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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.

Cools, R, Sheridan M, Jacobs E, D’Esposito.  2007.  Impulsive personality predicts dopamine-dependent changes in frontostriatal activity during component processes of working memory., 2007 May 16. Journal of Neuroscience. 27(20):5506-5514. Abstract2007_cools.pdf

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

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.

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.

Klein, HE, D’Esposito.  2007.  Neurocognitive inefficacy of the strategy process., 2007 Nov. Annals of the New York Academy of Sciences. 1118(1):163-185. Abstract2007_klein.pdf

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

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

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

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.

Gazzaley, A, Sheridan MA, Cooney JW, D’Esposito.  2007.  Age-related deficits in component processes of working memory., 2007 Sep. Neuropsychology. 21(5):532-539. Abstract2007_gazzaley_np.pdf

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

DeGutis, J, D’Esposito.  2007.  Distinct mechanisms in visual category learning., 2007 Sep. Cognitive, Affective & Behavioral Neuroscience. 7(3):251-259. Abstract2007_degutis_cabn.pdf

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

Gazzaley, A, Rissman J, Cooney JW, Rutman A, Seibert T, Clapp W, D’Esposito.  2007.  Functional interactions between prefrontal and visual association cortex contribute to top-down modulation of visual processing., 2007 Sep. Cerebral Cortex. 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.

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

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

Deouell, LY, Heller AS, Malach R, D’Esposito, Knight RT.  2007.  Cerebral responses to change in spatial location of unattended sounds., 2007 Sep 20. Neuron. 55(6):985-996. Abstract2007_deouell.pdf

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

D'Esposito, M.  2008.  From cognitive to neural models of working memory. Mental Processes in the Human Brain. , Oxford, UK: Oxford University Press
Curtis, CE, D'Esposito M.  2008.  The inhibition of unwanted actions. Psychology of Action, Vol. 2. , Oxford: Oxford University Press2008_curtis.pdf
Buchsbaum, BR, D'Esposito M.  2008.  Short term and working memory systems. Learning and Memory: A Comprehensive Reference. , Oxford: Elsevier2008_buchsbaum.pdf
D’Esposito.  2008.  Working memory., 2008. Handbook of Clinical Neurology / edited by P.J. Vinken and G.W. Bruyn. 88:237-247. Abstract2008_desposito_wm.pdf


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

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

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.

Silver, MA, Shenhav A, D’Esposito.  2008.  Cholinergic enhancement reduces spatial spread of visual responses in human early visual cortex., 2008 Dec 10. Neuron. 60(5):904-914. Abstract2008_silver.pdf

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

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

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

Cools, R, Gibbs SE, Miyakawa A, Jagust W, D’Esposito.  2008.  Working memory capacity predicts dopamine synthesis capacity in the human striatum., 2008 Jan 30. Journal of Neuroscience. 28(5):1208-1212. Abstract2008_cools.pdf

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

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.

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

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

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

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

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.

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.

Hooker, CI, Verosky SC, Miyakawa A, Knight RT, D’Esposito.  2008.  The influence of personality on neural mechanisms of observational fear and reward learning., 2008 Sep. Neuropsychologia. 46(11):2709-2724. Abstract2008_hooker.pdf

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

Hooker, CI, Verosky SC, Germine LT, Knight RT, D’Esposito.  2008.  Mentalizing about emotion and its relationship to empathy., 2008 Sep. Social Cognitive and Affective Neuroscience. 3(3):204-217. Abstract2008_hooker1.pdf

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

Gazzaley, A, Clapp W, Kelley J, McEvoy K, Knight RT, D’Esposito.  2008.  Age-related top-down suppression deficit in the early stages of cortical visual memory processing., 2008 Sep 2. Proceedings of the National Academy of Sciences of the United States of America. 105(35):13122-6. Abstract2008_gazzaley.pdf

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

Cools, R, D'Esposito M.  2009.  Dopaminergic modulation of flexible cognitive control in humans. Dopamine Handbook. , Oxford, UK: Oxford University Press
D'Esposito, M, Kayser A, Chen A.  2009.  Functional MRI: applications in cognitive neuroscience. Functional MRI Techniques and Protocols. : Humana Press
Buchsbaum, BR, D'Esposito M.  2009.  Is there anything special about working memory? Neuroimaging of Human Memory: Linking Cognitive Process to Neural Systems. , Oxford: Oxford University Press Abstract2009_buchsbaum.pdf


Van Boven, RW, Harrington GS, Hackney DB, Ebel A, Gauger G, Bremner DJ, D’Esposito, Detre JA, Haacke ME, Jack CR, Jagust W, Le Bihan D, Mathis CA, Mueller S, Mukherjee P, Schuff N, Chen AJ-W, Weiner MW.  2009.  Advances in neuroimaging of traumatic brain injury and posttraumatic stress disorder., 2009. Journal of Rehabilitation Research and Development. 46(6):717-757. Abstract2009_vanboven.pdf

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

DeGutis, J, D’Esposito.  2009.  Network changes in the transition from initial learning to well-practiced visual categorization., 2009. Frontiers in Human Neuroscience. 3:44. Abstract2009_degutis.pdf

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

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

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

Rajah, MN, Bastianetto S, Bromley-Brits K, Cools R, D’Esposito, Grady CL, Poirier J, Quirion R, Raz N, Rogaeva E, Song W, Pruessner J.  2009.  Biological changes associated with healthy versus pathological aging: a symposium review., 2009 Apr. Ageing Research Reviews. 8(2):140-146. Abstract2009_rajah.pdf

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

Badre, D, Hoffman J, Cooney JW, D’Esposito.  2009.  Hierarchical cognitive control deficits following damage to the human frontal lobe., 2009 Apr. Nature Neuroscience. 12(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.

