to Cognitive Neuroscience. : Kluwer Academic Publishers Abstract


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


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.

Hwang, K, Shine JM, D'Esposito M.  2018.  Frontoparietal Activity Interacts With Task-Evoked Changes in Functional Connectivity., 2018 Feb 03. Cerebral Cortex. 29(2):802-813. Abstract2018_hwang.pdf

Flexible interactions between brain regions enable neural systems to adaptively transfer and process information. However, the neural substrates that regulate adaptive communications between brain regions are understudied. In this human fMRI study, we investigated this issue by tracking time-varying, task-evoked changes in functional connectivity between localized occipitotemporal regions while participants performed different tasks on the same visually presented stimuli. We found that functional connectivity between ventral temporal and the primary visual regions selectively increased during the processing of task-relevant information. Further, additional task demands selectively strengthen these targeted connectivity patterns. To identify candidate regions that contribute to this increase in inter-regional coupling, we regressed the task-specific time-varying connectivity strength between primary visual and occipitotemporal regions against voxel-wise activity patterns elsewhere in the brain. This allowed us to identify a set of frontal and parietal regions whose activity increased as a function of task-evoked functional connectivity. These results suggest that frontoparietal regions may provide top-down biasing signals to influence task-specific interactions between brain regions.

Alsop, D, Detre JA, D’Esposito, Howard RS, Maldjian JA, Grossman M, Listerud J, Flamm ES, Judy KD, Atlas S.  1996.  Functional activation during an auditory comprehension task in patients with temporal lobe lesions., 1996 Aug. NeuroImage. 4(1):55-59. Abstract1996_alsop.pdf

Functional magnetic resonance imaging (fMRI) was used to map regional brain activation during an auditory comprehension task in two normal controls and two patients with left temporal lobe lesions. Activity in the superior temporal and angular gyrus regions was detected in all normal subjects. In the patients, the spatial distribution of activation ipsilateral to the lesions differed from the pattern observed in contralateral cortex or in control subjects. These studies highlight the potential of fMRI for mapping abnormal functional anatomy in the human brain.

Kayser, A, Buchsbaum BR, Erickson DT, D’Esposito.  2010.  The functional anatomy of a perceptual decision in the human brain., 2010 Mar. Journal of Neurophysiology. 103(3):1179-1194. Abstract2010_kayser_neurophysiology.pdf

Our ability to make rapid decisions based on sensory information belies the complexity of the underlying computations. Recently, "accumulator" models of decision making have been shown to explain the activity of parietal neurons as macaques make judgments concerning visual motion. Unraveling the operation of a decision-making circuit, however, involves understanding both the responses of individual components in the neural circuitry and the relationships between them. In this functional magnetic resonance imaging study of the decision process in humans, we demonstrate that an accumulator model predicts responses to visual motion in the intraparietal sulcus (IPS). Significantly, the metrics used to define responses within the IPS also reveal distinct but interacting nodes in a circuit, including early sensory detectors in visual cortex, the visuomotor integration system of the IPS, and centers of cognitive control in the prefrontal cortex, all of which collectively define a perceptual decision-making network.

Arnemann, KL, Chen AJ-W, Novakovic-Agopian T, Gratton C, Nomura EM, D'Esposito M.  2015.  Functional brain network modularity predicts response to cognitive training after brain injury., 2015 Mar 18. Neurology. 84(15):1568-1574. Abstract2015_arnemann.pdf

We tested the value of measuring modularity, a graph theory metric indexing the relative extent of integration and segregation of distributed functional brain networks, for predicting individual differences in response to cognitive training in patients with brain injury.

Sadaghiani, S, D'Esposito M.  2014.  Functional Characterization of the Cingulo-Opercular Network in the Maintenance of Tonic Alertness., 2014 Apr 25. Cerebral Cortex. 25(9):2763-2773. Abstract2014_sadaghiani.pdf

The complex processing architecture underlying attentional control requires delineation of the functional role of different control-related brain networks. A key component is the cingulo-opercular (CO) network composed of anterior insula/operculum, dorsal anterior cingulate cortex, and thalamus. Its function has been particularly difficult to characterize due to the network's pervasive activity and frequent co-activation with other control-related networks. We previously suggested this network to underlie intrinsically maintained tonic alertness. Here, we tested this hypothesis by separately manipulating the demand for selective attention and for tonic alertness in a two-factorial, continuous pitch discrimination paradigm. The 2 factors had independent behavioral effects. Functional imaging revealed that activity as well as functional connectivity in the CO network increased when the task required more tonic alertness. Conversely, heightened selective attention to pitch increased activity in the dorsal attention (DAT) network but not in the CO network. Across participants, performance accuracy showed dissociable correlation patterns with activity in the CO, DAT, and fronto-parietal (FP) control networks. These results support tonic alertness as a fundamental function of the CO network. They further the characterization of this function as the effortful process of maintaining cognitive faculties available for current processing requirements.

