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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.

Pappas, I, Hector H, Haws K, Curran B, Kayser AS, D'Esposito M.  2021.  Improved normalization of lesioned brains via cohort-specific templates., 2021 Jun 18. Human brain mapping. Abstract

In MRI studies, spatial normalization is required to infer results at the group level. In the presence of a brain lesion, such as in stroke patients, the normalization process can be affected by tissue loss, spatial deformations, signal intensity changes, and other stroke sequelae that introduce confounds into the group analysis results. Previously, most neuroimaging studies with lesioned brains have used normalization methods optimized for intact brains, raising potential concerns about the accuracy of the resulting transformations and, in turn, their reported group level results. In this study, we demonstrate the benefits of creating an intermediate, cohort-specific template in conjunction with diffeomorphism-based methods to normalize structural MRI images in stroke patients. We show that including this cohort-specific template improves accuracy compared to standard methods for normalizing lesioned brains. Critically, this method reduces overall differences in normalization accuracy between stroke patients and healthy controls, and may improve the localization and connectivity of BOLD signal in functional neuroimaging data.

Daffner, KR, Gale SA, Barrett AM, Boeve BF, Chatterjee A, Coslett BH, D'Esposito M, Finney GR, Gitelman DR, Hart JJ, Lerner AJ, Meador KJ, Pietras AC, Voeller KS, Kaufer DI.  2015.  Improving clinical cognitive testing: Report of the AAN Behavioral Neurology Section Workgroup., 2015 Jul 10. Neurology. 85(10):910-918. Abstract2015_daffner.pdf

To evaluate the evidence basis of single-domain cognitive tests frequently used by behavioral neurologists in an effort to improve the quality of clinical cognitive assessment.

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.

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

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

Ween, JE, Alexander M, D’Esposito, Roberts M.  1996.  Incontinence after stroke in a rehabilitation setting: outcome associations and predictive factors., 1996 Sep. Neurology. 47(3):659-663. Abstract1996_ween2.pdf

Urinary incontinence (UI) after stroke is common and associated with overall poor functional outcomes. There is controversy regarding which factors contribute to incontinence after stroke and which factors may be predictive of recovery of continence. This study investigated consecutive stroke admissions to an inpatient rehabilitation hospital and evaluated the impact of several pre-selected factors on the presence of UI and its recovery. We also studied the impact of UI on outcome in terms of functional abilities with the Functional Independence Measure (FIM) and in terms of disposition. UI on admission was associated with severe functional impairment with large infarctions and was probably caused by general severity rather than specific impairment of neuromicturition control. Patients with less impairment (admission FIM > 60) and small vessel strokes were likely to recover continence. UI on admission had a negative impact on outcome.

Gibbs, SE, D’Esposito.  2005.  Individual capacity differences predict working memory performance and prefrontal activity following dopamine receptor stimulation., 2005 Jun. Cognitive, Affective & Behavioral Neuroscience. 5(2):212-221. Abstract2005_gibbs.pdf

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

Aguirre, GK, Zarahn E, D’Esposito.  1998.  The inferential impact of global signal covariates in functional neuroimaging analyses., 1998 Oct. NeuroImage. 8(3):302-306. Abstract1998_aguirre_ni.pdf


Ranganath, C, Cohen MX, Dam C, D’Esposito.  2004.  Inferior temporal, prefrontal, and hippocampal contributions to visual working memory maintenance and associative memory retrieval., 2004 Apr 21. Journal of Neuroscience. 24(16):3917-3925. Abstract2004_ranganath_jn2004.pdf

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

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.

Bahlmann, J, Aarts E, D'Esposito M.  2015.  Influence of motivation on control hierarchy in the human frontal cortex., 2015 Feb 18. Journal of Neuroscience. 35(7):3207-3217. Abstract2015_bahlmann.pdf

The frontal cortex mediates cognitive control and motivation to shape human behavior. It is generally observed that medial frontal areas are involved in motivational aspects of behavior, whereas lateral frontal regions are involved in cognitive control. Recent models of cognitive control suggest a rostro-caudal gradient in lateral frontal regions, such that progressively more rostral (anterior) regions process more complex aspects of cognitive control. How motivation influences such a control hierarchy is still under debate. Although some researchers argue that both systems work in parallel, others argue in favor of an interaction between motivation and cognitive control. In the latter case it is yet unclear how motivation would affect the different levels of the control hierarchy. This was investigated in the present functional MRI study applying different levels of cognitive control under different motivational states (low vs high reward anticipation). Three levels of cognitive control were tested by varying rule complexity: stimulus-response mapping (low-level), flexible task updating (mid-level), and sustained cue-task associations (high-level). We found an interaction between levels of cognitive control and motivation in medial and lateral frontal subregions. Specifically, flexible updating (mid-level of control) showed the strongest beneficial effect of reward and only this level exhibited functional coupling between dopamine-rich midbrain regions and the lateral frontal cortex. These findings suggest that motivation differentially affects the levels of a control hierarchy, influencing recruitment of frontal cortical control regions depending on specific task demands.

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.

