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2021
Miller, JA, D'Esposito M, Weiner KS.  2021.  Using Tertiary Sulci to Map the "Cognitive Globe" of Prefrontal Cortex., 2021 Mar 03. Journal of cognitive neuroscience. :1-18. Abstract

Stuss considered the human prefrontal cortex (pFC) as a "cognitive globe" [Stuss, D. T., & Benson, D. F. Neuropsychological studies of the frontal lobes. , , 3-28, 1984] on which functions of the frontal lobe could be mapped. Here, we discuss classic and recent findings regarding the evolution, development, function, and cognitive role of shallow indentations or tertiary sulci in pFC, with the goal of using tertiary sulci to map the "cognitive globe" of pFC. First, we discuss lateral pFC (LPFC) tertiary sulci in classical anatomy and modern neuroimaging, as well as their development, with a focus on those within the middle frontal gyrus. Second, we discuss tertiary sulci in comparative neuroanatomy, focusing on primates. Third, we summarize recent findings showing the utility of tertiary sulci for understanding structural-functional relationships with functional network insights in ventromedial pFC and LPFC. Fourth, we revisit and update unresolved theoretical perspectives considered by C. Vogt and O. Vogt (Allgemeinere ergebnisse unserer hirnforschung. , , 279-462, 1919) and F. Sanides (Structure and function of the human frontal lobe. , , 209-219, 1964) that tertiary sulci serve as landmarks for cortical gradients. Together, the consideration of these classic and recent findings indicate that tertiary sulci are situated in a unique position within the complexity of the "cognitive globe" of pFC: They are the smallest and shallowest of sulci in pFC, yet can offer insights that bridge spatial scales (microns to networks), modalities (functional connectivity to behavior), and species. As such, the map of tertiary sulci within each individual participant serves as a coordinate system specific to that individual on which functions may be further mapped. We conclude with new theoretical and methodological questions that, if answered in future research, will likely lead to mechanistic insight regarding the structure and function of human LPFC.

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.

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.

Eichenbaum, A, Pappas I, Lurie D, Cohen JR, D'Esposito M.  2021.  Differential contributions of static and time-varying functional connectivity to human behavior., 2021. Network neuroscience (Cambridge, Mass.). 5(1):145-165. Abstract

Measures of human brain functional connectivity acquired during the resting-state track critical aspects of behavior. Recently, fluctuations in resting-state functional connectivity patterns-typically averaged across in traditional analyses-have been considered for their potential neuroscientific relevance. There exists a lack of research on the differences between traditional "static" measures of functional connectivity and newly considered "time-varying" measures as they relate to human behavior. Using functional magnetic resonance imagining (fMRI) data collected at rest, and a battery of behavioral measures collected outside the scanner, we determined the degree to which each modality captures aspects of personality and cognitive ability. Measures of time-varying functional connectivity were derived by fitting a hidden Markov model. To determine behavioral relationships, static and time-varying connectivity measures were submitted separately to canonical correlation analysis. A single relationship between static functional connectivity and behavior existed, defined by measures of personality and stable behavioral features. However, two relationships were found when using time-varying measures. The first relationship was similar to the static case. The second relationship was unique, defined by measures reflecting trialwise behavioral variability. Our findings suggest that time-varying measures of functional connectivity are capable of capturing unique aspects of behavior to which static measures are insensitive.

2020
Riddle, J, Vogelsang DA, Hwang K, Cellier D, D'Esposito M.  2020.  Distinct oscillatory dynamics underlie different components of hierarchical cognitive control., 2020 May 19. Journal of Neuroscience. 40(25):4945-4953. Abstract2020_riddle_jn.pdf

Hierarchical cognitive control enables us to execute actions guided by abstract goals. Previous research has suggested that neuronal oscillations at different frequency bands are associated with top-down cognitive control, however, whether distinct neural oscillations have similar or different functions for cognitive control is not well understood. The aim of the current study was to investigate the oscillatory neuronal mechanisms underlying two distinct components of hierarchical cognitive control: the level of abstraction of a rule, and the number of rules that must be maintained (set-size). We collected electroencephalography (EEG) data in 31 men and women who performed a hierarchical cognitive control task that varied in levels of abstraction and set-size. Results from time-frequency analysis in frontal electrodes showed an increase in theta amplitude for increased set-size, whereas an increase in delta was associated with increased abstraction. Both theta and delta amplitude correlated with behavioral performance in the tasks but in an opposite manner: theta correlated with response time slowing when the number of rules increased whereas delta correlated with response time when rules became more abstract. Phase amplitude coupling analysis revealed that delta phase coupled with beta amplitude during conditions with a higher level of abstraction, whereby beta band may potentially represent motor output that was guided by the delta phase. These results suggest that distinct neural oscillatory mechanisms underlie different components of hierarchical cognitive control.Cognitive control allows us to perform immediate actions while maintaining more abstract, overarching goals in mind and to choose between competing actions. We found distinct oscillatory signatures that correspond to two different components of hierarchical control: the level of abstraction of a rule and the number of rules in competition. An increase in the level of abstraction was associated with delta oscillations, whereas theta oscillations were observed when the number of rules increased. Oscillatory amplitude correlated with behavioral performance in the task. Finally, the expression of beta amplitude was coordinated via the phase of delta oscillations, and theta phase coupled with gamma amplitude. These results suggest that distinct neural oscillatory mechanisms underlie different components of hierarchical cognitive control.

Eichenbaum, A, Scimeca JM, D'Esposito M.  2020.  Dissociable Neural Systems Support the Learning and Transfer of Hierarchical Control Structure., 2020 Jul 20. Journal of Neuroscience. 40(34):6624-6637. Abstract2020_eichenbaum.pdf

Humans can draw insight from previous experiences in order to quickly adapt to novel environments that share a common underlying structure. Here we combine functional imaging and computational modeling to identify the neural systems that support the discovery and transfer of hierarchical task structure. Human subjects (male and female) completed multiple blocks of a reinforcement learning task that contained a global hierarchical structure governing stimulus-response action mapping. First, behavioral and computational evidence showed that humans successfully discover and transfer the hierarchical rule structure embedded within the task. Next, analysis of fMRI BOLD data revealed activity across a frontal-parietal network that was specifically associated with the discovery of this embedded structure. Finally, activity throughout a cingulo-opercular network supported the transfer and implementation of this discovered structure. Together, these results reveal a division of labor in which dissociable neural systems support the learning and transfer of abstract control structures.A fundamental and defining feature of human behavior is the ability to generalize knowledge from the past in order to support future action. Although the neural circuits underlying more direct forms of learning have been well established over the last century, we still lack a solid framework from which to investigate more abstract, higher order human learning and knowledge generalization. We designed a novel behavioral paradigm in order to specifically isolate a learning process in which previous knowledge, rather than directly indicating the correct action, instead guides the search for the correct action. Moreover, we identify that this learning process is achieved via the coordinated and temporally specific activity of two prominent cognitive control brain networks.

Tambini, A, D'Esposito M.  2020.  Causal Contribution of Awake Post-encoding Processes to Episodic Memory Consolidation., 2020 Jul 17. Current Biology. S0960-9822(20):30915-5. Abstract2020_tambini.pdf

Stable representations of past experience are thought to depend on processes that unfold after events are initially encoded into memory. Post-encoding reactivation and hippocampal-cortical interactions are leading candidate mechanisms thought to support memory retention and stabilization across hippocampal-cortical networks. Although putative consolidation mechanisms have been observed during sleep and periods of awake rest, the direct causal contribution of awake consolidation mechanisms to later behavior is unclear, especially in humans. Moreover, it has been argued that observations of putative consolidation processes are epiphenomenal and not causally important, yet there are few tools to test the functional contribution of these mechanisms in humans. Here, we combined transcranial magnetic stimulation (TMS) and fMRI to test the role of awake consolidation processes by targeting hippocampal interactions with lateral occipital cortex (LOC). We applied theta-burst TMS to LOC (and a control site) to interfere with an extended window (approximately 30-50 min) after memory encoding. Behaviorally, post-encoding TMS to LOC selectively impaired associative memory retention compared to multiple control conditions. In the control TMS condition, we replicated prior reports of post-encoding reactivation and memory-related hippocampal-LOC interactions during periods of awake rest using fMRI. However, post-encoding LOC TMS reduced these processes, such that post-encoding reactivation in LOC and memory-related hippocampal-LOC functional connectivity were no longer present. By targeting and manipulating post-encoding neural processes, these findings highlight the direct contribution of awake time periods to episodic memory consolidation. This combined TMS-fMRI approach provides an opportunity for causal manipulations of human memory consolidation.