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

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

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.

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

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

Kayser, A, Sun FT, D’Esposito.  2009.  A comparison of Granger causality and coherency in fMRI-based analysis of the motor system., 2009 Nov. Human Brain Mapping. 30(11):3475-3494. Abstract2009_kayser.pdf

The ability of functional MRI to acquire data from multiple brain areas has spurred developments not only in voxel-by-voxel analyses, but also in multivariate techniques critical to quantifying the interactions between brain areas. As the number of multivariate techniques multiplies, however, few studies in any modality have directly compared different connectivity measures, and fewer still have done so in the context of well-characterized neural systems. To focus specifically on the temporal dimension of interactions between brain regions, we compared Granger causality and coherency (Sun et al., 2004, 2005: Neuroimage 21:647-658, Neuroimage 28:227-237) in a well-studied motor system (1) to gain further insight into the convergent and divergent results expected from each technique, and (2) to investigate the leading and lagging influences between motor areas as subjects performed a motor task in which they produced different learned series of eight button presses. We found that these analyses gave convergent but not identical results: both techniques, for example, suggested an anterior-to-posterior temporal gradient of activity from supplemental motor area through premotor and motor cortices to the posterior parietal cortex, but the techniques were differentially sensitive to the coupling strength between areas. We also found practical reasons that might argue for the use of one technique over another in different experimental situations. Ultimately, the ideal approach to fMRI data analysis is likely to involve a complementary combination of methods, possibly including both Granger causality and coherency.

Badre, D, D’Esposito.  2009.  Is the rostro-caudal axis of the frontal lobe hierarchical?, 2009 Sep Nature Reviews: Neuroscience. 10(9):659-669. Abstract2009_badre_nature.pdf

The frontal lobes in the brain are a component of the cerebral system that supports goal-directed behaviour. However, their functional organization remains controversial. Recent studies have reported rostro-caudal distinctions in frontal cortex activity based on the abstractness of action representations. In addition, some have proposed that these differences reflect a hierarchical organization, whereby anterior frontal regions influence processing by posterior frontal regions during the realization of abstract action goals as motor acts. However, few have considered whether the anatomy and physiology of the frontal lobes support such a scheme. To address this gap, this Review surveys anatomical, neuroimaging, electrophysiological and developmental findings, and considers the question: could the organization of the frontal cortex be hierarchical?

Boettiger, CA, Kelley EA, Mitchell JM, D’Esposito, Fields HL.  2009.  Now or Later? An fMRI study of the effects of endogenous opioid blockade on a decision-making network., 2009 Sep Pharmacology, Biochemistry, and Behavior. 93(3):291-299. Abstract2009_boettiger.pdf

Previously, we found that distinct brain areas predict individual selection bias in decisions between small immediate ("Now") and larger delayed rewards ("Later"). Furthermore, such selection bias can be manipulated by endogenous opioid blockade. To test whether blocking endogenous opioids with naltrexone (NTX) alters brain activity during decision-making in areas predicting individual bias, we compared fMRI BOLD signal correlated with Now versus Later decision-making after acute administration of NTX (50 mg) or placebo. We tested abstinent alcoholics and control subjects in a double-blind two-session design. We defined regions of interest (ROIs) centered on activation peaks predicting Now versus Later selection bias. NTX administration significantly increased BOLD signal during decision-making in the right lateral orbital gyrus ROI, an area where enhanced activity during decision-making predicts Later bias. Exploratory analyses identified additional loci where BOLD signal during decision-making was enhanced (left orbitofrontal cortex, left inferior temporal gyrus, and cerebellum) or reduced (right superior temporal pole) by NTX. Additional analyses identified sites, including the right lateral orbital gyrus, in which NTX effects on BOLD signal predicted NTX effects on selection bias. These data agree with opioid receptor expression in human frontal and temporal cortices, and suggest possible mechanisms of NTX’s therapeutic effects.

D'Esposito, M.  2010.  Why Methods Matter in the Study of the Biological Basis of the Mind: A Behavioral Neurologist’s Perspective. The Cognitive Neuroscience of Mind: A Tribute to Michael S. Gazzaniga. , Cambridge: MIT Press Abstract2010_desposito.pdf


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

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

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.