Rypma, B, Berger JS, D’Esposito.  2002.  The influence of working-memory demand and subject performance on prefrontal cortical activity., 2002 Jul 1. Journal of Cognitive Neuroscience. 14(5):721-731. Abstract2002_rypma.pdf

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

Curtis, CE, D'Esposito M.  2008.  The inhibition of unwanted actions. Psychology of Action, Vol. 2. , Oxford: Oxford University Press2008_curtis.pdf
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

Levine, B, Rosenbaum SR, Solbakk A-K, D'Esposito M.  2021.  Introduction to the Special Issue., 2021 Jul 16. Journal of cognitive neuroscience. :1.
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.

Louis, CC, D'Esposito M, Moser JS.  2021.  Investigating interactive effects of worry and the catechol-o-methyltransferase gene (COMT) on working memory performance., 2021 Jun 25. Cognitive, affective & behavioral neuroscience. Abstract

Extant research indicates that worry is associated with reduced working memory. It remains unclear, however, what mechanisms contribute to impaired performance in worriers. Critically, dopamine in the prefrontal cortex heavily influences the stability of mental representations during working memory tasks, yet no research has probed its role in associations between worry and working memory. To address this gap, the current study was designed to examine the moderating role of dopamine on the association between worry and working memory, using the catechol-o-methyltransferase (COMT) gene as a proxy for basal levels of dopamine. Across four assessments, we examined within- and between-person variation in worry and its interactive effects with COMT to predict working memory performance. Within-person variation in worry interacted with COMT to predict accuracy, such that higher worry across time predicted less accuracy for homozygous Val carriers but not Met carriers. Our findings demonstrate that basal dopamine plays an important role in how increases in worry across time for an individual negatively impact working memory performance.

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

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

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?

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


Vogelsang, DA, D'Esposito M.  2018.  Is there evidence for a rostral-caudal gradient in fronto-striatal loops and what role does dopamine play? Frontiers in Decision Neuroscience. 12:242.2018_vogelsang.pdf
Rypma, B, D’Esposito.  2000.  Isolating the neural mechanisms of age-related changes in human working memory., 2000 May. Nature Neuroscience. 3(5):509-515. Abstract2000_rypma.pdf

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

Grossman, M, Payer F, Onishi K, D’Esposito, Morrison D, Sadek A, Alavi A.  1998.  Language comprehension and regional cerebral defects in frontotemporal degeneration and Alzheimer’s disease., 1998 Jan. Neurology. 50(1):157-163. Abstract1998_grossman_neuro.pdf

We related profiles of language comprehension difficulty to patterns of reduced cerebral functioning obtained with high-resolution single photon emission computed tomography (SPECT) in patients with neurodegenerative conditions. We found different patterns of reduced relative cerebral perfusion in patients with frontotemporal degeneration (FD) and patients with Alzheimer’s disease (AD). Cognitive assessments also showed different patterns of impaired comprehension in patients with FD and patients with AD. Grammatical comprehension difficulty in FD correlated with relative cerebral perfusion in left frontal and anterior temporal brain regions; impaired semantic processing in AD correlated with relative cerebral perfusion in inferior parietal and superior temporal regions of the left hemisphere. These findings are consistent with the hypothesis that a neural network distributed throughout the left hemisphere subserving different aspects of language comprehension, rather than a single brain region, is responsible for understanding language.

Grossman, M, D’Esposito, Hughes E, Onishi K, Biassou N, White-Devine T, Robinson KM.  1996.  Language comprehension profiles in Alzheimer’s disease, multi-infarct dementia, and frontotemporal degeneration., 1996 Jul. Neurology. 47(1):183-189. Abstract1996_grossman_neuro.pdf

We assessed language functioning in 116 age-, education-, and severity-matched patients with the clinical diagnosis of Alzheimer’s disease (AD), multi-infarct dementia (MID) due to small-vessel ischemic disease, or a frontotemporal form of degeneration (FD). Assessments of comprehension revealed that patients with AD are significantly impaired in their judgments of single word and picture meaning, whereas patients with FD had sentence comprehension difficulty due to impaired processing of grammatical phrase structure. Patients with MID did not differ from control subjects in their comprehension performance. Traditional aphasiologic measures did not distinguish between AD, MID, and FD. Selective patterns of comprehension difficulty in patients with different forms of dementia emphasize that language deficits cannot be explained entirely by the compromised memory associated with a progressive neurodegenerative illness.

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.

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.

Ranganath, C, Johnson MK, D’Esposito.  2000.  Left anterior prefrontal activation increases with demands to recall specific perceptual information., 2000 Nov 15. Journal of Neuroscience. 20(22):RC108. Abstract2000_ranganath.pdf

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

Nolde, SF, Johnson MK, D’Esposito.  1998.  Left prefrontal activation during episodic remembering: an event-related fMRI study., 1998 Oct 26. Neuroreport. 9(15):3509-3514. Abstract1998_nolde.pdf

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

Sadaghiani, S, Dombert PL, Løvstad M, Funderud I, Meling TR, Endestad T, Knight RT, Solbakk A-K, D'Esposito M.  2019.  Lesions to the Fronto-Parietal Network Impact Alpha-Band Phase Synchrony and Cognitive Control., 2018 Dec 07. Cerebral Cortex. 29(10):4143–4153. Abstract2019_sadaghiani.pdf