Kuo, B-C, Yeh Y-Y, Chen AJ-W, D'Esposito M.  2011.  Functional connectivity during top-down modulation of visual short-term memory representations., 2011 May. Neuropsychologia. 49:1589-1596. Abstract2011_kuo.pdf

Recent evidence has revealed that short-lived internal representations held in visual short-term memory (VSTM) can be modulated by top-down control via retrospective attention which impacts subsequent behavioral performance. However, the functional inter-regional interactions underlying these top-down modulatory effects are not fully characterized. Here we used event-related functional magnetic imaging to investigate whether the strength of functional connectivity between the frontal cortex and posterior visual areas varies with the efficacy of top-down modulation of memory traces. Top-down modulation was manipulated by the timing of retro-cuing (early or late) in a VSTM task. Univariate analyses revealed that more effective top-down modulation (early cueing vs. late cueing) increased activity in early visual areas. Importantly, coherency analyses revealed that top-down modulation produced stronger functional connectivity between frontal and posterior occipital regions. Also, participants with stronger functional connectivity exhibit better memory performance. These results suggest that augmented functional connectivity between frontal and posterior visual areas strengthens the VSTM representations of importance to behavioral goals.

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, Rao AA, D’Esposito.  2007.  Functional connectivity of cortical networks involved in bimanual motor sequence learning., 2007 May. Cerebral Cortex. 17(5):1227-1234. Abstract2007_sun.pdf

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

Bartrés-Faz, D, Serra-Grabulosa JM, Sun FT, Solé-Padullés C, Rami L, Molinuevo JL, Bosch B, Mercader JM, Bargalló N, Falcón C, Vendrell P, Junqué C, D’Esposito.  2008.  Functional connectivity of the hippocampus in elderly with mild memory dysfunction carrying the APOE epsilon4 allele., 2008 Nov. Neurobiology of Aging. 29(11):1644-1653. Abstract2007_bartres.pdf

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

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, Rissman J, Cooney JW, Rutman A, Seibert T, Clapp W, D’Esposito.  2007.  Functional interactions between prefrontal and visual association cortex contribute to top-down modulation of visual processing., 2007 Sep. Cerebral Cortex. 17 Suppl 1:i125-135. Abstract2007_gazzaley_cc.pdf

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

Wittmann, B, D'Esposito M.  2012.  Functional magnetic resonance imaging. Handbook of Research Methods in Psychology. , Washington, DC: American Psychological Association
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.

Maldjian, J, Atlas S, Howard RS, Greenstein E, Alsop D, Detre JA, Listerud J, D’Esposito, Flamm ES.  1996.  Functional magnetic resonance imaging of regional brain activity in patients with intracerebral arteriovenous malformations before surgical or endovascular therapy., 1996 Mar. Journal of Neurosurgery. 84(3):477-483. Abstract1996_maldjian.pdf

Functional magnetic resonance (MR) imaging was performed in six patients harboring proven intracerebral arteriovenous malformations (AVMs) using a noninvasive blood oxygen level-dependent technique based on the documented discrepancy between regional increases in blood flow and oxygen utilization in response to regional brain activation. Statistical functional MR maps were generated and overlaid directly onto conventional MR images obtained at the same session. In the six patients studied, a total of 23 separate functional MR imaging activation studies were performed. Of these, two runs were discarded because of motion artifacts. All of the remaining 21 studies demonstrated activation in or near expected regions for the paradigm employed. Qualitatively reproducible regional localizations of functional activity in unexpected sites were also seen. The authors’ findings indicating aberrant mapping of cortical function may be explained on the basis of the plasticity of brain function, in that the developing brain can take over function that would normally have been performed by regions of brain encompassed by the lesion. Preliminary results in this study’s small number of cases also indicate that activity demonstrated within the confines of the apparent AVM nidus may help predict the development of a posttherapy deficit. The authors demonstrate that functional MR imaging can be successfully and reproducibly performed in patients with intracerebral AVMs. Notwithstanding the paucity of normative data using functional MR imaging, the author’ findings support cortical reorganization associated with these congenital lesions. Blood oxygen level-dependent MR imaging is a noninvasive method used to localize areas of eloquent cortex in patients harboring AVMs; it may prove to be of value in treatment planning.