Lorenc, ES, Vandenbroucke ARE, Nee DE, de Lange FP, D'Esposito M.  2020.  Dissociable neural mechanisms underlie currently-relevant, future-relevant, and discarded working memory representations., 2020 Jul 08. Scientific Reports. 10(1):11195. Abstract2020_lorenc.pdf

In daily life, we use visual working memory (WM) to guide our actions. While attending to currently-relevant information, we must simultaneously maintain future-relevant information, and discard information that is no longer relevant. However, the neural mechanisms by which unattended, but future-relevant, information is maintained in working memory, and future-irrelevant information is discarded, are not well understood. Here, we investigated representations of these different information types, using functional magnetic resonance imaging in combination with multivoxel pattern analysis and computational modeling based on inverted encoding model simulations. We found that currently-relevant WM information in the focus of attention was maintained through representations in visual, parietal and posterior frontal brain regions, whereas deliberate forgetting led to suppression of the discarded representations in early visual cortex. In contrast, future-relevant information was neither inhibited nor actively maintained in these areas. These findings suggest that different neural mechanisms underlie the WM representation of currently- and future-relevant information, as compared to information that is discarded from WM.

Kimbrough, A, Lurie DJ, Collazo A, Kreifeldt M, Sidhu H, Macedo GC, D'Esposito M, Contet C, George O.  2020.  Brain-wide functional architecture remodeling by alcohol dependence and abstinence., 2020 Jan 14. Proceedings of the National Academy of Sciences of the United States of America. 117(4):2149-2159. Abstract2020_kimbrough.pdf

Alcohol abuse and alcohol dependence are key factors in the development of alcohol use disorder, which is a pervasive societal problem with substantial economic, medical, and psychiatric consequences. Although our understanding of the neurocircuitry that underlies alcohol use has improved, novel brain regions that are involved in alcohol use and novel biomarkers of alcohol use need to be identified. The present study used a single-cell whole-brain imaging approach to 1) assess whether abstinence from alcohol in an animal model of alcohol dependence alters the functional architecture of brain activity and modularity, 2) validate our current knowledge of the neurocircuitry of alcohol abstinence, and 3) discover brain regions that may be involved in alcohol use. Alcohol abstinence resulted in the whole-brain reorganization of functional architecture in mice and a pronounced decrease in modularity that was not observed in nondependent moderate drinkers. Structuring of the alcohol abstinence network revealed three major brain modules: 1) extended amygdala module, 2) midbrain striatal module, and 3) cortico-hippocampo-thalamic module, reminiscent of the three-stage theory. Many hub brain regions that control this network were identified, including several that have been previously overlooked in alcohol research. These results identify brain targets for future research and demonstrate that alcohol use and dependence remodel brain-wide functional architecture to decrease modularity. Further studies are needed to determine whether the changes in coactivation and modularity that are associated with alcohol abstinence are causal features of alcohol dependence or a consequence of excessive drinking and alcohol exposure.

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

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

Riddle, J, Scimeca JM, Cellier D, Dhanani S, D'Esposito M.  2020.  Causal Evidence for a Role of Theta and Alpha Oscillations in the Control of Working Memory., 2020 Apr 06. Current Biology. 30(9):1748-1754. Abstract2020_riddle_cb.pdf

Working memory (WM) relies on the prioritization of relevant information and suppression of irrelevant information [1, 2]. Prioritizing relevant information has been linked to theta frequency neural oscillations in lateral prefrontal cortex and suppressing irrelevant information has been linked to alpha oscillations in occipito-parietal cortex [3,11]. Here, we used a retrospective-cue WM paradigm to manipulate prioritization and suppression task demands designed to drive theta oscillations in prefrontal cortex and alpha oscillations in parietal cortex, respectively. To causally test the role of these neural oscillations, we applied rhythmic transcranial magnetic stimulation (TMS) in either theta or alpha frequency to prefrontal and parietal regions identified using functional MRI. The effect of rhythmic TMS on WM performance was dependent on whether the TMS frequency matched or mismatched the expected underlying task-driven oscillations of the targeted region. Functional MRI in the targeted regions predicted subsequent TMS effects across subjects supporting a model by which theta oscillations are excitatory to neural activity, and alpha oscillations are inhibitory. Together, these results causally establish dissociable roles for prefrontal theta oscillations and parietal alpha oscillations in the control of internally maintained WM representations.

Toker, D, Sommer FT, D'Esposito M.  2020.  A simple method for detecting chaos in nature., 2020. Communications Biology. 3:11. Abstract2020_toker.pdf

Chaos, or exponential sensitivity to small perturbations, appears everywhere in nature. Moreover, chaos is predicted to play diverse functional roles in living systems. A method for detecting chaos from empirical measurements should therefore be a key component of the biologist's toolkit. But, classic chaos-detection tools are highly sensitive to measurement noise and break down for common edge cases, making it difficult to detect chaos in domains, like biology, where measurements are noisy. However, newer tools promise to overcome these limitations. Here, we combine several such tools into an automated processing pipeline, and show that our pipeline can detect the presence (or absence) of chaos in noisy recordings, even for difficult edge cases. As a first-pass application of our pipeline, we show that heart rate variability is not chaotic as some have proposed, and instead reflects a stochastic process in both health and disease. Our tool is easy-to-use and freely available.

Hwang, K, Shine JM, Cellier D, D'Esposito M.  2020.  The Human Intraparietal Sulcus Modulates Task-Evoked Functional Connectivity., 2019 Jul 29. Cerebral Cortex. 30(3):875-887. Abstract2020_hwang.pdf

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

Kiyonaga, A, D'Esposito M.  2020.  Competition and Control During Working Memory. Elements in Perception. : Cambridge University Press2020_kiyonaga.pdf
Furman, DJ, White RL, Naskolnakorn JR, Ye S, Kayser AS, D'Esposito M.  2020.  Effects of dopaminergic drugs on cognitive control processes vary by genotype. Journal of Cognitive Neuroscience. 32(5):804-821.2020_furman.pdf
Turner, GR, Novakovic-Agopian T, Kornblith ES, Adnan A, Madore M, Chen AJ-W, D'Esposito M.  2020.  Goal-oriented attention regulation (GOALS) training in older adults. Aging and Mental Health. 24(3):464-473.2020_turner.pdf
2019
D'Esposito, M.  2019.  Are individual differences in human brain organization measured with functional MRI meaningful?, 2019 Oct 16 Proceedings of the National Academy of Sciences of the United States of America. 116(45):22432-22434.2019_despo_pnas.pdf
Baniqued, PL, Gallen CL, Kranz MB, Kramer AF, D'Esposito M.  2019.  Brain network modularity predicts cognitive training-related gains in young adults., 2019 May 24. Neuropsychologia. 131:205-215. Abstract2019_baniqued.pdf

The brain operates via networked activity in separable groups of regions called modules. The quantification of modularity compares the number of connections within and between modules, with high modularity indicating greater segregation, or dense connections within sub-networks and sparse connections between sub-networks. Previous work has demonstrated that baseline brain network modularity predicts executive function outcomes in older adults and patients with traumatic brain injury after cognitive and exercise interventions. In healthy young adults, however, the functional significance of brain modularity in predicting training-related cognitive improvements is not fully understood. Here, we quantified brain network modularity in young adults who underwent cognitive training with casual video games that engaged working memory and reasoning processes. Network modularity assessed at baseline was positively correlated with training-related improvements on untrained tasks. The relationship between baseline modularity and training gain was especially evident in initially lower performing individuals and was not present in a group of control participants that did not show training-related gains. These results suggest that a more modular brain network organization may allow for greater training responsiveness. On a broader scale, these findings suggest that, particularly in low-performing individuals, global network properties can capture aspects of brain function that are important in understanding individual differences in learning.