Long-range phase synchrony in the α-oscillation band (near 10 Hz) has been proposed to facilitate information integration across anatomically segregated regions. Which areas may top-down regulate such cross-regional integration is largely unknown. We previously found that the moment-to-moment strength of high-α band (10-12 Hz) phase synchrony co-varies with activity in a fronto-parietal (FP) network. This network is critical for adaptive cognitive control functions such as cognitive flexibility required during set-shifting. Using electroencephalography (EEG) in 23 patients with focal frontal lobe lesions (resected tumors), we tested the hypothesis that the FP network is necessary for modulation of high-α band phase synchrony. Global phase-synchrony was measured using an adaptation of the phase-locking value (PLV) in a sliding window procedure, which allowed for measurement of changes in EEG-based resting-state functional connectivity across time. As hypothesized, the temporal modulation (range and standard deviation) of high-α phase synchrony was reduced as a function of FP network lesion extent, mostly due to dorsolateral prefrontal cortex (dlPFC) lesions. Furthermore, patients with dlPFC lesions exhibited reduced cognitive flexibility as measured by the Trail-Making Test (set-shifting). Our findings provide evidence that the FP network is necessary for modulatory control of high-α band long-range phase synchrony, and linked to cognitive flexibility.

Wittmann, BC, D'Esposito M.  2014.  Levodopa administration modulates striatal processing of punishment-associated items in healthy participants., 2014 Jun 13. Psychopharmacology. 232(1):135–144. Abstract2014_wittman.pdf

Appetitive and aversive processes share a number of features such as their relevance for action and learning. On a neural level, reward and its predictors are associated with increased firing of dopaminergic neurons, whereas punishment processing has been linked to the serotonergic system and to decreases in dopamine transmission. Recent data indicate, however, that the dopaminergic system also responds to aversive stimuli and associated actions.

Grossman, M, Mickanin J, Onishi K, Robinson KM, D’Esposito.  1997.  Lexical acquisition in probable Alzheimer’s disease., 1997 Dec. Brain and Language. 60(3):443-463. Abstract1997_grossman.pdf

Patients with probable Alzheimer’s disease (pAD) were exposed to a new verb in a naturalistic fashion. We probed their knowledge of the word’s semantic and grammatical characteristics for several minutes following this exposure, and compared this with their performance on parallel measures assessing known words. Significant differences were seen between pAD patients and controls in the acquisition of the new verb’s semantic meaning and its argument structure, but pAD patients did not differ from controls in the acquisition of the new word’s grammatical form class. Individual patient analyses demonstrated parallel deficits restricted to the semantic meaning and argument structure of the new word and known words in several pAD patients, suggesting that a selective language impairment contributed to their word learning deficit. This pattern is consistent with an intimate relationship between semantic meaning and argument structure in semantic memory. Other pAD patients had difficulty learning about all aspects of the new word, despite good performance with known words, suggesting that compromised memory may have limited their lexical acquisition.

Kornblith, E, Posecion L, Abrams G, Chen AJ-W, Burciaga J, D'Esposito M, Novakovic-Agopian T.  2019.  Long-Term Effect of Cognitive Rehabilitation Regardless of Prerehabilitation Cognitive Status for Veterans with TBI., 2019 Aug 28. Applied Neuropsychology: Adult. :1-13. Abstract2019_kornblith.pdf

Persisting difficulties in executive functioning (EF) are common after traumatic brain injury (TBI). Cognitive rehabilitation can be effective, but the impact of pretreatment neurocognitive functioning on long term effects of rehabilitation is unknown. Because this information can impact treatment planning, we examined the relationship between prerehabilitation neurocognitive status and long-term effects of EF training. Archival data were drawn from a trial of Goal-Oriented Attentional Self-Regulation group-format EF training for Veterans with TBI [mild-severe; 11 years postinjury; 96% male, 32% nonwhite, 14.21 years education ( 1.72), 41.13 years old ( 11.39)]. Using prerehabilitation neurocognitive performance, participants were clustered into cognitive difficulty (CD) and cognitively normal (CN) groups. Six-plus months after EF rehabilitation training, participants completed a structured telephone interview and/or in-person cognitive/functional/emotional assessment using standardized measures of cognitive, daily, and emotional functioning frequently employed in TBI research. At 6+ months post-EF training compared to prerehabilitation, CD and CN improved in multiple cognitive (Overall Attention/EF: (1,18) = 26.17, partial  = .59; Total Memory: (1,18) = 6.82, partial  = .28) and functional domains (Goal Processing Scale [GPS] total score: (1,15) = 6.71, partial  = .31). CD improved more than CN on Learning and Memory functional domain [F(1,15) = 6.10, partial  = .29]. Results of our small archival analysis raise the possibility that Veterans with chronic TBI may demonstrate long-term effects of EF training.