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.

Nagel, IE, Schumacher EH, Goebel R, D’Esposito.  2008.  Functional MRI investigation of verbal selection mechanisms in lateral prefrontal cortex., 2008 Dec. NeuroImage. 43(4):801-807. Abstract2008_nagel.pdf

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

Detre, JA, Maccotta L, King D, Alsop D, Glosser G, D’Esposito, Zarahn E, Aguirre GK, French JA.  1998.  Functional MRI lateralization of memory in temporal lobe epilepsy., 1998 Apr. Neurology. 50(4):926-932. Abstract1998_detre.pdf

OBJECTIVE: To determine the feasibility of using functional magnetic resonance imaging (fMRI) to detect asymmetries in the lateralization of memory activation in patients with temporal lobe epilepsy (TLE). BACKGROUND: Assessment of mesial temporal lobe function is a critical aspect of the preoperative evaluation for epilepsy surgery, both for predicting postoperative memory deficits and for seizure lateralization. fMRI offers several potential advantages over the current gold standard, intracarotid amobarbital testing (IAT). fMRI has already been successfully applied to language lateralization in TLE. METHODS: fMRI was carried out in eight normal subjects and 10 consecutively recruited patients with TLE undergoing preoperative evaluation for epilepsy surgery. A complex visual scene encoding task known to activate mesial temporal structures was used during fMRI. Asymmetry ratios for mesial temporal activation were calculated, using regions of interest defined in normals. Patient findings were compared with the results of IAT performed as part of routine clinical evaluation. RESULTS: Task activation was nearly symmetric in normal subjects, whereas in patients with TLE, significant asymmetries were observed. In all nine patients in whom the IAT result was interpretable, memory asymmetry by fMRI concurred with the findings of IAT including two patients with paradoxical IAT memory lateralization ipsilateral to seizure focus. CONCLUSIONS: fMRI can be used to detect asymmetries in memory activation in patients with TLE. Because fMRI studies are noninvasive and provide excellent spatial resolution for functional activation, these preliminary results suggest a promising role for fMRI in improving the preoperative evaluation for epilepsy surgery.

Atlas, S, Howard RS, Maldjian J, Alsop D, Detre JA, Listerud J, D'Esposito M, Judy KD, Zager E, Stecker M.  1996.  Functional MRI of regional brain activity in patients with intracerebral gliomas: findings and implications for clinical management. Neurosurgery. 38(2):329-338.1996_atlas.pdf
D’Esposito, Aguirre GK, Zarahn E, Ballard D, Shin RK, Lease J.  1998.  Functional MRI studies of spatial and nonspatial working memory., 1998 Jul. Brain Research: Cognitive Brain Research. 7(1):1-13. Abstract1998_desposito_br.pdf

Single-unit recordings in monkeys have revealed neurons in the lateral prefrontal cortex that increase their firing during a delay between the presentation of information and its later use in behavior. Based on monkey lesion and neurophysiology studies, it has been proposed that a dorsal region of lateral prefrontal cortex is necessary for temporary storage of spatial information whereas a more ventral region is necessary for the maintenance of nonspatial information. Functional neuroimaging studies, however, have not clearly demonstrated such a division in humans. We present here an analysis of all reported human functional neuroimaging studies plotted onto a standardized brain. This analysis did not find evidence for a dorsal/ventral subdivision of prefrontal cortex depending on the type of material held in working memory, but a hemispheric organization was suggested (i.e., left-nonspatial; right-spatial). We also performed functional MRI studies in 16 normal subjects during two tasks designed to probe either nonspatial or spatial working memory, respectively. A group and subgroup analysis revealed similarly located activation in right middle frontal gyrus (Brodmann’s area 46) in both spatial and nonspatial [working memory-control] subtractions. Based on another model of prefrontal organization [M. Petrides, Frontal lobes and behavior, Cur. Opin. Neurobiol., 4 (1994) 207-211], a reconsideration of the previous imaging literature data suggested that a dorsal/ventral subdivision of prefrontal cortex may depend upon the type of processing performed upon the information held in working memory.