Finn, AS, Sheridan MA, Kam CHL, Hinshaw S, D’Esposito.  2010.  Longitudinal evidence for functional specialization of the neural circuit supporting working memory in the human brain., 2010 Aug 18. Journal of Neuroscience. 30(33):11062-11067. Abstract2010_finn.pdf

Although children perform more poorly than adults on many cognitive measures, they are better able to learn things such as language and music. These differences could result from the delayed specialization of neural circuits and asynchronies in the maturation of neural substrates required for learning. Working memory–the ability to hold information in mind that is no longer present in the environment–comprises a set of cognitive processes required for many, if not all, forms of learning. A critical neural substrate for working memory (the prefrontal cortex) continues to mature through early adulthood. What are the functional consequences of this late maturation for working memory? Using a longitudinal design, we show that although individuals recruit prefrontal cortex as expected during both early and late adolescence during a working memory task, this recruitment is correlated with behavior only in late adolescence. The hippocampus is also recruited, but only during early, and not late, adolescence. Moreover, the hippocampus and prefrontal cortex are coactive in early adolescence regardless of task demands or performance, in contrast to the pattern seen in late adolescents and adults, when these regions are coactive only under high task demands. Together, these data demonstrate that neural circuitry underlying working memory changes during adolescent development. The diminishing contribution of the hippocampus in working memory function with age is an important observation that informs questions about how children and adults learn differently.

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.

Hooker, CI, Verosky SC, Germine LT, Knight RT, D’Esposito.  2010.  Neural activity during social signal perception correlates with self-reported empathy., 2010 Jan 13. Brain Research. 1308:100-113. Abstract2010_hooker.pdf

Empathy is an important component of human relationships, yet the neural mechanisms that facilitate empathy are unclear. The broad construct of empathy incorporates both cognitive and affective components. Cognitive empathy includes mentalizing skills such as perspective-taking. Affective empathy consists of the affect produced in response to someone else’s emotional state, a process which is facilitated by simulation or "mirroring." Prior evidence shows that mentalizing tasks engage a neural network which includes the temporoparietal junction, superior temporal sulcus, and medial prefrontal cortex. On the other hand, simulation tasks engage the fronto-parietal mirror neuron system (MNS) which includes the inferior frontal gyrus (IFG) and the somotosensory related cortex (SRC). Here, we tested whether neural activity in these two neural networks was related to self-reports of cognitive and affective empathy in daily life. Participants viewed social scenes in which the shift of direction of attention of a character did or did not change the character’s mental and emotional state. As expected, the task robustly activated both mentalizing and MNS networks. We found that when detecting the character’s change in mental and emotional state, neural activity in both networks is strongly related to cognitive empathy. Specifically, neural activity in the IFG, SRC, and STS were related to cognitive empathy. Activity in the precentral gyrus was related to affective empathy. The findings suggest that both simulation and mentalizing networks contribute to multiple components of empathy.

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

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

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.

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.

Kayser, A, Erickson DT, Buchsbaum BR, D’Esposito.  2010.  Neural representations of relevant and irrelevant features in perceptual decision making., 2010 Nov 24. Journal of Neuroscience. 30(47):15778-15789. Abstract2010_kayser.pdf

Although perceptual decision making activates a network of brain areas involved in sensory, integrative, and motor functions, circuit activity can clearly be modulated by factors beyond the stimulus. Of particular interest is to understand how the network is modulated by top-down factors such as attention. Here, we demonstrate in a motion coherence task that selective attention produces marked changes in the blood oxygen level-dependent (BOLD) response in a subset of regions within a human perceptual decision-making circuit. Specifically, when motion is attended, the BOLD response decreases with increasing motion coherence in many regions, including the motion-sensitive area MT+, the intraparietal sulcus, and the inferior frontal sulcus. However, when motion is ignored, the negative parametric response in a subset of this circuit becomes positive. Through both modeling and connectivity analyses, we demonstrate that this inversion both reflects a top-down influence and segregates attentional from accumulation regions, thereby permitting us to further delineate the contributions of different regions to the perceptual decision.

D'Esposito, M, Badre D.  2011.  Combining the insights derived from lesion and fMRI studies to understand the function of prefrontal cortex. Mind and the Frontal Lobes: Cognition, Behavior, and Brain Imaging. , New York: Oxford University Press
D'Esposito, M, Kayser A, Chen A.  2011.  Functional MRI: cognitive neuroscience applications. Functional Neuroradiology: Principles and Clinical Applications. , Berlin: Springer-Verlag
Turner, G, D'Esposito M.  2011.  Functional neuroimaging of aging. Clinical Neurology of Aging, 3rd Edition. , Oxford: Oxford University Press
Wallace, DL, Vytlacil JJ, Nomura EM, Gibbs SE, D’Esposito.  2011.  The dopamine agonist bromocriptine differentially affects fronto-striatal functional connectivity during working memory., 2011. Frontiers in Human Neuroscience. 5:32. Abstract2011_wallace.pdf

We investigated the effect of bromocriptine, a dopamine agonist, on individual differences in behavior as well as frontal-striatal connectivity during a working memory task. After dopaminergic augmentation, frontal-striatal connectivity in low working memory capacity individuals increases, corresponding with behavioral improvement whereas decreases in connectivity in high working memory capacity individuals are associated with poorer behavioral performance. These findings corroborate an inverted U-shape response of dopamine function in behavioral performance and provide insight on the corresponding neural mechanisms.

Buchsbaum, BR, Ye D, D’Esposito.  2011.  Recency Effects in the Inferior Parietal Lobe during Verbal Recognition Memory., 2011. Frontiers in Human Neuroscience. 5:59. Abstract2011_buchsbaum_fihn.pdf

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

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.