Novakovic-Agopian, T, Kornblith E, Abrams G, McQuaid JR, Posecion L, Burciaga J, D'Esposito M, Chen AJW.  2019.  Long-term effects of executive function training among veterans with chronic TBI., 2019 Aug 19. Brain Injury. 33(12):1513-1521. Abstract2019_novakovic.pdf

: To investigate long-term effects of GOALS executive function training in Veterans with chronic TBI. In a recently completed study Veterans with chronic TBI showed improvement immediately post-GOALS but not control training on measures of executive function, functional task performance, and emotion regulation. We now examine the long-term maintenance of post-GOALS training changes in the same sample. : San Francisco VA Health Care System (SFVAHCS), and VA Northern California Health-Care System (VANCHS) in Martinez. : 24 Veterans with chronic TBI were assessed at baseline, post-GOALS training, and long-term follow-up 6+ months following completion of training with a structured telephone interview, neuropsychological and complex functional performance measures, and self-report measures of daily and emotional functioning. : Participants reported an increased likelihood of involvement in competitive employment/volunteering at follow-up (61%) compared to baseline (26%; χ2 = 5.66, < .01, ѱ = .35). Repeated measures MANOVAS indicated improvement on attention/executive function (F = 13.85, < .01, partial η2 = .42), complex functional task performance (GPS Total: F = 9.12, < .01, partial η2 = .38) and daily functioning (MPAI Total: F = 3.23, < .05, partial η2 = .21), and reduction in overall mood disturbance (POMS Total: F = 3.42, < .05, partial η2 = .22) at follow-up relative to baseline. : Training in attention regulation applied to participant-defined goals is associated with meaningful long-term improvement in cognitive skills, emotion regulation, and daily functioning in Veterans with chronic TBI.

Miller, JA, Tambini A, Kiyonaga A, D'Esposito M.  2022.  Long-term learning transforms prefrontal cortex representations during working memory., 2022 Oct 07. Neuron. Abstract

The role of the lateral prefrontal cortex (lPFC) in working memory (WM) is debated. Non-human primate (NHP) electrophysiology shows that the lPFC stores WM representations, but human neuroimaging suggests that the lPFC controls WM content in sensory cortices. These accounts are confounded by differences in task training and stimulus exposure. We tested whether long-term training alters lPFC function by densely sampling WM activity using functional MRI. Over 3 months, participants trained on both a WM and serial reaction time (SRT) task, wherein fractal stimuli were embedded within sequences. WM performance improved for trained (but not novel) fractals and, neurally, delay activity increased in distributed lPFC voxels across learning. Item-level WM representations became detectable within lPFC patterns, and lPFC activity reflected sequence relationships from the SRT task. These findings demonstrate that human lPFC develops stimulus-selective responses with learning, and WM representations are shaped by long-term experience, which could reconcile competing accounts of WM functioning.

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.

Curtis, CE, Rao VY, D’Esposito.  2004.  Maintenance of spatial and motor codes during oculomotor delayed response tasks., 2004 Apr 21. Journal of Neuroscience. 24(16):3944-3952. Abstract2004_curtis_jn.pdf

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

D’Esposito, Postle BR, Ballard D, Lease J.  1999.  Maintenance versus manipulation of information held in working memory: an event-related fMRI study., 1999 Oct. Brain and Cognition. 41(1):66-86. Abstract1999_desposito_bc.pdf

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

Rissman, J, Gazzaley A, D’Esposito.  2004.  Measuring functional connectivity during distinct stages of a cognitive task., 2004 Oct. NeuroImage. 23(2):752-763. Abstract2004_rissman.pdf

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

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

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

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

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

Bertolero, MA, Yeo TBT, Bassett DS, D'Esposito M.  2018.  A mechanistic model of connector hubs, modularity and cognition., 2018 Oct. Nature Human Behaviour. 2(10):765-777. Abstract2018_bertolero.pdf

The human brain network is modular-comprised of communities of tightly interconnected nodes. This network contains local hubs, which have many connections within their own communities, and connector hubs, which have connections diversely distributed across communities. A mechanistic understanding of these hubs and how they support cognition has not been demonstrated. Here, we leveraged individual differences in hub connectivity and cognition. We show that a model of hub connectivity accurately predicts the cognitive performance of 476 individuals in four distinct tasks. Moreover, there is a general optimal network structure for cognitive performance-individuals with diversely connected hubs and consequent modular brain networks exhibit increased cognitive performance, regardless of the task. Critically, we find evidence consistent with a mechanistic model in which connector hubs tune the connectivity of their neighbors to be more modular while allowing for task appropriate information integration across communities, which increases global modularity and cognitive performance.

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

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

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.

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.

Bertolero, MA, Yeo TBT, D'Esposito M.  2015.  The modular and integrative functional architecture of the human brain., 2015 Nov 23. Proceedings of the National Academy of Sciences of the United States of America. 112(49):E6798-E6807. Abstract2015_bertolero.pdf

Network-based analyses of brain imaging data consistently reveal distinct modules and connector nodes with diverse global connectivity across the modules. How discrete the functions of modules are, how dependent the computational load of each module is to the other modules' processing, and what the precise role of connector nodes is for between-module communication remains underspecified. Here, we use a network model of the brain derived from resting-state functional MRI (rs-fMRI) data and investigate the modular functional architecture of the human brain by analyzing activity at different types of nodes in the network across 9,208 experiments of 77 cognitive tasks in the BrainMap database. Using an author-topic model of cognitive functions, we find a strong spatial correspondence between the cognitive functions and the network's modules, suggesting that each module performs a discrete cognitive function. Crucially, activity at local nodes within the modules does not increase in tasks that require more cognitive functions, demonstrating the autonomy of modules' functions. However, connector nodes do exhibit increased activity when more cognitive functions are engaged in a task. Moreover, connector nodes are located where brain activity is associated with many different cognitive functions. Connector nodes potentially play a role in between-module communication that maintains the modular function of the brain. Together, these findings provide a network account of the brain's modular yet integrated implementation of cognitive functions.