D’Esposito, Detre JA, Aguirre GK, Stallcup M, Alsop D, Tippet LJ, Farah MJ.  1997.  A functional MRI study of mental image generation., 1997 May. Neuropsychologia. 35(5):725-730. Abstract1997_desposito_np.pdf

The neural substrates of mental image generation were investigated with functional MRI. Subjects listened to words under two different instructional conditions: to generate visual mental images of the words’ referents, or to simply listen to each word and wait for the next word. Analyses were performed which directly compared the regional brain activity during each condition, with the goal of discovering whether mental image generation engages modality-specific visual areas, whether it engages primary visual cortex, and whether it recruits the left hemisphere to a greater extent than the right. Results revealed that visual association cortex, and not primary visual cortex, was engaged during the mental image generation condition. Left inferior temporal lobe (Brodmann’s area 37) was the most reliably and robustly activated area across subjects, had activity which extended superiorly into occipital association cortex (area 19). The results of this experiment support the hypothesis that visual mental imagery is a function of visual association cortex, and that image generation is asymmetrically localized to the left.

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.

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.

D'Esposito, M, Kayser A, Chen A.  2009.  Functional MRI: applications in cognitive neuroscience. Functional MRI Techniques and Protocols. : Humana Press
D'Esposito, M, Kayser AS, Chen AJ-W.  2016.  Functional MRI: Applications in Cognitive Neuroscience. Functional MRI Techniques and Protocols, 2nd Edition. , New York: Springer
D’esposito, M.  2006.  Functional MRI: cognitive neuroscience applications. Functional MRI. , Berlin: Springer-Verlag Abstract2006_despo_cogfmri.pdf


D'Esposito, M, Kayser A, Chen A.  2011.  Functional MRI: cognitive neuroscience applications. Functional Neuroradiology: Principles and Clinical Applications. , Berlin: Springer-Verlag
D'Esposito, M, Sreenivasan KK, Kayser A.  2015.  Functional MRI: Cognitive Neuroscience Applications. FMRI: From Nuclear Spins to Brain Function. , New York: Springer
Postle, BR, Berger JS, D’Esposito.  1999.  Functional neuroanatomical double dissociation of mnemonic and executive control processes contributing to working memory performance., 1999 Oct 26. Proceedings of the National Academy of Sciences of the United States of America. 96(22):12959-12964. Abstract1999_postle_pnas.pdf

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

Turner, G, D'Esposito M.  2011.  Functional neuroimaging of aging. Clinical Neurology of Aging, 3rd Edition. , Oxford: Oxford University Press
D’Esposito.  2000.  Functional neuroimaging of cognition., 2000. Seminars in Neurology. 20(4):487-498. Abstract

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

DeGutis, J, Bentin S, Robertson LC, D’Esposito.  2007.  Functional plasticity in ventral temporal cortex following cognitive rehabilitation of a congenital prosopagnosic., 2007 Nov. Journal of Cognitive Neuroscience. 19(11):1790-1802. Abstract2007_degutis.pdf

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

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.

Willems, RM, Labruna L, D’Esposito, Ivry R, Casasanto D.  2011.  A functional role for the motor system in language understanding: evidence from theta-burst transcranial magnetic stimulation., 2011 Jul 1. Psychological Science. 22(7):849-854. Abstract2011_willems.pdf

Does language comprehension depend, in part, on neural systems for action? In previous studies, motor areas of the brain were activated when people read or listened to action verbs, but it remains unclear whether such activation is functionally relevant for comprehension. In the experiments reported here, we used off-line theta-burst transcranial magnetic stimulation to investigate whether a causal relationship exists between activity in premotor cortex and action-language understanding. Right-handed participants completed a lexical decision task, in which they read verbs describing manual actions typically performed with the dominant hand (e.g., "to throw," "to write") and verbs describing nonmanual actions (e.g., "to earn," "to wander"). Responses to manual-action verbs (but not to nonmanual-action verbs) were faster after stimulation of the hand area in left premotor cortex than after stimulation of the hand area in right premotor cortex. These results suggest that premotor cortex has a functional role in action-language understanding.

