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There is increasing evidence that the left lateral frontal cortex is hierarchically organized such that higher-order regions have an asymmetric top-down influence over lower order regions. However, questions remain about the underlying neuroarchitecture of this hierarchical control organization. Within the frontal cortex, dopamine plays an important role in cognitive control functions, and we hypothesized that dopamine may preferentially influence top-down connections within the lateral frontal hierarchy. Using a randomized, double-blind, within-subject design, we analyzed resting-state fMRI data of 66 healthy young participants who were scanned once each after administration of bromocriptine (a dopamine agonist with preferential affinity for D2 receptor), tolcapone (an inhibitor of catechol-O-methyltransferase), and placebo, to determine whether dopaminergic stimulation modulated effective functional connectivity between hierarchically organized frontal regions in the left hemisphere. We found that dopaminergic drugs modulated connections from the caudal middle frontal gyrus and the inferior frontal sulcus to both rostral and caudal frontal areas. In dorsal frontal regions, effectivity connectivity strength was increased, whereas in ventral frontal regions, effective connectivity strength was decreased. These findings suggest that connections within frontal cortex are differentially modulated by dopamine, which may bias the influence that frontal regions exert over each other., (© 2023 Massachusetts Institute of Technology.)

Cognitive control is the ability to flexibly adapt behavior in a goal-directed manner when habit will not suffice. Control can be separated into distinct forms based on the timescale (present-future) and/or medium (external-internal) over which it operates. Both the frontoparietal network (FPN) and cingulo-opercular network (CON) are engaged during control, but their respective functions and interactions remain unclear. Here, we examined activations in the FPN and CON with fMRI in humans (male and female) during a task that manipulated control across timescales/mediums. The findings show that the CON can be distinguished into the following two separable subnetworks mirroring the FPN: a rostral/ventral subnetwork sensitive to future-oriented control involving internal representations, and a caudal/dorsal subnetwork sensitive to present-oriented control involving external representations. Relative to the FPN, activation in the CON was particularly pronounced during transitions into and out of particular control demands. Moreover, the relationship of each CON subnetwork to behavior was mediated by a respective FPN subnetwork. Such data are consistent with the idea that the CON motivates the FPN, which, in turn, drives behavior. Within the CON, the dorsomedial prefrontal cortex (dmPFC) mediated the relationship between the anterior insula and FPN, suggesting that the dmPFC acts as the crux that links the CON to the FPN. Collectively, these data indicate that parallel CON-FPN subnetworks mediate controlled behaviors at distinct timescales/mediums. SIGNIFICANCE STATEMENT The cingulo-opercular network (CON) and frontoparietal network (FPN) are engaged in diverse, demanding tasks. A functional model describing how areas within these networks can be distinguished, and also interact, would facilitate understanding of how the brain adapts to demanding situations. During a comprehensive control task, fMRI data revealed that the FPN and CON can be fractionated into subnetworks based on control demands that are either externally oriented for use in the present, or control demands that operate internally to guide future behavior. Moreover, we found evidence for a chain of relationships from the CON to FPN to behavior consistent with the idea that the CON drives the FPN to adapt behavior., (Copyright © 2023 the authors.)