Gallen, CL, Baniqued PL, Chapman SB, Aslan S, Keebler M, Didehbani N, D'Esposito M.  2016.  Modular Brain Network Organization Predicts Response to Cognitive Training in Older Adults., 2016. PloS one. 11(12):e0169015. Abstract2016_gallen_plos.pdf

Cognitive training interventions are a promising approach to mitigate cognitive deficits common in aging and, ultimately, to improve functioning in older adults. Baseline neural factors, such as properties of brain networks, may predict training outcomes and can be used to improve the effectiveness of interventions. Here, we investigated the relationship between baseline brain network modularity, a measure of the segregation of brain sub-networks, and training-related gains in cognition in older adults. We found that older adults with more segregated brain sub-networks (i.e., more modular networks) at baseline exhibited greater training improvements in the ability to synthesize complex information. Further, the relationship between modularity and training-related gains was more pronounced in sub-networks mediating "associative" functions compared with those involved in sensory-motor processing. These results suggest that assessments of brain networks can be used as a biomarker to guide the implementation of cognitive interventions and improve outcomes across individuals. More broadly, these findings also suggest that properties of brain networks may capture individual differences in learning and neuroplasticity. Trail Registration:, NCT#00977418.

Smith, CT, Wallace DL, Dang LC, Aarts E, Jagust WJ, D'Esposito M, Boettiger CA.  2015.  Modulation of Impulsivity and Reward Sensitivity in Intertemporal Choice by Striatal and Midbrain Dopamine Synthesis in Healthy Adults., 2015 Dec 16. Journal of Neurophysiology. 115(3):1146-1156. Abstract2015_smith.pdf

Converging evidence links individual differences in mesolimbic and mesocortical dopamine (DA) to variation in the tendency to choose immediate rewards ("Now") over larger, delayed rewards ("Later"), or "Now bias". However, to date, no study of healthy young adults has evaluated the relationship between Now bias and DA using positron emission tomography (PET). Sixteen healthy adults (ages 24-34; 50% female) completed a delay-discounting task that quantified aspects of intertemporal reward choice, including Now bias and reward magnitude sensitivity. Participants also underwent PET scanning with 6-[(18)F]-fluoro-L-m-tyrosine (FMT), a radiotracer that measures DA synthesis capacity. Lower putamen FMT signal predicted elevated Now bias, a more rapidly declining discount rate with increasing delay time, and reduced willingness to accept low interest rate delayed rewards. In contrast, lower FMT signal in the midbrain predicted greater sensitivity to increasing magnitude of the Later reward. These data demonstrate that intertemporal reward choice in healthy humans varies with region-specific measures of DA processing, with regionally distinct associations with sensitivity to delay and to reward magnitude.

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

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

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.

Kimberg, DY, Aguirre GK, D’Esposito.  2000.  Modulation of task-related neural activity in task-switching: an fMRI study., 2000 Sep. Brain Research: Cognitive Brain Research. 10(1-2):189-196. Abstract2000_kimberg.pdf

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

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.

Cook, PF, Hoard VA, Dolui S, deB Frederick B, Redfern R, Dennison SE, Halaska B, Bloom J, Kruse-Elliott KT, Whitmer ER, Trumbull EJ, Berns GS, Detre JA, D'Esposito M, Gulland FMD, Reichmuth C, Johnson SP, Field CL, Inglis BA.  2021.  An MRI protocol for anatomical and functional evaluation of the California sea lion brain., 2021 Feb 10. Journal of neuroscience methods. :109097. Abstract

Domoic acid (DOM) is a neurotoxin produced by some harmful algae blooms in coastal waters. California sea lions (Zalophus californianus) exposed to DOM often strand on beaches where they exhibit a variety of symptoms, including seizures. These animals typically show hippocampal atrophy on MRI scans.

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.

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.

Thompson-Schill, SL, Aguirre GK, D’Esposito, Farah MJ.  1999.  A neural basis for category and modality specificity of semantic knowledge., 1999 Jun. Neuropsychologia. 37(6):671-676. Abstract1999_thompsonschill.pdf

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

D’Esposito, Detre JA, Alsop D, Shin RK, Atlas S, Grossman M.  1995.  The neural basis of the central executive system of working memory., 1995 Nov 16. Nature. 378(6554):279-281. Abstract1995_desposito_nature.pdf

Working memory refers to a system for temporary storage and manipulation of information in the brain, a function critical for a wide range of cognitive operations. It has been proposed that working memory includes a central executive system (CES) to control attention and information flow to and from verbal and spatial short-term memory buffers. Although the prefrontal cortex is activated during both verbal and spatial passive working memory tasks, the brain regions involved in the CES component of working memory have not been identified. We have used functional magnetic resonance imaging (fMRI) to examine brain activation during the concurrent performance of two tasks, which is expected to engage the CES. Activation of the prefrontal cortex was observed when both tasks are performed together, but not when they are performed separately. These results support the view that the prefrontal cortex is involved in human working memory.