Sreenivasan, KK, D'Esposito M.  2019.  The what, where and how of delay activity., 2019 May 13. Nature Reviews: Neuroscience. 20(8):466-481. Abstract2019_sreenivasan.pdf

Working memory is characterized by neural activity that persists during the retention interval of delay tasks. Despite the ubiquity of this delay activity across tasks, species and experimental techniques, our understanding of this phenomenon remains incomplete. Although initially there was a narrow focus on sustained activation in a small number of brain regions, methodological and analytical advances have allowed researchers to uncover previously unobserved forms of delay activity various parts of the brain. In light of these new findings, this Review reconsiders what delay activity is, where in the brain it is found, what roles it serves and how it may be generated.

Gallen, CL, D'Esposito M.  2019.  Brain Modularity: A Biomarker of Intervention-related Plasticity., 2019 Feb 27. Trends in Cognitive Sciences. 23(4):293-304. Abstract2019_gallen.pdf

Interventions using methods such as cognitive training and aerobic exercise have shown potential to enhance cognitive abilities. However, there is often pronounced individual variability in the magnitude of these gains. Here, we propose that brain network modularity, a measure of brain subnetwork segregation, is a unifying biomarker of intervention-related plasticity. We present work from multiple independent studies demonstrating that individual differences in baseline brain modularity predict gains in cognitive control functions across several populations and interventions, spanning healthy adults to patients with clinical deficits and cognitive training to aerobic exercise. We believe that this predictive framework provides a foundation for developing targeted, personalized interventions to improve cognition.

Berry, AS, White RL, Furman DJ, Naskolnakorn JR, Shah VD, D'Esposito M, Jagust WJ.  2019.  Dopaminergic mechanisms underlying normal variation in trait anxiety., 2019 Feb 08. Journal of Neuroscience. 39(14):2735-2744. Abstract2019_berry.pdf

Trait anxiety has been associated with altered activity within corticolimbic pathways connecting the amygdala and rostral anterior cingulate cortex (rACC), which receive rich dopaminergic input. Though the popular culture uses the term "chemical imbalance" to describe the pathophysiology of psychiatric conditions such as anxiety disorders, we know little about how individual differences in human dopamine neurochemistry are related to variation in anxiety and activity within corticolimbic circuits. We addressed this issue by examining inter-individual variability in dopamine release at rest using [C]raclopride positron emission tomography (PET), functional connectivity between amygdala and rACC using resting-state functional magnetic resonance imaging (fMRI), and trait anxiety measures in healthy adult male and female humans. To measure endogenous dopamine release, we collected two [C]raclopride PET scans per participant. We contrasted baseline [C]raclopride D2/3 receptor binding and D2/3 receptor binding following oral methylphenidate administration. Methylphenidate blocks the dopamine transporter, which increases extracellular dopamine and leads to reduced [C]raclopride D2/3 receptor binding via competitive displacement. We found that individuals with higher dopamine release in the amygdala and rACC self-reported lower trait anxiety. Lower trait anxiety was also associated with reduced rACC-amygdala functional connectivity at baseline. Further, functional connectivity showed a modest negative relationship with dopamine release such that reduced rACC-amygdala functional connectivity was accompanied by higher levels of dopamine release in these regions. Together, these findings contribute to hypodopaminergic models of anxiety and support the utility of combining fMRI and PET measures of neurochemical function to advance our understanding of basic affective processes in humans.It is common wisdom that individuals vary in their baseline levels of anxiety. We all have a friend or colleague we know to be more "tightly wound" than others, or, perhaps, we are the ones marveling at others' ability to "just go with the flow." While such observations about individual differences within non-clinical populations are commonplace, the neural mechanisms underlying normal variation in trait anxiety have not been established. Using multimodal brain imaging in humans, this study takes initial steps in linking intrinsic measures of neuromodulator release and functional connectivity within regions implicated in anxiety disorders. Our findings suggest that in healthy adults, higher levels of trait anxiety may arise, at least in part, from reduced dopamine neurotransmission.

Riddle, J, Hwang K, Cellier D, Dhanani S, D'Esposito M.  2019.  Causal Evidence for the Role of Neuronal Oscillations in Top-Down and Bottom-Up Attention., 2019 Feb 06. Journal of Cognitive Neuroscience. 31(5):768-779. Abstract2019_riddle.pdf

Beta and gamma frequency neuronal oscillations have been implicated in top-down and bottom-up attention. In this study, we used rhythmic TMS to modulate ongoing beta and gamma frequency neuronal oscillations in frontal and parietal cortex, while human participants performed a visual search task that manipulates bottom-up and top-down attention (single feature and conjunction search). Both task conditions will engage bottom-up attention processes, whereas the conjunction search condition will require more top-down attention. Gamma frequency TMS to superior precentral sulcus (sPCS) slowed saccadic RTs during both task conditions and induced a response bias to the contralateral visual field. In contrary, beta frequency TMS to sPCS and intraparietal sulcus decreased search accuracy only during the conjunction search condition that engaged more top-down attention. Furthermore, beta frequency TMS increased trial errors specifically when the target was in the ipsilateral visual field for the conjunction search condition. These results indicate that beta frequency TMS to sPCS and intraparietal sulcus disrupted top-down attention, whereas gamma frequency TMS to sPCS disrupted bottom-up, stimulus-driven attention processes. These findings provide causal evidence suggesting that beta and gamma oscillations have distinct functional roles for cognition.

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.

D'Esposito, M, Grafman JH.  2019.  Preface., 2019. Handbook of clinical neurology. 163:ix.
Buchsbaum, BR, D'Esposito M.  2019.  A sensorimotor view of verbal working memory., 2018 Nov 20. Cortex. 112:134-148. Abstract2019_buchsbaum.pdf

The divide-and-conquer approach to the study of human cognition has succeeded in focusing researchers' efforts on behavioral phenomena that fall under well-defined categories such as attention, perception, language, memory, emotion, and motor control. The result has been the development of coherent bodies of work in each area replete with successful explanatory theories and a rich collection of paradigms, tasks, and analytic techniques. There has been a renewed in recent years in combining and integrating ideas across these domains, as well as in incorporating neuroscientific data, as a way to build more powerful and general models of cognition. Here we review the history and current state of integration between verbal short-term memory (VeSTM) and language, two domains of study that have significant areas of overlap but have not been fully integrated. We review evidence from cognitive neuroscience that has generally shown VeSTM to greatly depend on the network of brain regions that are known to form the core sensory-motor basis of human language. Whereas classic psychological models of VeSTM posit the existence of dedicated short-term storage buffers, we suggest that temporary verbal memory emerges from the coordinated interplay of a fronto-temporal sensory-motor circuit that has evolved to support the perception and production of speech. Phonological rehearsal in the service of temporary maintenance is achieved by feedforward and feedback pathways connecting the auditory- and motor-speech systems via a sensorymotor interface component situated in the Sylvian-parietal-temporal region (Spt). Reciprocal connectivity between the frontal and temporal speech systems enables the kind of "round-tripping" of dual speech codes long hypothesized by cognitive models such as Baddeley and Hitch's "phonological loop".

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.

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

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

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.