Cognitive control guides non-habitual, goal directed behaviors allowing us to flexibly adapt to ongoing demands. Previous work has suggested that multiple cognitive control processes exist that can be classed according to their action on present-oriented/external information versus future-oriented/internal information. These processes can be mapped onto the lateral prefrontal cortex (LPFC) such that increasingly rostral areas are involved in increasingly future-oriented/internal control processes. Whether and how such processes are organized to support goal-directed behavior remains unclear. On the one hand, the LPFC may flexibly adapt based upon demands. On the other hand, there may be a consistent control architecture such as a control hierarchy that generalizes across demands. Previous work using fMRI in humans during a comprehensive control task that engaged several control processes at once found that an area in mid-LPFC consistently exerted widespread influence throughout the LPFC. These data suggested that the mid-LPFC forms an apex of a putative control hierarchy. However, whether such an architecture generalizes across tasks remains to be tested. Here, we utilized a modified comprehensive control task designed to alter how control processes influence one another to test the generalizability of the LPFC control architecture. Univariate fMRI activations revealed distinct control-related activations relative to past work. Despite these changes, effective connectivity modeling revealed a directed architecture similar to previous findings with the mid-LPFC exerting the most widespread influences throughout LPFC. These results suggest that the fundamental control architecture of the LPFC is relatively fixed, and that different demands are accommodated through modulations of this fixed architecture., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: The reward circuit is important for motivation and learning, and dysregulations of the reward circuit are prominent in anhedonic depression. Noninvasive interventions that can selectively target the reward circuit may hold promise for the treatment of anhedonia., Methods: We tested a novel transcranial magnetic stimulation intervention for modulating the reward circuit. A total of 35 healthy individuals participated in a crossover controlled study targeting the reward circuit or a control site with intermittent theta burst stimulation (iTBS), an excitatory form of transcranial magnetic stimulation. Individual reward circuit targets were defined based upon functional magnetic resonance imaging functional connectivity with the ventral striatum, yielding targets in the rostromedial prefrontal cortex (rmPFC). Reward circuit function was assessed at baseline using functional magnetic resonance imaging, and reward circuit modulation was assessed using an event-related potential referred to as the reward positivity, which has been shown to reliably track reward sensitivity, as well as individual differences in depression and risk for depression., Results: Relative to control iTBS, rmPFC iTBS enhanced the reward positivity. This effect was moderated by reward function, suggesting greater enhancements in individuals with lower reward function. This effect was also moderated by rmPFC-ventral striatum connectivity insofar as iTBS reached the rmPFC, suggesting that efficacy relies jointly on the strength of the rmPFC-ventral striatum pathway and ability of transcranial magnetic stimulation to target the rmPFC., Conclusions: These data suggest that the reward circuit can be modulated by rmPFC iTBS, and amenability to such modulations is related to measures of reward circuit function. This provides the first step toward a novel noninvasive treatment of disorders of the reward circuit., (Copyright © 2022 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Working memory (WM) is the ability to maintain and manipulate internal representations. WM recruits varying brain regions based on task demands. Although the hippocampus has historically been associated with long-term memory (LTM), several studies provide evidence for its involvement during WM tasks. Slotnick (this issue) posits that this involvement is due to LTM processes. This argument rests on the assumption that processes are not shared among WM and LTM, and that WM processes are necessarily sustained. We argue that there are processes utilized by both WM and LTM, and that such processes need not be sustained to support WM.

Coordinating among the demands of the external environment and internal plans requires cognitive control supported by a fronto-parietal control network (FPCN). Evidence suggests that multiple control systems span the FPCN whose operations are poorly understood. Previously (Nee and D'Esposito, 2016; 2017), we detailed frontal dynamics that support control processing, but left open their role in broader cortical function. Here, I show that the FPCN consists of an external/present-oriented to internal/future-oriented cortical gradient extending outwardly from sensory-motor cortices. Areas at the ends of this gradient act in a segregative manner, exciting areas at the same level, but suppressing areas at different levels. By contrast, areas in the middle of the gradient excite areas at all levels, promoting integration of control processing. Individual differences in integrative dynamics predict higher level cognitive ability and amenability to neuromodulation. These data suggest that an intermediary zone within the FPCN underlies integrative processing that supports cognitive control., Competing Interests: DN No competing interests declared, (© 2021, Nee.)

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.

In non-habitual situations, cognitive control aligns actions with both short- and long-term goals. The capacity for cognitive control is tightly tied to the prefrontal cortex, whose expansion in humans relative to other species is thought to support our superior cognitive control. However, the posterolateral cerebellum has also expanded greatly relative to non-human primates and has an organizational structure that mirrors the prefrontal cortex. Nevertheless, cerebellar contributions to cognitive control are poorly understood. Here, we sought to explore whether a functional hierarchical processing framework, applied to the cerebellum, could elucidate cerebellar contributions to cognitive control. Using functional magnetic resonance imaging, we show that a gradient within the posterolateral cerebellum supports cognitive control with motor-adjacent cerebellar sub-regions supporting control of concrete, proximal actions and motor-distal, cerebellar sub-regions supporting abstract, future processing. This gradient was functionally hierarchical, with regions higher in the hierarchy influencing the relationship between regions lower in the hierarchy. This functional hierarchy provides the infrastructure by which context can inform current actions and prepare for future goals. Crucially, this mirrors the hierarchical organization of cognitive control within the prefrontal cortex. Based on these findings, we propose that the cerebellum contains within itself a parallel but separate hierarchical organization that, along with the prefrontal cortex, supports complex cognition., Competing Interests: Declaration of Interests The authors declare no competing interests., (Copyright © 2020 Elsevier Inc. All rights reserved.)