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


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


Aguirre, GK, Zarahn E, D’Esposito.  1998.  Neural components of topographical representation., 1998 Feb 3. Proceedings of the National Academy of Sciences of the United States of America. 95(3):839-846. Abstract1998_aguirre_pnas.pdf

Studies of patients with focal brain damage suggest that topographical representation is subserved by dissociable neural subcomponents. This article offers a condensed review of the literature of "topographical disorientation" and describes several functional MRI studies designed to test hypotheses generated by that review. Three hypotheses are considered: (i) The parahippocampal cortex is critically involved in the acquisition of exocentric spatial information in humans; (ii) separable, posterior, dorsal, and ventral cortical regions subserve the perception and long term representation of position and identity, respectively, of landmarks; and (iii) there is a distinct area of the ventral occipitotemporal cortex that responds maximally to building stimuli and may play a role in the perception of salient landmarks. We conclude with a discussion of the inferential limitations of neuroimaging and lesion studies. It is proposed that combining these two approaches allows for inferences regarding the computational involvement of a neuroanatomical substrate in a given cognitive process although neither method can strictly support this conclusion alone.

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

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

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


Ochsner, KN, Beer JS, Robertson ER, Cooper JC, Gabrieli JDE, Kihsltrom JF, D’Esposito.  2005.  The neural correlates of direct and reflected self-knowledge., 2005 Dec. NeuroImage. 28(4):797-814. Abstract2005_ochsner.pdf

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

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

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

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

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

Schumacher, EH, D’Esposito.  2002.  Neural implementation of response selection in humans as revealed by localized effects of stimulus-response compatibility on brain activation., 2002 Nov. Human Brain Mapping. 17(3):193-201. Abstract2002_schumacher.pdf

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

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

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

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

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

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

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

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.

Polk, TA, Stallcup M, Aguirre GK, Alsop D, D’Esposito, Detre JA, Farah MJ.  2002.  Neural specialization for letter recognition., 2002 Feb 15. Journal of Cognitive Neuroscience. 14(2):145-159. Abstract2002_polk.pdf

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

D’Esposito, Postle BR, Jonides J, Smith EE.  1999.  The neural substrate and temporal dynamics of interference effects in working memory as revealed by event-related functional MRI., 1999 Jun 22. Proceedings of the National Academy of Sciences of the United States of America. 96(13):7514-7519. Abstract1999_desposito_pnas.pdf

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

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.

Ances, BM, D’Esposito.  2000.  Neuroimaging of recovery of function after stroke: implications for rehabilitation., 2000. Neurorehabilitation and Neural Repair. 14(3):171-179. Abstract2000_ances.pdf

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

Fischer, R, Alexander M, D’Esposito, Otto R.  1995.  Neuropsychological and neuroanatomical correlates of confabulation., 1995 Feb. Journal of Clinical and Experimental Neuropsychology. 17(1):20-28. Abstract1995_fischer.pdf

In the present exploratory investigation we report nine confabulatory patients of comparable age, education, and general level of intelligence in the acute epoch of recovery after rupture and clipping of ACoA aneurysms. Five of the nine cases had "spontaneous" confabulation, severe anterograde amnesia, markedly poor attentional and executive functions, and denial of illness. These patients all had multiple lesions that involved basal forebrain, ventral frontal lobe, and striatum. The other four patients manifested only "momentary" or "provoked" confabulations. These patients also had severe anterograde amnesia but showed relatively mild deficits in executive functions. These patients had lesions restricted to the basal forebrain except for one who had additional orbital frontal damage. Analysis of these two groups of confabulatory patients suggests that there is a common profile of deficits and anatomic foundation associated with confabulation; "spontaneous" confabulation appears to require extensive, simultaneous disruption of medial basal forebrain and frontal cognitive systems resulting in profound executive and memory deficits, whereas more limited lesions to the basal forebrain or orbital frontal cortex will result in "transient" or "provoked" confabulatory responses and a more restricted profile of cognitive deficits.

D'Esposito, M, Gazzaley A.  2005.  Neurorehabilitation of executive function. Textbook of Neural Repair and Rehabilitation. , Cambridge: Cambridge University Press Abstract2005_desposito_neurorehab.pdf


Turner, GR, D'Esposito M.  2014.  Neurorehabilitation of Executive Functions. . Textbook of Neural Repair and Rehabilitation. , Cambridge, UK: Cambridge University Press
Kayser, A, D'Esposito M.  2012.  Neurotechnologies. Encyclopedia of Human Behavior, 2nd Edition. , Oxford: Elsevier
Kayser, AS, D'Esposito M.  2017.  Neurotechnologies. Reference Module in Neuroscience and Biobehavioral Psychology. , Oxford, UK: Elsevier
Ranganath, C, Lokendra S, D'Esposito M.  2002.  A new view of the medial temporal lobes and the structure of memory. , Berkeley, CA: International Computer Science Institute2002_ranganath.pdf
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.

Grossman, M, Galetta S, D’Esposito.  1997.  Object recognition difficulty in visual apperceptive agnosia., 1997 Apr. Brain and Cognition. 33(3):306-342. Abstract1997_grossman_bc.pdf

Two patients with visual apperceptive agnosia were examined on tasks assessing the appreciation of visual material. Elementary visual functioning was relatively preserved, but they had profound difficulty recognizing and naming line drawings. More detailed evaluation revealed accurate recognition of regular geometric shapes and colors, but performance deteriorated when the shapes were made more complex visually, when multiple-choice arrays contained larger numbers of simple targets and foils, and when a mental manipulation such as a rotation was required. The recognition of letters and words was similarly compromised. Naming, recognition, and anomaly judgments of colored pictures and real objects were more accurate than similar decisions involving black-and-white line drawings. Visual imagery for shapes, letters, and objects appeared to be more accurate than visual perception of the same materials. We hypothesize that object recognition difficulty in visual apperceptive agnosia is due to two related factors: the impaired appreciation of the visual perceptual features that constitute objects, and a limitation in the cognitive resources that are available for processing demanding material within the visual modality.