Wallace, DL, Aarts E, d'Oleire Uquillas F, Dang LC, Greer SM, Jagust WJ, D'Esposito M.  2015.  Genotype status of the dopamine-related catechol-O-methyltransferase (COMT) gene corresponds with desirability of "unhealthy" foods., 2015 May 8. Appetite. 92:74-80. Abstract2015_wallace.pdf

The role of dopamine is extensively documented in weight regulation and food intake in both animal models and humans. Yet the role of dopamine has not been well studied in individual differences for food desirability. Genotype status of the dopamine-related catechol-O-methyltransferase (COMT) gene has been shown to influence dopamine levels, with greater COMT enzymatic activity in val/val individuals corresponding to greater degradation of dopamine. Decreased dopamine has been associated with poorer cognitive control and diminished goal-directed behavior in various behavioral paradigms. Additionally, dopaminergic-rich regions such as the frontal cortex and dorsal striatum have been shown to be important for supporting food-related decision-making. However, the role of dopamine, as assessed by COMT genotype status, in food desirability has not been fully explored. Therefore, we utilized an individual's COMT genotype status (n=61) and investigated food desirability based on self-rated "healthy" and "unhealthy" food perceptions. Here we found val/val individuals (n=19) have greater desirability for self-rated "unhealthy" food items, but not self-rated "healthy" food items, as compared to val/met (n=24) and met/met (n=18) individuals (p<0.005). Utilizing an objective health measure for the food items, we also found val/val and val/met individuals have greater desirability for objectively defined "unhealthy" food items, as compared to met/met individuals (p<0.01). This work further substantiates a role of dopamine in food-related behaviors and more specifically in relationship to food desirability for "unhealthy" food items.

Chen, AJ-W, Britton M, Turner GR, Vytlacil J, Thompson TW, D'Esposito M.  2012.  Goal-directed attention alters the tuning of object-based representations in extrastriate cortex., 2012. Frontiers in Human Neuroscience. 6:187. Abstract2012_chen.pdf

Humans survive in environments that contain a vast quantity and variety of visual information. All items of perceived visual information must be represented within a limited number of brain networks. The human brain requires mechanisms for selecting only a relevant fraction of perceived information for more in-depth processing, where neural representations of that information may be actively maintained and utilized for goal-directed behavior. Object-based attention is crucial for goal-directed behavior and yet remains poorly understood. Thus, in the study we investigate how neural representations of visual object information are guided by selective attention. The magnitude of activation in human extrastriate cortex has been shown to be modulated by attention; however, object-based attention is not likely to be fully explained by a localized gain mechanism. Thus, we measured information coded in spatially distributed patterns of brain activity with fMRI while human participants performed a task requiring selective processing of a relevant visual object category that differed across conditions. Using pattern classification and spatial correlation techniques, we found that the direction of selective attention is implemented as a shift in the tuning of object-based information representations within extrastriate cortex. In contrast, we found that representations within lateral prefrontal cortex (PFC) coded for the attention condition rather than the concrete representations of object category. In sum, our findings are consistent with a model of object-based selective attention in which representations coded within extrastriate cortex are tuned to favor the representation of goal-relevant information, guided by more abstract representations within lateral PFC.

Turner, GR, Novakovic-Agopian T, Kornblith ES, Adnan A, Madore M, Chen AJ-W, D'Esposito M.  2020.  Goal-oriented attention regulation (GOALS) training in older adults. Aging and Mental Health. 24(3):464-473.2020_turner.pdf
Samanez-Larkin, GR, D’Esposito.  2008.  Group comparisons: imaging the aging brain., 2008 Sep. Social Cognitive and Affective Neuroscience. 3(3):290-297. Abstract2008_samanezlarkin.pdf

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

Badre, D, Hoffman J, Cooney JW, D’Esposito.  2009.  Hierarchical cognitive control deficits following damage to the human frontal lobe., 2009 Apr. Nature Neuroscience. 12(4):515-522. Abstract2009_badre.pdf

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

Nee, DE, D'Esposito M.  2016.  The hierarchical organization of the lateral prefrontal cortex., 2016. eLife. 5:e12112. Abstract2016_nee_elife.pdf

Higher-level cognition depends on the lateral prefrontal cortex (LPFC), but its functional organization has remained elusive. An influential proposal is that the LPFC is organized hierarchically whereby progressively rostral areas of the LPFC process/represent increasingly abstract information facilitating efficient and flexible cognition. However, support for this theory has been limited. Here, human fMRI data revealed rostral/caudal gradients of abstraction in the LPFC. Dynamic causal modeling revealed asymmetrical LPFC interactions indicative of hierarchical processing. Contrary to dominant assumptions, the relative strength of efferent versus afferent connections positioned mid LPFC as the apex of the hierarchy. Furthermore, cognitive demands induced connectivity modulations towards mid LPFC consistent with a role in integrating information for control operations. Moreover, the strengths of these dynamics were related to trait-measured higher-level cognitive ability. Collectively, these results suggest that the LPFC is hierarchically organized with the mid LPFC positioned to synthesize abstract and concrete information to control behavior.