This meta-analysis aims to evaluate whether the extant literature justifies any definitive conclusions about whether and how SITBs may be associated with brain differences. A total of 77 papers (N = 4,903) published through January 1, 2019 that compared individuals with and without SITBs were included, resulting in 882 coordinates. A pooled meta-analysis assessing for general risk for SITBs indicated a lack of convergence on structural differences. When all types of control groups were considered, functional differences in the left posterior cingulate cortex (PCC), right amygdala, left hippocampus, and right thalamus were significant using multi-level kernel density analysis (p corrected  < 0.05) but nonsignificant using activation-likelihood estimation. These results suggest that a propensity for internally-oriented, emotional processing coupled with under-active pain processing could potentially underlie SITBs, but additional research is needed to test this possibility. Separate analyses for types of SITBs suggested that the brain differences associated with deliberate self-harm were consistent with the overall findings. Checkered moderator effects were detected. Overall, the meta-analytic evidence was not robust. More studies are needed to reach definitive conclusions about whether SITBs are associated with brain differences.

Competing Interests: The author declares no competing interests.

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. These 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.

Any mature field of research in psychology-such as short-term/working memory-is characterized by a wealth of empirical findings. It is currently unrealistic to expect a theory to explain them all; theorists must satisfice with explaining a subset of findings. The aim of the present article is to make the choice of that subset less arbitrary and idiosyncratic than is current practice. We propose criteria for identifying benchmark findings that every theory in a field should be able to explain: Benchmarks should be reproducible, generalize across materials and methodological variations, and be theoretically informative. We propose a set of benchmarks for theories and computational models of short-term and working memory. The benchmarks are described in as theory-neutral a way as possible, so that they can serve as empirical common ground for competing theoretical approaches. Benchmarks are rated on three levels according to their priority for explanation. Selection and ratings of the benchmarks is based on consensus among the authors, who jointly represent a broad range of theoretical perspectives on working memory, and they are supported by a survey among other experts on working memory. The article is accompanied by a web page providing an open forum for discussion and for submitting proposals for new benchmarks; and a repository for reference data sets for each benchmark. (PsycINFO Database Record, ((c) 2018 APA, all rights reserved).)

We respond to the comments of Logie and Vandierendonck to our article proposing benchmark findings for evaluating theories and models of short-term and working memory. The response focuses on the two main points of criticism: (a) Logie and Vandierendonck argue that the scope of the set of benchmarks is too narrow. We explain why findings on how working memory is used in complex cognition, findings on executive functions, and findings from neuropsychological case studies are currently not included in the benchmarks, and why findings with visual and spatial materials are less prevalent among them. (b) The critics question the usefulness of the benchmarks and their ratings for advancing theory development. We explain why selecting and rating benchmarks is important and justifiable, and acknowledge that the present selection and rating decisions are in need of continuous updating. The usefulness of the benchmarks of all ratings is also enhanced by our concomitant online posting of data for many of these benchmarks. (PsycINFO Database Record, ((c) 2018 APA, all rights reserved).)

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 used a functional magnetic resonance imaging 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 they suggest a dynamic tradeoff between visual and parietal regions that allows flexible adaptation to task demands in service of VWM. SIGNIFICANCE STATEMENT 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. Although 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., (Copyright © 2018 the authors 0270-6474/18/385267-10$15.00/0.)

Objective: Declines in working memory are a ubiquitous finding within the cognitive-aging literature. A unitary inhibitory selection mechanism that serves to guide attention toward task-relevant information and resolve interference from task-irrelevant information has been proposed to underlie such deficits. However, inhibition can occur at multiple time points in the memory-processing stream. Here, we tested whether the time point at which inhibition occurs in the memory-processing stream affects age-related memory decline., Method: Clinically healthy younger (n = 23) and older (n = 22) adults performed two similar item-recognition working memory tasks. In one task, participants received an instruction cue telling them which words to attend to followed by a memory set, promoting perceptual inhibition at the time of encoding. In the other task, participants received the instruction cue after they received the memory set, fostering inhibition of items already in memory., Results: We found that older and younger adults differed in their ability to inhibit items both during encoding and when items had to be inhibited in memory but that these age differences were exaggerated when irrelevant information had to be inhibited from memory. These results provide insights into the mechanisms that support cognitive changes to memory processes in healthy aging.