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

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

Novakovic-Agopian, T, Kornblith ES, Abrams G, Burciaga-Rosales J, Loya F, D'Esposito M, Chen AJ-W.  2018.  Training in Goal-Oriented Attentional Self-Regulation Improves Executive Functioning in Veterans with Chronic TBI., 2018 May 02. Journal of Neurotrauma. 35(23):2784-2795. Abstract2018_novakovic.pdf

Deficits in executive control functions are some of the most common and disabling consequences of both military and civilian brain injury. However, effective interventions are scant. The goal of this study was to assess whether cognitive rehabilitation training that was successfully applied in chronic civilian brain injury would be effective for military Veterans with TBI. In a prior study, participants with chronic acquired brain injury significantly improved after training in goal-oriented attentional self-regulation (GOALS) on measures of attention/executive function, functional task performance, and goal-directed control over neural processing on fMRI. The objective of this study was to assess effects of GOALS training in Veterans with chronic TBI. 33 Veterans with chronic TBI and executive difficulties in their daily life completed either five weeks of manualized Goal-Oriented Attentional Self-Regulation (GOALS) training or Brain-Health Education (BHE) matched in time and intensity. Evaluator-blinded assessments at baseline and post training included neuropsychological and complex functional task performance and self-report measures of emotional regulation. After GOALS, but not BHE training, participants significantly improved from baseline on primary outcome measures of: Overall Complex Attention/Executive Function composite neuropsychological performance score [F = 7.10, p =.01; partial 2 = .19], and on overall complex functional task performance (Goal Processing Scale Overall Performance) [F=6.92, p=.01, partial 2 =.20]. Additionally, post-GOALS participants indicated significant improvement on emotional regulation self-report measures [POMS Confusion Score F=6.05, p=.02, partial2=.20]. Training in attentional self-regulation applied to participant defined goals may improve cognitive functioning in Veterans with chronic TBI. Attention regulation training may not only impact executive control functioning in real world complex tasks, but may also improve emotional regulation and functioning. Implications for treatment of Veterans with TBI are discussed.

Scimeca, JM, Kiyonaga A, D'Esposito M.  2018.  Reaffirming the Sensory Recruitment Account of Working Memory., 2018 Mar. Trends in Cognitive Sciences. 22(3):190-192.2018_scimeca.pdf
Tambini, A, Nee DE, D'Esposito M.  2018.  Hippocampal-targeted Theta-burst Stimulation Enhances Associative Memory Formation., 2018 Jun 19. Journal of Cognitive Neuroscience. 30(10):1452-1472. Abstract2018_tambini.pdf

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

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

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

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

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

Haight, T, Nick Bryan R, Erus G, Hsieh M-K, Davatzikos C, Nasrallah I, D'Esposito M, Jacobs DR, Lewis C, Schreiner P, Sidney S, Meirelles O, Launer LJ.  2018.  White matter microstructure, white matter lesions, and hypertension: An examination of early surrogate markers of vascular-related brain change in midlife., 2018. NeuroImage: Clinical. 18:753-761. Abstract2018_haight.pdf

We examined imaging surrogates of white matter microstructural abnormalities which may precede white matter lesions (WML) and represent a relevant marker of cerebrovascular injury in adults in midlife.

Blumenfeld, RS, Bliss DP, D'Esposito M.  2018.  Quantitative Anatomical Evidence for a Dorsoventral and Rostrocaudal Segregation within the Nonhuman Primate Frontal Cortex., 2017 Oct 24. Journal of Cognitive Neuroscience. 30(3):353-364. Abstract2018_blumenfeld.pdf

The intrinsic white matter connections of the frontal cortex are highly complex, and the organization of these connections is not fully understood. Quantitative graph-theoretical methods, which are not solely reliant on human observation and interpretation, can be powerful tools for describing the organizing network principles of frontal cortex. Here, we examined the network structure of frontal cortical subregions by applying graph-theoretical community detection analyses to a graph of frontal cortex compiled from over 400+ macaque white-matter tracing studies. We find evidence that the lateral frontal cortex can be partitioned into distinct modules roughly organized along the dorsoventral and rostrocaudal axis.

Nee, DE, D'Esposito M.  2018.  The Representational Basis of Working Memory., 2016 Sep 28. Current Topics in Behavioral Neurosciences. 37:213-230. Abstract2018_nee.pdf

Working memory refers to a system involved in the online maintenance and manipulation of information in the absence of external input. Due to the importance of working memory in higher-level cognition, a wealth of neuroscience studies has investigated its neural basis. These studies have often led to conflicting viewpoints regarding the importance of the prefrontal cortex (PFC) and posterior sensory cortices. Here, we review evidence for each position. We suggest that the relative contributions of the PFC and sensory cortices to working memory can be understood with respect to processing demands. We argue that procedures that minimize processing demands lead to increased importance of sensory representations, while procedures that permit transformational processing lead to representational abstraction that relies on the PFC. We suggest that abstract PFC representations support top-down control over posterior representations while also providing bottom-up inputs into higher-level cognitive processing. Although a number of contemporary studies have studied working memory while using procedures that minimize the role of the PFC, we argue that consideration of the PFC is critical for our understanding of working memory and higher-level cognition more generally.

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
Bliss, DP, Sun JJ, D'Esposito M.  2018.  Serial dependence is absent at the time of perception but grows in visual working memory. Scientific Reports. 7(1):14739.2018_bliss.pdf
Nee, DE, D'Esposito M.  2018.  Working memory: An evolving concept. The Stevens' Handbook of Experimental Psychology and Cognitive Neuroscience, 4th Edition. : John Wiley and Sons
2017
Nee, DE, D'Esposito M.  2017.  Causal evidence for lateral prefrontal cortex dynamics supporting cognitive control., 2017 Sep 13. eLife. 6:e28040. Abstract2017_nee.pdf

The lateral prefrontal cortex (LPFC) is essential for higher-level cognition, but how its interactions support cognitive control remains elusive. Previously (Nee and D'Esposito, 2016), dynamic causal modeling (DCM) indicated that mid LPFC integrates abstract, rostral and concrete, caudal influences to inform context-appropriate action. Here, we use continuous theta-burst transcranial magnetic stimulation (cTBS) to causally test this model. cTBS was applied to three LPFC sites and a control site in counterbalanced sessions. Behavioral modulations resulting from cTBS were largely predicted by information flow within the previously estimated DCM. However, cTBS to caudal LPFC unexpectedly impaired processes presumed to involve rostral LPFC. Adding a pathway from caudal to mid-rostral LPFC significantly improved the model fit and accounted for the observed behavioral findings. These data provide causal evidence for LPFC dynamics supporting cognitive control and demonstrate the utility of combining DCM with causal manipulations to test and refine models of cognition.

Adnan, A, Chen AJW, Novakovic-Agopian T, D'Esposito M, Turner GR.  2017.  Brain Changes Following Executive Control Training in Older Adults., 2017 Sep 01. Neurorehabilitation and Neural Repair. 31(10-11):910–922. Abstract2017_adnan.pdf

While older adults are able to attend to goal-relevant information, the capacity to ignore irrelevant or distracting information declines with advancing age. This decline in selective attention has been associated with poor modulation of brain activity in sensory cortices by anterior brain regions implicated in cognitive control.