Tambini, A, Nee DE, D'Esposito M.  2018.  Hippocampal-targeted Theta-burst Stimulation Enhances Associative Memory Formation., 2018 Jun 19. Journal of Cognitive Neuroscience. 30(10):1452-1472. Abstract2018_tambini.pdf

The hippocampus plays a critical role in episodic memory, among other cognitive functions. However, few tools exist to causally manipulate hippocampal function in healthy human participants. Recent work has targeted hippocampal-cortical networks by performing TMS to a region interconnected with the hippocampus, posterior inferior parietal cortex (pIPC). Such hippocampal-targeted TMS enhances associative memory and influences hippocampal functional connectivity. However, it is currently unknown which stages of mnemonic processing (encoding or retrieval) are affected by hippocampal-targeted TMS. Here, we examined whether hippocampal-targeted TMS influences the initial encoding of associations (vs. items) into memory. To selectively influence encoding and not retrieval, we performed continuous theta-burst TMS before participants encoded object-location associations and assessed memory after the direct effect of stimulation dissipated. Relative to control TMS and baseline memory, pIPC TMS enhanced associative memory success and confidence. Item memory was unaffected, demonstrating a selective influence on associative versus item memory. The strength of hippocampal-pIPC functional connectivity predicted TMS-related memory benefits, which was mediated by parahippocampal and retrosplenial cortices. Our findings indicate that hippocampal-targeted TMS can specifically modulate the encoding of new associations into memory without directly influencing retrieval processes and suggest that the ability to influence associative memory may be related to the fidelity of hippocampal TMS targeting. Our results support the notion that pIPC TMS may serve as a potential tool for manipulating hippocampal function in healthy participants. Nonetheless, future work combining hippocampal-targeted continuous theta-burst TMS with neuroimaging is needed to better understand the neural basis of TMS-induced memory changes.

Cole, MA, Soda CN, D'Esposito M.  2016.  History of Functional Brain Imaging. The Oxford Handbook of the History of Clinical Neuropsychology. , Oxford, UK: Oxford University Press
Hwang, K, Shine JM, Cellier D, D'Esposito M.  2020.  The Human Intraparietal Sulcus Modulates Task-Evoked Functional Connectivity., 2019 Jul 29. Cerebral Cortex. 30(3):875-887. Abstract2020_hwang.pdf

Past studies have demonstrated that flexible interactions between brain regions support a wide range of goal-directed behaviors. However, the neural mechanisms that underlie adaptive communication between brain regions are not well understood. In this study, we combined theta-burst transcranial magnetic stimulation (TMS) and functional magnetic resonance imaging to investigate the sources of top-down biasing signals that influence task-evoked functional connectivity. Subjects viewed sequences of images of faces and buildings and were required to detect repetitions (2-back vs. 1-back) of the attended stimuli category (faces or buildings). We found that functional connectivity between ventral temporal cortex and the primary visual cortex (VC) increased during processing of task-relevant stimuli, especially during higher memory loads. Furthermore, the strength of functional connectivity was greater for correct trials. Increases in task-evoked functional connectivity strength were correlated with increases in activity in multiple frontal, parietal, and subcortical (caudate and thalamus) regions. Finally, we found that TMS to superior intraparietal sulcus (IPS), but not to primary somatosensory cortex, decreased task-specific modulation in connectivity patterns between the primary VC and the parahippocampal place area. These findings demonstrate that the human IPS is a source of top-down biasing signals that modulate task-evoked functional connectivity among task-relevant cortical regions.

D’Esposito, Ballard D, Aguirre GK, Zarahn E.  1998.  Human prefrontal cortex is not specific for working memory: a functional MRI study., 1998 Oct. NeuroImage. 8(3):274-282. Abstract1998_despo_ni.pdf

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

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.