Sadaghiani, S, Poline J-B, Kleinschmidt A, D'Esposito M.  2015.  Ongoing dynamics in large-scale functional connectivity predict perception., 2015 Jun 23. Proceedings of the National Academy of Sciences of the United States of America. 112(27):8463-8468. Abstract2015_sadaghiani.pdf

Most brain activity occurs in an ongoing manner not directly locked to external events or stimuli. Regional ongoing activity fluctuates in unison with some brain regions but not others, and the degree of long-range coupling is called functional connectivity, often measured with correlation. Strength and spatial distributions of functional connectivity dynamically change in an ongoing manner over seconds to minutes, even when the external environment is held constant. Direct evidence for any behavioral relevance of these continuous large-scale dynamics has been limited. Here, we investigated whether ongoing changes in baseline functional connectivity correlate with perception. In a continuous auditory detection task, participants perceived the target sound in roughly one-half of the trials. Very long (22-40 s) interstimulus intervals permitted investigation of baseline connectivity unaffected by preceding evoked responses. Using multivariate classification, we observed that functional connectivity before the target predicted whether it was heard or missed. Using graph theoretical measures, we characterized the difference in functional connectivity between states that lead to hits vs. misses. Before misses compared with hits and task-free rest, connectivity showed reduced modularity, a measure of integrity of modular network structure. This effect was strongest in the default mode and visual networks and caused by both reduced within-network connectivity and enhanced across-network connections before misses. The relation of behavior to prestimulus connectivity was dissociable from that of prestimulus activity amplitudes. In conclusion, moment to moment dynamic changes in baseline functional connectivity may shape subsequent behavioral performance. A highly modular network structure seems beneficial to perceptual efficiency.

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


Voytek, B, Kayser AS, Badre D, Fegen D, Chang EF, Crone NE, Parvizi J, Knight RT, D'Esposito M.  2015.  Oscillatory dynamics coordinating human frontal networks in support of goal maintenance., 2015 Jul 27. Nature Neuroscience. 18(9):1318-1324. Abstract2015_voytek.pdf

Humans have a capacity for hierarchical cognitive control-the ability to simultaneously control immediate actions while holding more abstract goals in mind. Neuropsychological and neuroimaging evidence suggests that hierarchical cognitive control emerges from a frontal architecture whereby prefrontal cortex coordinates neural activity in the motor cortices when abstract rules are needed to govern motor outcomes. We utilized the improved temporal resolution of human intracranial electrocorticography to investigate the mechanisms by which frontal cortical oscillatory networks communicate in support of hierarchical cognitive control. Responding according to progressively more abstract rules resulted in greater frontal network theta phase encoding (4-8 Hz) and increased prefrontal local neuronal population activity (high gamma amplitude, 80-150 Hz), which predicts trial-by-trial response times. Theta phase encoding coupled with high gamma amplitude during inter-regional information encoding, suggesting that inter-regional phase encoding is a mechanism for the dynamic instantiation of complex cognitive functions by frontal cortical subnetworks.

Miller, JA, Voorhies WI, Lurie DJ, D'Esposito M, Weiner KS.  2021.  Overlooked tertiary sulci serve as a meso-scale link between microstructural and functional properties of human lateral prefrontal cortex., 2021 Jan 15. The Journal of neuroscience : the official journal of the Society for Neuroscience. Abstract

Understanding the relationship between neuroanatomy and function in portions of cortex that perform functions largely specific to humans such as lateral prefrontal cortex (LPFC) is of major interest in systems and cognitive neuroscience. When considering neuroanatomical-functional relationships in LPFC, shallow indentations in cortex known as tertiary sulci have been largely unexplored. Here, by implementing a multi-modal approach and manually defining 936 neuroanatomical structures in 72 hemispheres (in both males and females), we show that a subset of these overlooked tertiary sulci serve as a meso-scale link between microstructural (myelin content) and functional (network connectivity) properties of human LPFC in individual participants. For example, the () is a tertiary sulcus with three components that differ in their myelin content, resting state connectivity profiles, and engagement across meta-analyses of 83 cognitive tasks. Further, generating microstructural profiles of myelin content across cortical depths for each component and the surrounding middle frontal gyrus (MFG) shows that both gyral and sulcal components of the MFG have greater myelin content in deeper compared to superficial layers and that the myelin content in superficial layers of the gyral components is greater than sulcal components. These findings support a classic, yet largely unconsidered theory that tertiary sulci may serve as landmarks in association cortices, as well as a modern cognitive neuroscience theory proposing a functional hierarchy in LPFC. As there is a growing need for computational tools that automatically define tertiary sulci throughout cortex, we share probabilistic sulcal maps with the field.: Lateral prefrontal cortex (LPFC) is critical for functions that are thought to be specific to humans compared to other mammals. However, relationships between fine-scale neuroanatomical structures largely specific to hominoid cortex and functional properties of LPFC remain elusive. Here, we show that these structures, which have been largely unexplored throughout history, surprisingly serve as markers for anatomical and functional organization in human LPFC. These findings have theoretical, methodological, developmental, and evolutionary implications for improved understanding of neuroanatomical-functional relationships not only in LPFC, but also in association cortices more broadly. Finally, these findings ignite new questions regarding how morphological features of these neglected neuroanatomical structures contribute to functions of association cortices that are critical for human-specific aspects of cognition.