The frontal lobes are important for cognitive control, yet their functional organization remains controversial. An influential class of theory proposes that the frontal lobes are organized along their rostrocaudal axis to support hierarchical cognitive control. Here, we take an updated look at the literature on hierarchical control, with particular focus on the functional organization of lateral frontal cortex. Our review of the evidence supports neither a unitary model of lateral frontal function nor a unidimensional abstraction gradient. Rather, separate frontal networks interact via local and global hierarchical structure to support diverse task demands., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

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.

The lateral prefrontal cortex (LPFC) is essential for higher-level cognition, but the nature of its interactions in supporting 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 test this model causally. 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 that are 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.

Working memory (WM) is a cognitive system responsible for actively maintaining and processing relevant information and is central to successful cognition. A process critical to WM is the resolution of proactive interference (PI), which involves suppressing memory intrusions from prior memories that are no longer relevant. Most studies that have examined resistance to PI in a process-pure fashion used verbal material. By contrast, studies using non-verbal material are scarce, and it remains unclear whether the effect of PI is domain-general or whether it applies solely to the verbal domain. The aim of the present study was to examine the effect of PI in visual WM using both objects with high and low nameability. Using a Directed-Forgetting paradigm, we varied discriminability between WM items on two dimensions, one verbal (high-nameability vs. low-nameability objects) and one perceptual (colored vs. gray objects). As in previous studies using verbal material, effects of PI were found with object stimuli, even after controlling for verbal labels being used (i.e., low-nameability condition). We also found that the addition of distinctive features (color, verbal label) increased performance in rejecting intrusion probes, most likely through an increase in discriminability between content-context bindings in WM.

Neuroimaging studies of the medial prefrontal cortex (mPFC) suggest that the dorsal anterior cingulate cortex (dACC) region is responsive to a wide variety of stimuli and psychological states, such as pain, cognitive control, and prediction error (PE). In contrast, a recent meta-analysis argues that the dACC is selective for pain, whereas the supplementary motor area (SMA) and pre-SMA are specifically associated with higher-level cognitive processes (Lieberman and Eisenberger, 2015). To empirically test this claim, we manipulated effects of pain, conflict, and PE in a single experiment using human subjects. We observed a robust dorsal-ventral dissociation within the mPFC with cognitive effects of PE and conflict overlapping dorsally and pain localized more ventrally. Classification of subjects based on the presence or absence of a paracingulate sulcus showed that PE effects extended across the dorsal area of the dACC and into the pre-SMA. These results begin to resolve recent controversies by showing the following: (1) the mPFC includes dissociable regions for pain and cognitive processing; and (2) meta-analyses are correct in localizing cognitive effects to the dACC, although these effects extend to the pre-SMA as well. These results both provide evidence distinguishing between different theories of mPFC function and highlight the importance of taking individual anatomical variability into account when conducting empirical studies of the mPFC., Significance Statement: Decades of neuroimaging research have shown the mPFC to represent a wide variety of stimulus processing and cognitive states. However, recently it has been argued whether distinct regions of the mPFC separately process pain and cognitive phenomena. To address this controversy, this study directly compared pain and cognitive processes within subjects. We found a double dissociation within the mPFC with pain localized ventral to the cingulate sulcus and cognitive effects localized more dorsally within the dACC and spreading into the pre-supplementary motor area. This provides empirical evidence to help resolve the current debate about the functional architecture of the mPFC., (Copyright © 2016 the authors 0270-6474/16/3612385-08$15.00/0.)

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.

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.