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

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

Buchsbaum, BR, Baldo J, Okada K, Berman KF, Dronkers N, D’Esposito, Hickok G.  2011.  Conduction aphasia, sensory-motor integration, and phonological short-term memory - An aggregate analysis of lesion and fMRI data., 2011 Jan 20. Brain and Language. 119(3):119-128. Abstract2011_buchsbaum.pdf

Conduction aphasia is a language disorder characterized by frequent speech errors, impaired verbatim repetition, a deficit in phonological short-term memory, and naming difficulties in the presence of otherwise fluent and grammatical speech output. While traditional models of conduction aphasia have typically implicated white matter pathways, recent advances in lesions reconstruction methodology applied to groups of patients have implicated left temporoparietal zones. Parallel work using functional magnetic resonance imaging (fMRI) has pinpointed a region in the posterior most portion of the left planum temporale, area Spt, which is critical for phonological working memory. Here we show that the region of maximal lesion overlap in a sample of 14 patients with conduction aphasia perfectly circumscribes area Spt, as defined in an aggregate fMRI analysis of 105 subjects performing a phonological working memory task. We provide a review of the evidence supporting the idea that Spt is an interface site for the integration of sensory and vocal tract-related motor representations of complex sound sequences, such as speech and music and show how the symptoms of conduction aphasia can be explained by damage to this system.

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.

Rokem, A, Landau AN, Prinzmetal W, Wallace DL, Silver MA, D’Esposito.  2011.  Modulation of Inhibition of Return by the Dopamine D2 Receptor Agonist Bromocriptine Depends on Individual DAT1 Genotype., 2011 Jul 28. Cerebral Cortex. 22(5):1133-1138. Abstract2011_rokem.pdf

Involuntary visual spatial attention is captured when a salient cue appears in the visual field. If a target appears soon after the cue, response times to targets at the cue location are faster relative to other locations. However, after longer cue-target intervals, responses to targets at the cue location are slower, due to inhibition of return (IOR). IOR depends on striatal dopamine (DA) levels: It varies with different alleles of the DA transporter gene DAT1 and is reduced in patients with Parkinson’s disease, a disease characterized by reduced striatal dopaminergic transmission. We examined the role of DA in involuntary attention and IOR by administering the DA D2 receptor-specific agonist bromocriptine to healthy human subjects. There was no effect of either DAT1 genotype or bromocriptine on involuntary attention, but participants with DAT1 alleles predicting higher striatal DA had a larger IOR. Furthermore, bromocriptine increased the magnitude of IOR in participants with low striatal DA but abolished the IOR in subjects with high striatal DA. This inverted U-shaped pattern resembles previously described relationships between DA levels and performance on cognitive tasks and suggests an involvement of striatal DA in IOR that does not include a role in involuntary attention.

Cools, R, D’Esposito.  2011.  Inverted-U-shaped dopamine actions on human working memory and cognitive control., 2011 Jun 15. Biological Psychiatry. 69(12):e113-125. Abstract2011_cools.pdf

Brain dopamine (DA) has long been implicated in cognitive control processes, including working memory. However, the precise role of DA in cognition is not well-understood, partly because there is large variability in the response to dopaminergic drugs both across different behaviors and across different individuals. We review evidence from a series of studies with experimental animals, healthy humans, and patients with Parkinson’s disease, which highlight two important factors that contribute to this large variability. First, the existence of an optimum DA level for cognitive function implicates the need to take into account baseline levels of DA when isolating the effects of DA. Second, cognitive control is a multifactorial phenomenon, requiring a dynamic balance between cognitive stability and cognitive flexibility. These distinct components might implicate the prefrontal cortex and the striatum, respectively. Manipulating DA will thus have paradoxical consequences for distinct cognitive control processes, depending on distinct basal or optimal levels of DA in different brain regions.

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.

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

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

Altamirano, LJ, Fields HL, D’Esposito, Boettiger CA.  2011.  Interaction Between Family History of Alcoholism and Locus of Control in the Opioid Regulation of Impulsive Responding Under the Influence of Alcohol., 2011 May 13. Alcoholism: Clinical and Experimental Research. 35(11):1905-1914. Abstract2011_altamirano.pdf

{Background: Naltrexone (NTX) is an opioid antagonist indicated for the treatment of alcoholism, which is not universally effective. Thus, identifying individual predictors of NTX’s behavioral effects is critical to optimizing its therapeutic use. Moreover, given the high rate of relapse during treatment for alcoholism, understanding NTX’s behavioral effects when combined with moderate ethanol intake is important. Our previous study of abstinent alcoholics and control subjects showed that a more internal Locus of Control score predicted increased impulsive choice on NTX (Mitchell et al., 2007, Neuropsychopharmacology 32:439-449). Here, we tested whether this predictive relationship remains in the context of moderate alcohol intake. Methods: In this study, we tested the effect of acute NTX (50 mg) on impulsive choice, motor inhibition, and attentional bias after ingestion of moderate ethanol (\~{}0.3 g/kg

Krawczyk, DC, D'Esposito M.  2011.  Modulation of working memory function by motivation through loss-aversion., 2011 Nov 24. Human Brain Mapping. 34(4):762-774. Abstract2011_krawczyk.pdf