Hwang, K, Bertolero M, Liu W, D'Esposito M.  2017.  The human thalamus is an integrative hub for functional brain networks., 2017 Apr 27. Journal of Neuroscience. 37(23):5594-5607. Abstract2017_hwang.pdf

The thalamus is globally connected with distributed cortical regions, yet the functional significance of this extensive thalamocortical connectivity remains largely unknown. By performing graph-theoretic analyses on thalamocortical functional connectivity data collected from human participants, we found that most thalamic subdivisions display network properties capable of integrating multimodal information across diverse cortical functional networks. From a meta-analysis of a large dataset of functional brain imaging experiments, we further found that the thalamus is involved in multiple cognitive functions. Finally, we found that focal thalamic lesions in humans have widespread distal effects, disrupting the modular organization of cortical functional networks. This converging evidence suggests that the human thalamus is a critical hub region that could integrate diverse information being processed throughout the cerebral cortex, as well as maintain the modular structure of cortical functional networks.SIGNIFICANCE STATEMENTThe thalamus is traditionally viewed as a passive relay station of information from sensory organs or subcortical structures to the cortex. However, the thalamus has extensive connections with the entire cerebral cortex, which can also serve to integrate information processing between cortical regions. In this study, we demonstrate that multiple thalamic subdivisions displays network properties capable of integrating information across multiple functional brain networks. Moreover, the thalamus is engaged by tasks requiring multiple cognitive functions. These findings support the idea that the thalamus is involved in integrating information across cortical networks.

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.

Kornblith, E, Abrams G, Chen AJ-W, Burciaga J, D'Esposito M, Novakovic-Agopian T.  2018.  Impact of baseline neurocognitive functioning on outcomes following rehabilitation of executive function training for veterans with history of traumatic brain injury., 2018 Oct 08. Applied Neuropsychology: Adult. 27(2):108-120. Abstract2018_kornblith.pdf

Traumatic brain injury (TBI) is common among Veterans, and sequelae frequently include deficits in attention and executive function and problems with emotional regulation. Although rehabilitation has been shown to be effective, it is not clear how patient characteristics such as baseline cognitive status may impact response to rehabilitation in this sample. Explore the relationship between baseline neuropsychological status and postintervention functional outcomes in Veterans with chronic TBI. Thirty-three Veterans with chronic mild-severe TBI completed a neuropsychological evaluation, a functional assessment of executive function (EF), and measures of emotional and everyday functioning pre- and post-EF training or control training. Performance on baseline neuropsychological measures was used to cluster participants. Participants' performance at baseline and postintervention assessments was compared by cluster using multivariate analyses of variance (MANOVAs). Cognitive Difficulty (CD; n = 19) and Cognitively Normal (CN; n = 14) clusters were identified. CD was characterized by z ≤ -.75 on neuropsychological measures of overall attention/EF, working memory, and memory. CD participants performed worse on functional EF assessment and endorsed more PTSD symptoms and community integration problems, at baseline. CD participants improved post-EF training, but not control training, on neuropsychological and functional measures. CN participants did not show statistically significant improvement. For Veterans with chronic TBI, cognitive assessment can aid in identifying functional impairment and assist treatment planning. Cognitive rehabilitation training appears to be a beneficial treatment option for TBI patients with cognitive, emotional, and daily living difficulties.

Sheridan, MA, Sarsour K, Jutte D, D'Esposito M, Boyce TW.  2012.  The impact of social disparity on prefrontal function in childhood., 2012. PloS one. 7(4):e35744. Abstract2012_sheridan.pdf

The prefrontal cortex (PFC) develops from birth through late adolescence. This extended developmental trajectory provides many opportunities for experience to shape the structure and function of the PFC. To date, a few studies have reported links between parental socioeconomic status (SES) and prefrontal function in childhood, raising the possibility that aspects of environment associated with SES impact prefrontal function. Considering that behavioral measures of prefrontal function are associated with learning across multiple domains, this is an important area of investigation. In this study, we used fMRI to replicate previous findings, demonstrating an association between parental SES and PFC function during childhood. In addition, we present two hypothetical mechanisms by which SES could come to affect PFC function of this association: language environment and stress reactivity. We measured language use in the home environment and change in salivary cortisol before and after fMRI scanning. Complexity of family language, but not the child's own language use, was associated with both parental SES and PFC activation. Change in salivary cortisol was also associated with both SES and PFC activation. These observed associations emphasize the importance of both enrichment and adversity-reduction interventions in creating good developmental environments for all children.