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2014
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. Abstract

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.

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. Abstract

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.

D'Esposito, M, Postle BR.  2014.  The Cognitive Neuroscience of Working Memory., 2014 Sep 19. Annual review of psychology. Abstract

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.

2015
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. Abstract

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. Abstract

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. Abstract

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

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. Abstract

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.

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. :jn.00261.2015. Abstract

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.

Bahlmann, J, Aarts E, D'Esposito M.  2015.  Influence of motivation on control hierarchy in the human frontal cortex., 2015 Feb 18. The Journal of neuroscience : the official journal of the Society for Neuroscience. 35(7):3207-17. Abstract

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.

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. Abstract

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.

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. Abstract

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.

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. Abstract

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.

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. Abstract

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.

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. Abstract

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.

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. Abstract

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.

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):956-63. Abstract

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.

Rahnev, D, Koizumi A, McCurdy LY, D'Esposito M, Lau H.  2015.  Confidence Leak in Perceptual Decision Making., 2015 Sep 25. Psychological science. Abstract

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.

2016
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. Abstract

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 Abstract

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. Abstract

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.

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. Abstract

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.

Peters, J, D'Esposito M.  2016.  Effects of Medial Orbitofrontal Cortex Lesions on Self-Control in Intertemporal Choice., 2016 Aug 31. Current biology : CB. Abstract

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.

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. Abstract

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.

Cohen, JR, D'Esposito M.  2016.  The Segregation and Integration of Distinct Brain Networks and Their Relationship to Cognition., 2016 Nov 30. The Journal of neuroscience : the official journal of the Society for Neuroscience. 36(48):12083-12094. Abstract

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.

Nee, DE, D'Esposito M.  2016.  The Representational Basis of Working Memory., 2016 Sep 28. Current topics in behavioral neurosciences. Abstract

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.

2017
Hwang, K, Bertolero M, Liu W, D'Esposito M.  2017.  The human thalamus is an integrative hub for functional brain networks., 2017 Apr 27. The Journal of neuroscience : the official journal of the Society for Neuroscience. Abstract

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.

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 : official publication of the American College of Neuropsychopharmacology. Abstract

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.

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. The Journal of neuroscience : the official journal of the Society for Neuroscience. Abstract

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.

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. :1545968317728580. Abstract

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.

Nee, DE, D'Esposito M.  2017.  Causal evidence for lateral prefrontal cortex dynamics supporting cognitive control., 2017 Sep 13. eLife. 6 Abstract

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.