Cognitive performance is affected by motivation. Few studies, however, have investigated the neural mechanisms of the influence of motivation through potential monetary punishment on working memory. We employed functional MRI during a delayed recognition task that manipulated top-down control demands with added monetary incentives to some trials in the form of potential losses of bonus money. Behavioral performance on the task was influenced by loss-threatening incentives in the form of faster and more accurate performance. As shown previously, we found enhancement of activity for relevant stimuli occurs throughout all task periods (e.g., stimulus encoding, maintenance, and response) in both prefrontal and visual association cortex. Further, these activation patterns were enhanced for trials with possible monetary loss relative to nonincentive trials. During the incentive cue, the amygdala and striatum showed significantly greater activation when money was at a possible loss on the trial. We also evaluated patterns of functional connectivity between regions responsive to monetary consequences and prefrontal areas responsive to the task. This analysis revealed greater delay period connectivity between and the left insula and prefrontal cortex with possible monetary loss relative to nonincentive trials. Overall, these results reveal that incentive motivation can modulate performance on working memory tasks through top-down signals via amplification of activity within prefrontal and visual association regions selective to processing the perceptual inputs of the stimuli to be remembered. Hum Brain Mapp , 2011. © 2011 Wiley Periodicals, Inc.

D'Esposito, M, Gazzaley A.  2011.  Can age-associated memory decline be treated?, 2011 Oct 6 New England Journal of Medicine. 365(14):1346-1347. Abstract2011_desposito_nejm.pdf


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

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

Wittmann, B, D'Esposito M.  2012.  Functional magnetic resonance imaging. Handbook of Research Methods in Psychology. , Washington, DC: American Psychological Association
Kayser, A, D'Esposito M.  2012.  Neurotechnologies. Encyclopedia of Human Behavior, 2nd Edition. , Oxford: Elsevier
D'Esposito, M, Chen A.  2012.  Remediating frontal lobe dysfunction: from bench to bedside. The Oxford Handbook of Frontal Lobe Functions. , New York: Oxford University Press
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.

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.

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

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

Blumenfeld, RS, Nomura EM, Gratton C, D'Esposito M.  2012.  Lateral Prefrontal Cortex is Organized into Parallel Dorsal and Ventral Streams Along the Rostro-Caudal Axis., 2012 Aug 9. Cerebral Cortex. 23(10):2457-2466. Abstract2012_blumenfeld_cc.pdf

Anatomical connectivity differences between the dorsal and ventral lateral prefrontal cortex (PFC) of the non-human primate strongly suggests that these regions support different functions. However, after years of study, it remains unclear whether these regions are functionally distinct. In contrast, there has been a groundswell of recent studies providing evidence for a rostro-caudal functional organization, along the lateral as well as dorsomedial frontal cortex. Thus, it is not known whether dorsal and ventral regions of lateral PFC form distinct functional networks and how to reconcile any dorso-ventral organization with the medio-lateral and rostro-caudal axes. Here, we used resting-state connectivity data to identify parallel dorsolateral and ventrolateral streams of intrinsic connectivity with the dorsomedial frontal cortex. Moreover, we show that this connectivity follows a rostro-caudal gradient. Our results provide evidence for a novel framework for the intrinsic organization of the frontal cortex that incorporates connections between medio-lateral, dorso-ventral, and rostro-caudal axes.

Handwerker, DA, Gonzalez-Castillo J, D'Esposito M, Bandettini PA.  2012.  The continuing challenge of understanding and modeling hemodynamic variation in fMRI., 2012 Feb 14. NeuroImage. 62(2):1017-1023. Abstract2012_handwerker.pdf

Interpretation of fMRI data depends on our ability to understand or model the shape of the hemodynamic response (HR) to a neural event. Although the HR has been studied almost since the beginning of fMRI, we are still far from having robust methods to account for the full range of known HR variation in typical fMRI analyses. This paper reviews how the authors and others contributed to our understanding of HR variation. We present an overview of studies that describe HR variation across voxels, healthy volunteers, populations, and dietary or pharmaceutical modulations. We also describe efforts to minimize the effects of HR variation in intrasubject, group, population, and connectivity analyses and the limits of these methods.

Kayser, AS, D’esposito M.  2012.  Abstract Rule Learning: The Differential Effects of Lesions in Frontal Cortex., 2012 Jan 31. Cerebral Cortex. 23(1):230-240. Abstract2012_kayser.pdf

Learning progressively more abstract stimulus-response mappings requires progressively more anterior regions of the lateral frontal cortex. Using an individual differences approach, we studied subjects with frontal lesions performing a hierarchical reinforcement-learning task to investigate how frontal cortex contributes to abstract rule learning. We predicted that subjects with lesions of the left pre-premotor (pre-PMd) cortex, a region implicated in abstract rule learning, would demonstrate impaired acquisition of second-order, as opposed to first-order, rules. We found that 4 subjects with such lesions did indeed demonstrate a second-order rule-learning impairment, but that these subjects nonetheless performed better than subjects with other frontal lesions in a second-order rule condition. This finding resulted from both their restricted exploration of the feature space and the task structure of this condition, for which they identified partially representative first-order rules. Significantly, across all subjects, suboptimal but above-chance performance in this condition correlated with increasing disconnection of left pre-PMd from the putative functional hierarchy, defined by reduced functional connectivity between left pre-PMd and adjacent nodes. These findings support the theory that activity within lateral frontal cortex shapes the search for relevant stimulus-response mappings, while emphasizing that the behavioral correlate of impairments depends critically on task structure.