Gratton, C, Yousef S, Aarts E, Wallace DL, D'Esposito M, Silver MA.  2017.  Cholinergic, but not dopaminergic or noradrenergic, enhancement sharpens visual spatial perception in humans., 2017 Mar 23. Journal of Neuroscience. 37(16):4405-4415. Abstract2017_gratton.pdf

The neuromodulator acetylcholine (ACh) modulates spatial integration in visual cortex by altering the balance of inputs that generate neuronal receptive fields. These cholinergic effects may provide a neurobiological mechanism underlying the modulation of visual representations by visual spatial attention. However, the consequences of cholinergic enhancement on visuospatial perception in humans are unknown. We conducted two experiments to test whether enhancing cholinergic signaling selectively alters perceptual measures of visuospatial interactions in human subjects. In Experiment 1, a double-blind placebo-controlled pharmacology study, we measured how flanking distractors influenced detection of a small contrast decrement of a peripheral target, as a function of target/flanker distance. We found that cholinergic enhancement with the cholinesterase inhibitor donepezil improved target detection, and modeling suggested that this was mainly due to a narrowing of the extent of facilitatory perceptual spatial interactions. In Experiment 2, we tested whether these effects were selective to the cholinergic system or would also be observed following enhancements of related neuromodulators dopamine (DA) or norepinephrine (NE). Unlike cholinergic enhancement, DA (bromocriptine) and NE (guanfacine) manipulations did not improve performance or systematically alter the spatial profile of perceptual interactions between targets and distractors. These findings reveal mechanisms by which cholinergic signaling influences visual spatial interactions in perception and improves processing of a visual target among distractors - effects that are notably similar to those of spatial selective attention.Significance StatementAcetylcholine influences how visual cortical neurons integrate signals across space - perhaps providing a neurobiological mechanism for the effects of visual selective attention. However, the influence of cholinergic enhancement on visuospatial perception remains unknown. Here we demonstrate that cholinergic enhancement improves detection of a target flanked by distractors, consistent with sharpened visuospatial perceptual representations. Furthermore, while most pharmacological studies focus on a single neurotransmitter, many neuromodulators can have related effects on cognition and perception. Thus, we also demonstrate that enhancing noradrenergic and dopaminergic systems does not systematically improve visuospatial perception or alter its tuning. Our results link visuospatial tuning effects of acetylcholine at the neuronal and perceptual levels and provide insights into the connection between cholinergic signaling and visual attention.

Berry, AS, Shah VD, Furman DJ, White RL, Baker SL, O'Neil JP, Janabi M, D'Esposito M, Jagust WJ.  2017.  Dopamine Synthesis Capacity is Associated with D2/3 Receptor Binding but not Dopamine Release., 2017 Aug 17. Neuropsychopharmacology. 43(6):1201-1211. Abstract2017_berry.pdf

Positron Emission Tomography (PET) imaging allows the estimation of multiple aspects of dopamine function including dopamine synthesis capacity, dopamine release, and D2/3 receptor binding. Though dopaminergic dysregulation characterizes a number of neuropsychiatric disorders including schizophrenia and addiction, there has been relatively little investigation into the nature of relationships across dopamine markers within healthy individuals. Here we used PET imaging in 40 healthy adults to compare, within individuals, estimates of dopamine synthesis capacity (Ki) using 6-[(18)F]fluoro-l-m-tyrosine ([(18)F]FMT; a substrate for aromatic amino acid decarboxylase), baseline D2/3 receptor binding potential using [(11)C]raclopride (a weak competitive D2/3 receptor antagonist), and dopamine release using [(11)C]raclopride paired with oral methylphenidate administration. Methylphenidate increases synaptic dopamine by blocking the dopamine transporter. We estimated dopamine release by contrasting baseline D2/3 receptor binding and D2/3 receptor binding following methylphenidate. Analysis of relationships among the three measurements within striatal regions of interest revealed a positive correlation between [(18)F]FMT Ki and the baseline (placebo) [(11)C]raclopride measure, such that participants with greater synthesis capacity showed higher D2/3 receptor binding potential. In contrast, there was no relationship between [(18)F]FMT and methylphenidate-induced [(11)C]raclopride displacement. These findings shed light on the nature of regulation between pre- and postsynaptic dopamine function in healthy adults, which may serve as a template from which to identify and describe alteration with disease.Neuropsychopharmacology accepted article preview online, 17 August 2017. doi:10.1038/npp.2017.180.

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

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

Baniqued, PL, Gallen CL, Voss MW, Burzynska AZ, Wong CN, Cooke GE, Duffy K, Fanning J, Ehlers DK, Salerno EA, Aguiñaga S, McAuley E, Kramer AF, D'Esposito M.  2017.  Brain Network Modularity Predicts Exercise-Related Executive Function Gains in Older Adults., 2017. Frontiers in Aging Neuroscience. 9:426. Abstract2017_baniqued.pdf

Recent work suggests that the brain can be conceptualized as a network comprised of groups of sub-networks or modules. The extent of segregation between modules can be quantified with a modularity metric, where networks with high modularity have dense connections within modules and sparser connections between modules. Previous work has shown that higher modularity predicts greater improvements after cognitive training in patients with traumatic brain injury and in healthy older and young adults. It is not known, however, whether modularity can also predict cognitive gains after a physical exercise intervention. Here, we quantified modularity in older adults (N = 128, mean age = 64.74) who underwent one of the following interventions for 6 months (NCT01472744 on ClinicalTrials.gov): (1) aerobic exercise in the form of brisk walking (Walk), (2) aerobic exercise in the form of brisk walking plus nutritional supplement (Walk+), (3) stretching, strengthening and stability (SSS), or (4) dance instruction. After the intervention, the Walk, Walk+ and SSS groups showed gains in cardiorespiratory fitness (CRF), with larger effects in both walking groups compared to the SSS and Dance groups. The Walk, Walk+ and SSS groups also improved in executive function (EF) as measured by reasoning, working memory, and task-switching tests. In the Walk, Walk+, and SSS groups that improved in EF, higher baseline modularity was positively related to EF gains, even after controlling for age, in-scanner motion and baseline EF. No relationship between modularity and EF gains was observed in the Dance group, which did not show training-related gains in CRF or EF control. These results are consistent with previous studies demonstrating that individuals with a more modular brain network organization are more responsive to cognitive training. These findings suggest that the predictive power of modularity may be generalizable across interventions aimed to enhance aspects of cognition and that, especially in low-performing individuals, global network properties can capture individual differences in neuroplasticity.

Bliss, DP, D'Esposito M.  2017.  Synaptic augmentation in a cortical circuit model reproduces serial dependence in visual working memory., 2017. PloS one. 12(12):e0188927. Abstract2017_bliss.pdf

Recent work has established that visual working memory is subject to serial dependence: current information in memory blends with that from the recent past as a function of their similarity. This tuned temporal smoothing likely promotes the stability of memory in the face of noise and occlusion. Serial dependence accumulates over several seconds in memory and deteriorates with increased separation between trials. While this phenomenon has been extensively characterized in behavior, its neural mechanism is unknown. In the present study, we investigate the circuit-level origins of serial dependence in a biophysical model of cortex. We explore two distinct kinds of mechanisms: stable persistent activity during the memory delay period and dynamic "activity-silent" synaptic plasticity. We find that networks endowed with both strong reverberation to support persistent activity and dynamic synapses can closely reproduce behavioral serial dependence. Specifically, elevated activity drives synaptic augmentation, which biases activity on the subsequent trial, giving rise to a spatiotemporally tuned shift in the population response. Our hybrid neural model is a theoretical advance beyond abstract mathematical characterizations, offers testable hypotheses for physiological research, and demonstrates the power of biological insights to provide a quantitative explanation of human behavior.