Aguirre, GK, Detre JA, Alsop D, D’Esposito.  1996.  The parahippocampus subserves topographical learning in man., 1996 Nov-Dec. Cerebral Cortex. 6(6):823-829. Abstract1996_aguirre.pdf

The hippocampus has been proposed as the site of neural representation of large-scale environmental space, based upon the identification of place cells (neurons with receptive fields for current position in the environment) within the rat hippocampus and the demonstration that hippocampal lesions impair place learning in the rat. The inability to identify place cells within the monkey hippocampus and the observation that unilateral hippocampal lesions do not selectively impair topographic behavior in humans suggest that alternate regions may subserve this function in man. To examine the contribution of the hippocampus and adjacent medial-temporal lobe structures to topographic learning in the human, a ’virtual’ maze was used as a task environment during functional magnetic resonance imaging studies. During the learning and recall of topographic information, medial-temporal activity was confined to the para- hippocampal gyri. This activity accords well with the lesion site known to produce topographical disorientation in humans. Activity was also observed in cortical areas known to project to the parahippocampus and previously proposed to contribute to a network subserving spatially guided behavior.

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

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

Gratton, C, Lee TG, Nomura EM, D'Esposito M.  2014.  Perfusion MRI indexes variability in the functional brain effects of theta-burst transcranial magnetic stimulation., 2014. PloS one. 9(7):e101430. Abstract2014_gratton.pdf

Transcranial Magnetic Stimulation (TMS) is an important tool for testing causal relationships in cognitive neuroscience research. However, the efficacy of TMS can be variable across individuals and difficult to measure. This variability is especially a challenge when TMS is applied to regions without well-characterized behavioral effects, such as in studies using TMS on multi-modal areas in intrinsic networks. Here, we examined whether perfusion fMRI recordings of Cerebral Blood Flow (CBF), a quantitative measure sensitive to slow functional changes, reliably index variability in the effects of stimulation. Twenty-seven participants each completed four combined TMS-fMRI sessions during which both resting state Blood Oxygen Level Dependent (BOLD) and perfusion Arterial Spin Labeling (ASL) scans were recorded. In each session after the first baseline day, continuous theta-burst TMS (TBS) was applied to one of three locations: left dorsolateral prefrontal cortex (L dlPFC), left anterior insula/frontal operculum (L aI/fO), or left primary somatosensory cortex (L S1). The two frontal targets are components of intrinsic networks and L S1 was used as an experimental control. CBF changes were measured both before and after TMS on each day from a series of interleaved resting state and perfusion scans. Although TBS led to weak selective increases under the coil in CBF measurements across the group, individual subjects showed wide variability in their responses. TBS-induced changes in rCBF were related to TBS-induced changes in functional connectivity of the relevant intrinsic networks measured during separate resting-state BOLD scans. This relationship was selective: CBF and functional connectivity of these networks were not related before TBS or after TBS to the experimental control region (S1). Furthermore, subject groups with different directions of CBF change after TBS showed distinct modulations in the functional interactions of targeted networks. These results suggest that CBF is a marker of individual differences in the effects of TBS.

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

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

D’Esposito.  1991.  The Pharmacology of Memory. Abstract


Biassou, N, Grossman M, Onishi K, Mickanin J, Hughes E, Robinson KM, D’Esposito.  1995.  Phonologic processing deficits in Alzheimer’s disease., 1995 Dec. Neurology. 45(12):2165-2169. Abstract1995_biassou.pdf

We investigated phonologic production in patients with mild to moderate Alzheimer’s disease (AD) on a repetition task. AD patients produced significantly more speech errors than age-matched controls. AD patients’ errors, unlike those of controls, resulted in the transformation of real words into pseudowords, occurred disproportionately in word-initial positions, and were not influenced by the phonologic environment. This pattern of errors suggests a lexical phonologic retrieval deficit in AD.

D’Esposito.  1996.  The physiological basis of executive functioning and working memory. The Neuroscientist. 2(6):345-352. Abstract1996_desposito.pdf


Chen, AJ-W, D'Esposito M.  2015.  Plasticity in prefrontal cortical networks after brain injury: finding the optimal paths. Cognitive Plasticity in Neurological Disorders. , Oxford, UK: Oxford University Press
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
D'Esposito, M.  2000.  Post-concussive syndrome. Penn Neurology 2000: Management of Common Neurological Problems. Abstract


D'Esposito, M, Grafman JH.  2019.  Preface., 2019. Handbook of clinical neurology. 163:ix.
Ranganath, C, Johnson MK, D’Esposito.  2003.  Prefrontal activity associated with working memory and episodic long-term memory., 2003. Neuropsychologia. 41(3):378-389. Abstract2003_ranganath.pdf

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