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.

Cohen, JR, Sreenivasan KK, D'Esposito M.  2012.  Correspondence Between Stimulus Encoding- and Maintenance-Related Neural Processes Underlies Successful Working Memory., 2012 Nov 11. Cerebral Cortex. 24(3):593-599. Abstract2012_cohen.pdf

The ability to actively maintain information in working memory (WM) is vital for goal-directed behavior, but the mechanisms underlying this process remain elusive. We hypothesized that successful WM relies upon a correspondence between the neural processes associated with stimulus encoding and the neural processes associated with maintenance. Using functional magnetic resonance imaging, we identified regional activity and inter-regional connectivity during stimulus encoding and the maintenance of those stimuli when they were no longer present. We compared correspondence in these neural processes across encoding and maintenance epochs with WM performance. Critically, greater correspondence between encoding and maintenance in 1) regional activity in the lateral prefrontal cortex (PFC) and 2) connectivity between lateral PFC and extrastriate cortex was associated with increased performance. These findings suggest that the conservation of neural processes across encoding and maintenance supports the integrity of representations in WM.

Sadaghiani, S, Scheeringa R, Lehongre K, Morillon B, Giraud A-L, D'Esposito M, Kleinschmidt A.  2012.  Alpha-Band Phase Synchrony Is Related to Activity in the Fronto-Parietal Adaptive Control Network., 2012 Oct 10. Journal of Neuroscience. 32(41):14305-14310. Abstract2012_sadaghiani.pdf

Neural oscillations in the alpha band (8-12 Hz) are increasingly viewed as an active inhibitory mechanism that gates and controls sensory information processing as a function of cognitive relevance. Extending this view, phase synchronization of alpha oscillations across distant cortical regions could regulate integration of information. Here, we investigated whether such long-range cross-region coupling in the alpha band is intrinsically and selectively linked to activity in a distinct functionally specialized brain network. If so, this would provide new insight into the functional role of alpha band phase synchrony. We adapted the phase-locking value to assess fluctuations in synchrony that occur over time in ongoing activity. Concurrent EEG and functional magnetic resonance imaging (fMRI) were recorded during resting wakefulness in 26 human subjects. Fluctuations in global synchrony in the upper alpha band correlated positively with activity in several prefrontal and parietal regions (as measured by fMRI). fMRI intrinsic connectivity analysis confirmed that these regions correspond to the well known fronto-parietal (FP) network. Spectral correlations with this network's activity confirmed that no other frequency band showed equivalent results. This selective association supports an intrinsic relation between large-scale alpha phase synchrony and cognitive functions associated with the FP network. This network has been suggested to implement phasic aspects of top-down modulation such as initiation and change in moment-to-moment control. Mechanistically, long-range upper alpha band synchrony is well suited to support these functions. Complementing our previous findings that related alpha oscillation power to neural structures serving tonic control, the current findings link alpha phase synchrony to neural structures underpinning phasic control of alertness and task requirements.

Novakovic-Agopian, T, Chen AJ-W, Rome S, Rossi A, Abrams G, Dʼesposito M, Turner G, McKim R, Muir J, Hills N, Kennedy C, Garfinkle J, Murphy M, Binder D, Castelli H.  2012.  Assessment of Subcomponents of Executive Functioning in Ecologically Valid Settings: The Goal Processing Scale., 2012 Oct 16. Journal of Head Trauma Rehabilitation. 29(2):136-146. Abstract2012_novakovic.pdf

OBJECTIVES:: To validate a new functional assessment tool, the Goal Processing Scale (GPS), and to apply it for testing for sources of dysfunction in patients with acquired brain injury. Determining which component processes of executive functioning underlie poor performance in complex, low-structure settings would be valuable for the assessment of deficits and for evaluating the effectiveness of treatments. PARTICIPANTS:: Nineteen individuals with chronic acquired brain injury (mean age = 41.4 years; chronicity: 6 months to 39 years). MAIN MEASURES:: Two functional assessment tasks: (1) GPS, which evaluates functional performance in the context of achieving a goal in a "real-world" setting, with rating scales measuring overall performance and 8 subdomains of executive functioning; (2) Multiple Errands Test, an unstructured assessment of ability to adhere to rules and complete multiple "real-world" tasks in a short time; and (3) a neuropsychological battery. RESULTS:: Intraclass correlation coefficients for 2 independent raters ranged from 0.75 to 0.98 for the GPS overall composite score and the subdomain scores. Performance on GPS overall and several subdomain scores correlated with performance on the Multiple Errands Test. Working memory and learning/memory neuropsychological measures predicted functional performance as measured using the GPS. DISCUSSION:: The GPS shows high interrater reliability, suggesting convergent validity with an established functional performance measure, and produces useful information regarding strengths and weaknesses in different subdomains of executive functioning. Working memory and learning/memory appear to be key determinants of goal-directed functioning for these individuals with brain injury.

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.