Bertolero, MA, Yeo TBT, D'Esposito M.  2017.  The Diverse Club. Nature Communications. 8:1277.2017_bertolero.pdf
Gazzaley, A, Lee TG, D'Esposito M.  2017.  The Frontal Lobes and Executive Control. The Human Frontal Lobes, 3rd Edition. , New York: Guilford Publications
Kayser, AS, D'Esposito M.  2017.  Neurotechnologies. Reference Module in Neuroscience and Biobehavioral Psychology. , Oxford, UK: Elsevier
Buchsbaum, BR, D'Esposito M.  2017.  Short Term and Working Memory. Learning and Memory: A Comprehensive Reference, 2nd Edition. , Oxford, UK: Academic Press
2016
Cohen, JR, D'Esposito M.  2016.  The Segregation and Integration of Distinct Brain Networks and Their Relationship to Cognition., 2016 Nov 30. Journal of Neuroscience. 36(48):12083-12094. Abstract2016_cohen.pdf

A critical feature of the human brain that gives rise to complex cognition is its ability to reconfigure its network structure dynamically and adaptively in response to the environment. Existing research probing task-related reconfiguration of brain network structure has concluded that, although there are many similarities in network structure during an intrinsic, resting state and during the performance of a variety of cognitive tasks, there are meaningful differences as well. In this study, we related intrinsic, resting state network organization to reconfigured network organization during the performance of two tasks: a sequence tapping task, which is thought to probe motor execution and likely engages a single brain network, and an n-back task, which is thought to probe working memory and likely requires coordination across multiple networks. We implemented graph theoretical analyses using functional connectivity data from fMRI scans to calculate whole-brain measures of network organization in healthy young adults. We focused on quantifying measures of network segregation (modularity, system segregation, local efficiency, number of provincial hub nodes) and measures of network integration (global efficiency, number of connector hub nodes). Using these measures, we found converging evidence that local, within-network communication is critical for motor execution, whereas integrative, between-network communication is critical for working memory. These results confirm that the human brain has the remarkable ability to reconfigure its large-scale organization dynamically in response to current cognitive demands and that interpreting reconfiguration in terms of network segregation and integration may shed light on the optimal network structures underlying successful cognition.

Rahnev, D, Nee DE, Riddle J, Larson AS, D'Esposito M.  2016.  Causal evidence for frontal cortex organization for perceptual decision making., 2016 May 9. Proceedings of the National Academy of Sciences of the United States of America. 113(21):6059-6064. Abstract2016_rahnev.pdf

Although recent research has shown that the frontal cortex has a critical role in perceptual decision making, an overarching theory of frontal functional organization for perception has yet to emerge. Perceptual decision making is temporally organized such that it requires the processes of selection, criterion setting, and evaluation. We hypothesized that exploring this temporal structure would reveal a large-scale frontal organization for perception. A causal intervention with transcranial magnetic stimulation revealed clear specialization along the rostrocaudal axis such that the control of successive stages of perceptual decision making was selectively affected by perturbation of successively rostral areas. Simulations with a dynamic model of decision making suggested distinct computational contributions of each region. Finally, the emergent frontal gradient was further corroborated by functional MRI. These causal results provide an organizational principle for the role of frontal cortex in the control of perceptual decision making and suggest specific mechanistic contributions for its different subregions.

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

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

Gallen, CL, Turner GR, Adnan A, D'Esposito M.  2016.  Reconfiguration of brain network architecture to support executive control in aging., 2016 Aug. Neurobiology of Aging. 44:42-52. Abstract2016_gallen.pdf

Aging is accompanied by declines in executive control abilities and changes in underlying brain network architecture. Here, we examined brain networks in young and older adults during a task-free resting state and an N-back task and investigated age-related changes in the modular network organization of the brain. Compared with young adults, older adults showed larger changes in network organization between resting state and task. Although young adults exhibited increased connectivity between lateral frontal regions and other network modules during the most difficult task condition, older adults also exhibited this pattern of increased connectivity during less-demanding task conditions. Moreover, the increase in between-module connectivity in older adults was related to faster task performance and greater fractional anisotropy of the superior longitudinal fasciculus. These results demonstrate that older adults who exhibit more pronounced network changes between a resting state and task have better executive control performance and greater structural connectivity of a core frontal-posterior white matter pathway.

Chapman, SB, Aslan S, Spence JS, Keebler MW, DeFina LF, Didehbani N, Perez AM, Lu H, D'Esposito M.  2016.  Distinct Brain and Behavioral Benefits from Cognitive vs. Physical Training: A Randomized Trial in Aging Adults., 2016. Frontiers in Human Neuroscience. 10:338. Abstract2016_chapman.pdf

Insidious declines in normal aging are well-established. Emerging evidence suggests that non-pharmacological interventions, specifically cognitive and physical training, may counter diminishing age-related cognitive and brain functions. This randomized trial compared effects of two training protocols: cognitive training (CT) vs. physical training (PT) on cognition and brain function in adults 56-75 years. Sedentary participants (N = 36) were randomized to either CT or PT group for 3 h/week over 12 weeks. They were assessed at baseline-, mid-, and post-training using neurocognitive, MRI, and physiological measures. The CT group improved on executive function whereas PT group's memory was enhanced. Uniquely deploying cerebral blood flow (CBF) and cerebral vascular reactivity (CVR) MRI, the CT cohort showed increased CBF within the prefrontal and middle/posterior cingulate cortex (PCC) without change to CVR compared to PT group. Improvements in complex abstraction were positively associated with increased resting CBF in dorsal anterior cingulate cortex (dACC). Exercisers with higher CBF in hippocampi bilaterally showed better immediate memory. The preliminary evidence indicates that increased cognitive and physical activity improves brain health in distinct ways. Reasoning training enhanced frontal networks shown to be integral to top-down cognitive control and brain resilience. Evidence of increased resting CBF without changes to CVR implicates increased neural health rather than improved vascular response. Exercise did not improve cerebrovascular response, although CBF increased in hippocampi of those with memory gains. Distinct benefits incentivize testing effectiveness of combined protocols to strengthen brain health.

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

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

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: ClinicalTrials.gov, NCT#00977418.

D'Esposito, M, Kayser AS, Chen AJ-W.  2016.  Functional MRI: Applications in Cognitive Neuroscience. Functional MRI Techniques and Protocols, 2nd Edition. , New York: Springer
Cole, MA, Soda CN, D'Esposito M.  2016.  History of Functional Brain Imaging. The Oxford Handbook of the History of Clinical Neuropsychology. , Oxford, UK: Oxford University Press
2015
Rahnev, D, Koizumi A, McCurdy LY, D'Esposito M, Lau H.  2015.  Confidence Leak in Perceptual Decision Making., 2015 Sep 25. Psychological Science. 26(11):1664-1680. Abstract2015_rahnev.pdf

People live in a continuous environment in which the visual scene changes on a slow timescale. It has been shown that to exploit such environmental stability, the brain creates a continuity field in which objects seen seconds ago influence the perception of current objects. What is unknown is whether a similar mechanism exists at the level of metacognitive representations. In three experiments, we demonstrated a robust intertask confidence leak-that is, confidence in one's response on a given task or trial influencing confidence on the following task or trial. This confidence leak could not be explained by response priming or attentional fluctuations. Better ability to modulate confidence leak predicted higher capacity for metacognition as well as greater gray matter volume in the prefrontal cortex. A model based on normative principles from Bayesian inference explained the results by postulating that observers subjectively estimate the perceptual signal strength in a stable environment. These results point to the existence of a novel metacognitive mechanism mediated by regions in the prefrontal cortex.

Cole, MA, Muir JJ, Gans JJ, Shin LM, D'Esposito M, Harel BT, Schembri A.  2015.  Simultaneous Treatment of Neurocognitive and Psychiatric Symptoms in Veterans with Post-Traumatic Stress Disorder and History of Mild Traumatic Brain Injury: A Pilot Study of Mindfulness-Based Stress Reduction., 2015 Sep. Military Medicine. 180(9):956-963. Abstract2015_cole.pdf

Treating patient populations with significant psychiatric and neurocognitive symptomatology can present a unique clinical dilemma: progress in psychotherapy can be significantly fettered by cognitive deficits, whereas neurocognitive rehabilitation efforts can be ineffective because of psychiatric overlay. Application of mindfulness-based interventions to address either cognitive or psychiatric symptoms in isolation appears efficacious in many contexts; however, it remains unclear whether this type of intervention might help address simultaneous neurocognitive and psychiatric symptomatology. In a pre-post mixed methods design pilot study, nine Veterans with post-traumatic stress disorder (PTSD) and a history of mild traumatic brain injury with chronic cognitive complaints participated in Mindfulness-Based Stress Reduction (MBSR). Clinical interview, questionnaires, and attention and PTSD measures were administered immediately before, immediately after, and 3 months after MBSR completion. Qualitative and quantitative findings suggest high levels of safety, feasibility, and acceptability. Measurement of attention revealed significant improvement immediately following MBSR (p < 0.05, d = 0.57) and largely sustained improvement 3 months after completion of MBSR (p < 0.10, d = 0.48). Significant reduction in PTSD symptoms was found immediately after MBSR (p < 0.05, d = -1.56), and was sustained 3 months following MBSR completion (p < 0.05, d = -0.93). These results warrant a randomized controlled trial follow-up. Potential mechanisms for the broad effects observed will be explored.