The functions of the prefrontal cortex (PFC) underlie higher-level cognition. Varying proposals suggest that the PFC is organized along a rostral-caudal gradient of abstraction with more abstract representations/processes associated with more rostral areas. However, the operational definition of abstraction is unclear. Here, we contrasted 2 prominent theories of abstraction--temporal and relational--using fMRI. We further examined whether integrating abstract rules--a function common to each theory--recruited the PFC independently of other abstraction effects. While robust effects of relational abstraction were present in the PFC, temporal abstraction effects were absent. Instead, we found activations specific to the integration of relational rules in areas previously shown to be associated with temporal abstraction. We suggest that previous effects of temporal abstraction were due to confounds with integration demands. We propose an integration framework to understand the functions of the PFC that resolves discrepancies in prior data., (© The Author 2013. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

A number of theories have been proposed to account for the role of anterior cingulate cortex (ACC) and the broader medial prefrontal cortex (mPFC) in cognition. The recent Prediction of Response Outcome (PRO) computational model casts the mPFC in part as performing two theoretically distinct functions: learning to predict the various possible outcomes of actions, and then evaluating those predictions against the actual outcomes. Simulations have shown that this new model can account for an unprecedented range of known mPFC effects, but the central theory of distinct prediction and evaluation mechanisms within ACC remains untested. Using combined computational neural modeling and fMRI, we show here that prediction and evaluation signals are indeed each represented in the ACC, and furthermore, they are represented in distinct regions within ACC. Our task independently manipulated both the number of predicted outcomes and the degree to which outcomes violated expectancies, the former providing assessment of regions sensitive to prediction and the latter providing assessment of regions sensitive to evaluation. Using quantitative regressors derived from the PRO computational model, we show that prediction-based model signals load on a network including the posterior and perigenual ACC, but outcome evaluation model signals load on the mid-dorsal ACC. These findings are consistent with distinct prediction and evaluation signals as posited by the PRO model and provide new perspective on a large set of known effects within ACC., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background: One of the most common deficits in patients with schizophrenia (SZ) is in working memory (WM), which has wide-reaching impacts across cognition. However, previous approaches to studying WM in SZ have used tasks that require multiple cognitive-control processes, making it difficult to determine which specific cognitive and neural processes underlie the WM impairment., Methods: We used functional magnetic resonance imaging to investigate component processes of WM in SZ. Eighteen healthy controls (HCs) and 18 patients with SZ performed an item-recognition task that permitted separate neural assessments of 1) WM maintenance, 2) inhibition, and 3) interference control in response to recognition probes., Results: Before inhibitory demands, posterior ventrolateral prefrontal cortex (VLPFC), an area involved in WM maintenance, was activated to a similar degree in both HCs and patients, indicating preserved maintenance operations in SZ. When cued to inhibit items from WM, HCs showed reduced activation in posterior VLPFC, commensurate with appropriately inhibiting items from WM. However, these inhibition-related reductions were absent in patients. When later probed with items that should have been inhibited, patients showed reduced behavioral performance and increased activation in mid-VLPFC, an area implicated in interference control. A mediation analysis indicated that impaired inhibition led to increased reliance on interference control and reduced behavioral performance., Conclusions: In SZ, impaired control over memory, manifested through proactive inhibitory deficits, leads to increased reliance on reactive interference-control processes. The strain on interference-control processes results in reduced behavioral performance. Thus, inhibitory deficits in SZ may underlie widespread impairments in WM and cognition., (© 2013 Society of Biological Psychiatry Published by Society of Biological Psychiatry All rights reserved.)

Short-term memory (STM), the brief maintenance of information in the absence of external stimulation, is central to higher-level cognition. Behavioral and neural data indicate that information maintained in STM can be represented in qualitatively distinct states. These states include a single chunk held in the focus of attention available for immediate processing (the "focus"), a capacity-limited set of additional actively maintained items that the focus can access (the "active state"), and passively maintained items (the "passive state"). Little is known about how information is shifted among these states. Here, we used fMRI in humans to examine the neural correlates of shifting information among representational states of STM. We used a paradigm that has demonstrated dissociable performance costs associated with shifting the focus among active items and switching sets of items between active and passive states. Behavioral results confirmed distinct behavioral costs associated with different representational states. Neural results indicated that the caudal superior frontal sulcus (cSFS), in the vicinity of the frontal eye fields, was associated with shifting the focus, consistent with the role of this region in internal and external attention. By contrast, the ventral premotor cortex (PMv) was associated with shifting between active and passive states. Increased cSFS-medial temporal lobe (MTL) connectivity was associated with shifting the focus, while cSFS-MTL connectivity was disrupted when the active state was changed. By contrast, PMv-MTL connectivity increased when the active state was switched. These data indicate that dissociable frontal-MTL interactions mediate shifts of information among different representational states in STM., (Copyright © 2014 the authors 0270-6474/14/347964-12$15.00/0.)