Voytek, B, D'Esposito M, Crone N, Knight RT.  2012.  A method for event-related phase/amplitude coupling., 2012 Sep 14. NeuroImage. 64:416-424. Abstract2012_voytek.pdf

Phase/amplitude coupling (PAC) is emerging as an important electrophysiological measure of local and long-distance neuronal communication. Current techniques for calculating PAC provide a numerical index that represents an average value across an arbitrarily long time period. This requires researchers to rely on block design experiments and temporal concatenation at the cost of the sub-second temporal resolution afforded by electrophysiological recordings. Here we present a method for calculating event-related phase/amplitude coupling (ERPAC) designed to capture the temporal evolution of task-related changes in PAC across events or between distant brain regions that is applicable to human or animal electromagnetic recording.

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
Postle, BR, Awh E, Serences J, Sutterer D, D'Esposito M.  2013.  The positional-specificity effect reveals a passive-trace contribution to visual short-term memory. PLOS One. 8(12):e83483.2013_postle.pdf
Buchsbaum, B, D'Esposito M.  2013.  Working memory. Oxford Handbook of Cognitive Neuroscience. , Oxford: Oxford University Press
Finn, AS, Hudson Kam CL, Ettlinger M, Vytlacil J, D'Esposito M.  2013.  Learning language with the wrong neural scaffolding: the cost of neural commitment to sounds., 2013. Frontiers in Systems Neuroscience. 7:85. Abstract2013_finn.pdf

Does tuning to one's native language explain the "sensitive period" for language learning? We explore the idea that tuning to (or becoming more selective for) the properties of one's native-language could result in being less open (or plastic) for tuning to the properties of a new language. To explore how this might lead to the sensitive period for grammar learning, we ask if tuning to an earlier-learned aspect of language (sound structure) has an impact on the neural representation of a later-learned aspect (grammar). English-speaking adults learned one of two miniature artificial languages (MALs) over 4 days in the lab. Compared to English, both languages had novel grammar, but only one was comprised of novel sounds. After learning a language, participants were scanned while judging the grammaticality of sentences. Judgments were performed for the newly learned language and English. Learners of the similar-sounds language recruited regions that overlapped more with English. Learners of the distinct-sounds language, however, recruited the Superior Temporal Gyrus (STG) to a greater extent, which was coactive with the Inferior Frontal Gyrus (IFG). Across learners, recruitment of IFG (but not STG) predicted both learning success in tests conducted prior to the scan and grammatical judgment ability during the scan. Data suggest that adults' difficulty learning language, especially grammar, could be due, at least in part, to the neural commitments they have made to the lower level linguistic components of their native language.

Stelzel, C, Fiebach CJ, Cools R, Tafazoli S, D'Esposito M.  2013.  Dissociable fronto-striatal effects of dopamine D2 receptor stimulation on cognitive versus motor flexibility., 2013 Apr 11. Cortex. 49(10):2799-2811. Abstract2013_stelzel.pdf

Genetic and pharmacological studies suggest an important role of the dopamine D2 receptor (DRD2) in flexible behavioral adaptation, mostly shown in reward-based learning paradigms. Recent evidence from imaging genetics indicates that also intentional cognitive flexibility, associated with lateral frontal cortex, is affected by variations in DRD2 signaling. In the present functional magnetic resonance imaging (MRI) study, we tested the effects of a direct pharmacological manipulation of DRD2 stimulation on intentional flexibility in a task-switching context, requiring switches between cognitive task rules and between response hands. In a double blind, counterbalanced design, participants received either a low dose of the DRD2 agonist bromocriptine or a placebo in two separate sessions. Bromocriptine modulated the blood-oxygen-level-dependent (BOLD) signal during rule switching: rule-switching-related activity in the left posterior lateral frontal cortex and in the striatum was increased compared to placebo, at comparable performance levels. Fronto-striatal connectivity under bromocriptine was slightly increased for rule switches compared to rule repetitions. Hand-switching-related activity, in contrast, was reduced under bromocriptine in sensorimotor regions. Our results provide converging evidence for an involvement of DRD2 signaling in fronto-striatal mechanisms underlying intentional flexibility, and indicate that the neural mechanisms underlying different types of flexibility (cognitive vs motor) are affected differently by increased dopaminergic stimulation.

Gratton, C, Sreenivasan KK, Silver MA, D'Esposito M.  2013.  Attention selectively modifies the representation of individual faces in the human brain., 2013 Apr 17. Journal of Neuroscience. 33(16):6979-6989. Abstract2013_gratton.pdf

Attention modifies neural tuning for low-level features, but it is unclear how attention influences tuning for complex stimuli. We investigated this question in humans using fMRI and face stimuli. Participants were shown six faces (F1-F6) along a morph continuum, and selectivity was quantified by constructing tuning curves for individual voxels. Face-selective voxels exhibited greater responses to their preferred face than to nonpreferred faces, particularly in posterior face areas. Anterior face areas instead displayed tuning for face categories: voxels in these areas preferred either the first (F1-F3) or second (F4-F6) half of the morph continuum. Next, we examined the effects of attention on voxel tuning by having subjects direct attention to one of the superimposed images of F1 and F6. We found that attention selectively enhanced responses in voxels preferring the attended face. Together, our results demonstrate that single voxels carry information about individual faces and that the nature of this information varies across cortical face areas. Additionally, we found that attention selectively enhances these representations. Our findings suggest that attention may act via a unitary principle of selective enhancement of responses to both simple and complex stimuli across multiple stages of the visual hierarchy.