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.

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

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

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

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

Sadaghiani, S, 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.

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.

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.

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.

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.

Haight, TJ, Bryan NR, Erus G, Davatzikos C, Jacobs DR, D'Esposito M, Lewis CE, Launer LJ.  2015.  Vascular risk factors, cerebrovascular reactivity, and the default-mode brain network., 2015 Apr 23. NeuroImage. 115:7-16. Abstract2015_haight.pdf

Cumulating evidence from epidemiologic studies implicates cardiovascular health and cerebrovascular function in several brain diseases in late life. We examined vascular risk factors with respect to a cerebrovascular measure of brain functioning in subjects in mid-life, which could represent a marker of brain changes in later life. Breath-hold functional MRI (fMRI) was performed in 541 women and men (mean age 50.4 years) from the Coronary Artery Risk Development in Young Adults (CARDIA) Brain MRI sub-study. Cerebrovascular reactivity (CVR) was quantified as percentage change in blood-oxygen level dependent (BOLD) signal in activated voxels, which was mapped to a common brain template and log-transformed. Mean CVR was calculated for anatomic regions underlying the default-mode network (DMN) - a network implicated in AD and other brain disorders - in addition to areas considered to be relatively spared in the disease (e.g. occipital lobe), which were utilized as reference regions. Mean CVR was significantly reduced in the posterior cingulate/precuneus (β = -0.063, 95% CI: -0.106, -0.020), anterior cingulate (β = -0.055, 95% CI: -0.101, -0.010), and medial frontal lobe (β = -0.050, 95% CI: -0.092, -0.008) relative to mean CVR in the occipital lobe, after adjustment for age, sex, race, education, and smoking status, in subjects with pre-hypertension/hypertension compared to normotensive subjects. By contrast, mean CVR was lower, but not significantly, in the inferior parietal lobe (β = -0.024, 95% CI: -0.062, 0.014) and the hippocampus (β = -0.006, 95% CI: -0.062, 0.050) relative to mean CVR in the occipital lobe. Similar results were observed in subjects with diabetes and dyslipidemia compared to those without these conditions, though the differences were non-significant. Reduced CVR may represent diminished vascular functionality for the DMN for individuals with prehypertension/ hypertension in mid-life, and may serve as a preclinical marker for brain dysfunction in later life.

Cameron, IGM, Riddle JM, D'Esposito M.  2015.  Dissociable Roles of Dorsolateral Prefrontal Cortex and Frontal Eye Fields During Saccadic Eye Movements., 2015. Frontiers in Human Neuroscience. 9:613. Abstract2015_cameron.pdf

The dorsolateral prefrontal cortex (DLPFC) and the frontal eye fields (FEF) have both been implicated in the executive control of saccades, yet possible dissociable roles of each region have not been established. Specifically, both establishing a "task set" as well as suppressing an inappropriate response have been linked to DLPFC and FEF activity, with behavioral outcome measures of these mechanisms mainly being the percentage of pro-saccade errors made on anti-saccade trials. We used continuous theta-burst stimulation (cTBS) to disrupt FEF or DLPFC function in humans during an anti-saccade task to assess the causal role of these regions in these executive control processes, and in programming saccades towards (pro-saccade) or away (anti-saccade) from visual targets. After right FEF cTBS, as compared to control cTBS to the right primary somatosensory cortex (rS1), anti-saccade amplitude of the first saccade decreased and the number of anti-saccades to acquire final position increased; however direction errors to the visual target were not different. In contrast, after left DLPFC cTBS, as compared to left S1 cTBS, subjects displayed greater direction errors for contralateral anti-saccades; however, there were no impairments on the number of saccades or the saccade amplitude. These results are consistent with the notion that DLPFC is necessary for executive control of saccades, whereas FEF is necessary for visuo-motor aspects of anti-saccade programming.

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

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

Launer, LJ, Lewis CE, Schreiner PJ, Sidney S, Battapady H, Jacobs DR, Lim KO, D'Esposito M, Zhang Q, Reis J, Davatzikos C, Bryan NR.  2015.  Vascular Factors and Multiple Measures of Early Brain Health: CARDIA Brain MRI Study., 2015. PloS one. 10(3):e0122138. Abstract2015_launer.pdf

To identify early changes in brain structure and function that are associated with cardiovascular risk factors (CVRF).

D'Esposito, M, Sreenivasan KK, Kayser A.  2015.  Functional MRI: Cognitive Neuroscience Applications. FMRI: From Nuclear Spins to Brain Function. , New York: Springer
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
Nee, DE, D'Esposito M.  2015.  Working Memory. Brain Mapping: An Encyclopedic Reference. : Academic Press: Elsevier
2014
D'Esposito, M, Postle BR.  2014.  The Cognitive Neuroscience of Working Memory., 2014 Sep 19. Annual Review of Psychology. 66:115-142. Abstract2014_desposito.pdf

For more than 50 years, psychologists and neuroscientists have recognized the importance of a working memory to coordinate processing when multiple goals are active and to guide behavior with information that is not present in the immediate environment. In recent years, psychological theory and cognitive neuroscience data have converged on the idea that information is encoded into working memory by allocating attention to internal representations, whether semantic long-term memory (e.g., letters, digits, words), sensory, or motoric. Thus, information-based multivariate analyses of human functional MRI data typically find evidence for the temporary representation of stimuli in regions that also process this information in non-working memory contexts. The prefrontal cortex (PFC), on the other hand, exerts control over behavior by biasing the salience of mnemonic representations and adjudicating among competing, context-dependent rules. The "control of the controller" emerges from a complex interplay between PFC and striatal circuits and ascending dopaminergic neuromodulatory signals. Expected final online publication date for the Annual Review of Psychology Volume 66 is November 30, 2014. Please see http://www.annualreviews.org/catalog/pubdates.aspx for revised estimates.

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

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

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

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

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.

Van Vleet, TM, Chen A, Vernon A, Novakovic-Agopian T, D'Esposito MT.  2014.  Tonic and phasic alertness training: a novel treatment for executive control dysfunction following mild traumatic brain injury., 2014 Jul 1. Neurocase. 21(4):489-498. Abstract2014_vanvleet.pdf

Many individuals with traumatic brain injury (TBI) suffer difficulty regulating fundamental aspects of attention (focus, sustained attention) and may also exhibit hypo- or hyper-states of alertness. Deficits in the state of attention may underlie or exacerbate higher order executive dysfunction. Recent studies indicate that computerized cognitive training targeting attentional control and alertness can ameliorate attention deficits evident in patients with TBI or acquired brain injury. The current study examined whether improvements in attentional state following training can also influence performance on higher-order executive function and mood in individuals with mild TBI (mTBI). The current study examined five patients with executive control deficits as a result of mTBI, with or without persistent anxiety. Three patients engaged in ~5 hours of an executive control training task targeting inhibitory control and sustained attention; two additional patients were re-tested following the same period of time. Performance on standard neuropsychological measures of attention, executive function, and mood were evaluated pre- and post-training. The results indicate that tonic and phasic alertness training may improve higher-order executive function and mood regulation in individuals with TBI.

Sreenivasan, KK, Vytlacil J, D'Esposito M.  2014.  Distributed and Dynamic Storage of Working Memory Stimulus Information in Extrastriate Cortex., 2014 Jan 6. Journal of Cognitive Neuroscience. 26(5):1141–1153. Abstract2014_sreenivasan.pdf

The predominant neurobiological model of working memory (WM) posits that stimulus information is stored via stable elevated activity within highly selective neurons. On the basis of this model, which we refer to as the canonical model, the storage of stimulus information is largely associated with lateral pFC (lPFC). A growing number of studies describe results that cannot be fully explained by the canonical model, suggesting that it is in need of revision. In this study, we directly test key elements of the canonical model. We analyzed fMRI data collected as participants performed a task requiring WM for faces and scenes. Multivariate decoding procedures identified patterns of activity containing information about the items maintained in WM (faces, scenes, or both).Although information about WM items was identified in extrastriate visual cortex (EC) and lPFC, only EC exhibited a pattern of results consistent with a sensory representation. Information in both regions persisted even in the absence of elevated activity, suggesting that elevated population activity may not represent the storage of information in WM. Additionally, we observed that WM information was distributed across EC neural populations that exhibited a broad range of selectivity for the WM items rather than restricted to highly selective EC populations. Finally, we determined that activity patterns coding for WM information were not stable, but instead varied over the course of a trial, indicating that the neural code for WM information is dynamic rather than static. Together, these findings challenge the canonical model of WM.

Bahlmann, J, Blumenfeld RS, D'Esposito M.  2014.  The Rostro-Caudal Axis of Frontal Cortex Is Sensitive to the Domain of Stimulus Information., 2014 Jan 22. Cerebral Cortex . 25(7):1815-1826. Abstract2014_bahlmann.pdf

Evidence suggests that lateral frontal cortex implements cognitive control processing along its rostro-caudal axis, yet other evidence supports a dorsal-ventral functional organization for processes engaged by different stimulus domains (e.g., spatial vs. nonspatial). This functional magnetic resonance imaging study investigated whether separable dorsolateral and ventrolateral rostro-caudal gradients exist in humans, while participants performed tasks requiring cognitive control at 3 levels of abstraction with language or spatial stimuli. Abstraction was manipulated by using 3 different task sets that varied in relational complexity. Relational complexity refers to the process of manipulating the relationship between task components (e.g., to associate a particular cue with a task) and drawing inferences about that relationship. Tasks using different stimulus domains engaged distinct posterior regions, but within the lateral frontal cortex, we found evidence for a single rostro-caudal gradient that was organized according to the level of abstraction and was independent of processing of the stimulus domain. However, a pattern of dorsal/ventral segregation of processing engaged by domain-specific information was evident in each separable frontal region only within the most rostral region recruited by task demands. These results suggest that increasingly abstract information is represented in the frontal cortex along distinct rostro-caudal gradients that also segregate along a dorsal-ventral axis dependent on task demands.

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

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

Aarts, E, Wallace DL, Dang LC, Jagust WJ, Cools R, D'Esposito M.  2014.  Dopamine and the Cognitive Downside of a Promised Bonus., 2014 Feb 13. Psychological Science. 25(4):1003-1009. Abstract2014_aarts.pdf

It is often assumed that the promise of a monetary bonus improves cognitive control. We show that in fact appetitive motivation can also impair cognitive control, depending on baseline levels of dopamine-synthesis capacity in the striatum. These data not only demonstrate that appetitive motivation can have paradoxical detrimental effects for cognitive control but also provide a mechanistic account of these effects.

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

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

Vytlacil, J, Kayser A, Miyakawa A, D'Esposito M.  2014.  An approach for identifying brainstem dopaminergic pathways using resting state functional MRI., 2014. PloS one. 9(1):e87109. Abstract2014_vytlacil.pdf

Here, we present an approach for identifying brainstem dopaminergic pathways using resting state functional MRI. In a group of healthy individuals, we searched for significant functional connectivity between dopamine-rich midbrain areas (substantia nigra; ventral tegmental area) and a striatal region (caudate) that was modulated by both a pharmacological challenge (the administration of the dopaminergic agonist bromocriptine) and a dopamine-sensitive cognitive trait (an individual's working memory capacity). A significant inverted-U shaped connectivity pattern was found in a subset of midbrain-striatal connections, demonstrating that resting state fMRI data is sufficiently powerful to identify brainstem neuromodulatory brain networks.

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.

Cohen, JR, Gallen CL, Jacobs EG, Lee TG, D'Esposito M.  2014.  Quantifying the Reconfiguration of Intrinsic Networks during Working Memory., 2014. PloS one. 9(9):e106636. Abstract2014_cohen.pdf

Rapid, flexible reconfiguration of connections across brain regions is thought to underlie successful cognitive control. Two intrinsic networks in particular, the cingulo-opercular (CO) and fronto-parietal (FP), are thought to underlie two operations critical for cognitive control: task-set maintenance/tonic alertness and adaptive, trial-by-trial updating. Using functional magnetic resonance imaging, we directly tested whether the functional connectivity of the CO and FP networks was related to cognitive demands and behavior. We focused on working memory because of evidence that during working memory tasks the entire brain becomes more integrated. When specifically probing the CO and FP cognitive control networks, we found that individual regions of both intrinsic networks were active during working memory and, as expected, integration across the two networks increased during task blocks that required cognitive control. Crucially, increased integration between each of the cognitive control networks and a task-related, non-cognitive control network (the hand somatosensory-motor network; SM) was related to increased accuracy. This implies that dynamic reconfiguration of the CO and FP networks so as to increase their inter-network communication underlies successful working memory.

Blumenfeld, RS, Bliss DP, Perez F, D'Esposito M.  2014.  CoCoTools: Open-source Software for Building Connectomes Using the CoCoMac Anatomical Database., 2013 Oct 11. Journal of Cognitive Neuroscience. 26(4):722-745. Abstract2014_blumenfeld.pdf

Neuroanatomical tracer studies in the nonhuman primate macaque monkey are a valuable resource for cognitive neuroscience research. These data ground theories of cognitive function in anatomy, and with the emergence of graph theoretical analyses in neuroscience, there is high demand for these data to be consolidated into large-scale connection matrices ("macroconnectomes"). Because manual review of the anatomical literature is time consuming and error prone, computational solutions are needed to accomplish this task. Here we describe the "CoCoTools" open-source Python library, which automates collection and integration of macaque connectivity data for visualization and graph theory analysis. CoCoTools both interfaces with the CoCoMac database, which houses a vast amount of annotated tracer results from 100 years (1905-2005) of neuroanatomical research and implements coordinate-free registration algorithms, which allow studies that use different parcellations of the brain to be translated into a single graph. We show that using CoCoTools to translate all of the data stored in CoCoMac produces graphs with properties consistent with what is known about global brain organization. Moreover, in addition to describing CoCoTools' processing pipeline, we provide worked examples, tutorials, links to on-line documentation, and detailed appendices to aid scientists interested in using CoCoTools to gather and analyze CoCoMac data.

Wallace, DL, Aarts E, Dang LC, Greer SM, Jagust W, D'Esposito M.  2014.  Dorsal striatal dopamine, food preference, and health perception in humans. PLoS One. 9(5):e96319.2014_wallace.pdf
Turner, GR, D'Esposito M.  2014.  Neurorehabilitation of Executive Functions. . Textbook of Neural Repair and Rehabilitation. , Cambridge, UK: Cambridge University Press
Sreenivasan, KK, Curtis CE, D'Esposito M.  2014.  Revising the role of persistent neural activity in working memory. Trends in Cognitive Science. 18(2):82-89.2014_sreenivasan.pdf
2013
Sneve, MH, Magnussen S, Alnæs D, Endestad T, D'Esposito M.  2013.  Top-Down Modulation from Inferior Frontal Junction to FEFs and Intraparietal Sulcus during Short-term Memory for Visual Features., 2013 May 22. Journal of Cognitive Neuroscience. 25(11):1944-1956. Abstract2013_sneve.pdf

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

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.

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.

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

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

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

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