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

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

Lee, TG, Blumenfeld RS, D'Esposito M.  2013.  Disruption of dorsolateral but not ventrolateral prefrontal cortex improves unconscious perceptual memories., 2013 Aug 7. Journal of Neuroscience. 33(32):13233-13237. Abstract2013_lee.pdf

Attentive encoding often leads to more accurate responses in recognition memory tests. However, previous studies have described conditions under which taxing explicit memory resources by attentional distraction improved perceptual recognition memory without awareness. These findings lead to the hypothesis that explicit memory processes mediated by the prefrontal cortex (PFC) can interfere with memory processes necessary for implicit recognition memory. The present study directly tested this hypothesis by applying transcranial magnetic stimulation separately over either dorsolateral (DLPFC) or ventrolateral PFC (VLPFC) in humans before performance of a visual memory task. Disruption of DLPFC function led to improvement in recognition accuracy only in responses in which the participant's awareness of memory retrieval was absent. However, disruption of VLPFC function led to subtle shifts in recollection and familiarity accuracy. We conclude that explicit memory processes mediated by the DLPFC can indirectly interfere with implicit recognition memory.

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.

Yoon, JH, Minzenberg MJ, Raouf S, D'Esposito M, Carter CS.  2013.  Impaired Prefrontal-Basal Ganglia Functional Connectivity and Substantia Nigra Hyperactivity in Schizophrenia., 2013 Jan 3. Biological Psychiatry. 74(2):122-129. Abstract2013_yoon.pdf

BACKGROUND: The theory that prefrontal cortex (PFC) dysfunction in schizophrenia leads to excess subcortical dopamine has generated widespread interest because it provides a parsimonious account for two core features of schizophrenia, cognitive deficits and psychosis, respectively. However, there has been limited empirical validation of this model. Moreover, the identity of the specific subcortical brain regions and circuits that may be impaired as a result of PFC dysfunction and mediate its link to psychosis in schizophrenia remains unclear. We undertook this event-related functional magnetic resonance imaging study to test the hypothesis that PFC dysfunction is associated with altered function of and connectivity with dopamine regulating regions of the basal ganglia. METHODS: Eighteen individuals with schizophrenia or schizoaffective disorder and 19 healthy control participants completed event-related functional magnetic resonance imaging during working memory. We conducted between-group contrasts of task-evoked, univariate activation maps to identify regions of altered function in schizophrenia. We also compared the groups on the level of functional connectivity between a priori identified PFC and basal ganglia regions to determine if prefrontal disconnectivity in patients was present. RESULTS: We observed task-evoked hyperactivity of the substantia nigra that occurred in association with prefrontal and striatal hypoactivity in the schizophrenia group. The magnitude of prefrontal functional connectivity with these dysfunctional basal ganglia regions was decreased in the schizophrenia group. Additionally, the level of nigrostriatal functional connectivity predicted the level of psychosis. CONCLUSIONS: These results suggest that functional impairments of the prefrontal striatonigral circuit may be a common pathway linking the pathogenesis of cognitive deficits and psychosis in schizophrenia.

Hooker, CI, Bruce L, Fisher M, Verosky SC, Miyakawa A, D'Esposito M, Vinogradov S.  2013.  The influence of combined cognitive plus social-cognitive training on amygdala response during face emotion recognition in schizophrenia., 2013 Jun 5. Psychiatry Research. 213(2):99-107. Abstract2013_hooker.pdf

Both cognitive and social-cognitive deficits impact functional outcome in schizophrenia. Cognitive remediation studies indicate that targeted cognitive and/or social-cognitive training improves behavioral performance on trained skills. However, the neural effects of training in schizophrenia and their relation to behavioral gains are largely unknown. This study tested whether a 50-h intervention which included both cognitive and social-cognitive training would influence neural mechanisms that support social ccognition. Schizophrenia participants completed a computer-based intervention of either auditory-based cognitive training (AT) plus social-cognition training (SCT) (N=11) or non-specific computer games (CG) (N=11). Assessments included a functional magnetic resonance imaging (fMRI) task of facial emotion recognition, and behavioral measures of cognition, social cognition, and functional outcome. The fMRI results showed the predicted group-by-time interaction. Results were strongest for emotion recognition of happy, surprise and fear: relative to CG participants, AT+SCT participants showed a neural activity increase in bilateral amygdala, right putamen and right medial prefrontal cortex. Across all participants, pre-to-post intervention neural activity increase in these regions predicted behavioral improvement on an independent emotion perception measure (MSCEIT: Perceiving Emotions). Among AT+SCT participants alone, neural activity increase in right amygdala predicted behavioral improvement in emotion perception. The findings indicate that combined cognition and social-cognition training improves neural systems that support social-cognition skills.

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

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

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
Turner, GR, D'Esposito M.  2014.  Neurorehabilitation of Executive Functions. . Textbook of Neural Repair and Rehabilitation. , Cambridge, UK: Cambridge University Press
Sreenivasan, KK, Curtis CE, D'Esposito M.  2014.  Revising the role of persistent neural activity in working memory. Trends in Cognitive Science. 18(2):82-89.2014_sreenivasan.pdf