The ability to hold information briefly in mind in the absence of external stimulation forms the core of much of higher-order cognition. This ability is referred to as short-term memory (STM). However, single-term labels such as this belie the complexity of the underlying construct. Here, we review evidence that STM is an amalgamation of three qualitatively distinct states. We argue that these distinct states emerge from the combination of frontal selection mechanisms (often considered the domain of attention and cognitive control), medial temporal binding mechanisms (often considered the domain of long-term memory, LTM), and synaptic plasticity. These various contributions lead to a single representation amenable to elaborated processing (focus of attention), a limited set of active representations among which attention can be flexibly switched (direct-access region), and passive representations whose residual traces facilitate re-activation (activated LTM). We suggest that selection and binding mechanisms are typically engaged simultaneously, providing multiple forms and routes of short-term maintenance. We propose that such a framework can resolve discrepancies among recent studies that have attempted to understand the relationship between attention and STM on the one hand, and between LTM and STM on the other. We anticipate that recent advances in neuroimaging and neurophysiology will elucidate the mechanisms underlying shifts and transformations among these representational states, providing a window into the dynamic processes of higher-order cognition.

Recent theories propose that the prefrontal cortex (PFC) is organized in a hierarchical fashion with more abstract, higher level information represented in anterior regions and more concrete, lower level information represented in posterior regions. This hierarchical organization affords flexible adjustments of action plans based on the context. Computational models suggest that such hierarchical organization in the PFC is achieved through interactions with the basal ganglia (BG) wherein the BG gate relevant contexts into the PFC. Here, we tested this proposal using functional magnetic resonance imaging (fMRI). Participants were scanned while updating working memory (WM) with 2 levels of hierarchical contexts. Consistent with PFC abstraction proposals, higher level context updates involved anterior portions of the PFC (BA 46), whereas lower level context updates involved posterior portions of the PFC (BA 6). Computational models were only partially supported as the BG were sensitive to higher, but not lower level context updates. The posterior parietal cortex (PPC) showed the opposite pattern. Analyses examining changes in functional connectivity confirmed dissociable roles of the anterior PFC-BG during higher level context updates and posterior PFC-PPC during lower level context updates. These results suggest that hierarchical contexts are organized by distinct frontal-striatal and frontal-parietal networks.

Recent research has suggested that short-term memory (STM) can be partitioned into three distinct states. By this model, a single item is held in the focus of attention making it available for immediate processing (focus of attention), a capacity-limited set of additional items is actively maintained for future processing (direct access region), and other recently presented information is passively active, but can nevertheless influence ongoing cognition (activated portion of long-term memory). While there is both behavioral and neural support for this 3-state model in verbal STM, it is unclear whether the model generalizes to non-verbal STM. Here, we tested a 3-state model of visual STM using fMRI. We found a triple dissociation of regions involved in the access of each hypothesized state. The inferior parietal cortex mediated access to the focus of attention, the medial temporal lobe (MTL) including the hippocampus mediated access to the direct access region, and the left ventrolateral prefrontal cortex (VLPFC) mediated access to the activated portion of long-term memory. Direct comparison with previously collected verbal STM data revealed overlapping neural activations involved in the access of each state across different forms of content suggesting that mechanisms of access are domain general. These data support a 3-state model of STM., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Working memory (WM) enables the online maintenance and manipulation of information and is central to intelligent cognitive functioning. Much research has investigated executive processes of WM in order to understand the operations that make WM "work." However, there is yet little consensus regarding how executive processes of WM are organized. Here, we used quantitative meta-analysis to summarize data from 36 experiments that examined executive processes of WM. Experiments were categorized into 4 component functions central to WM: protecting WM from external distraction (distractor resistance), preventing irrelevant memories from intruding into WM (intrusion resistance), shifting attention within WM (shifting), and updating the contents of WM (updating). Data were also sorted by content (verbal, spatial, object). Meta-analytic results suggested that rather than dissociating into distinct functions, 2 separate frontal regions were recruited across diverse executive demands. One region was located dorsally in the caudal superior frontal sulcus and was especially sensitive to spatial content. The other was located laterally in the midlateral prefrontal cortex and showed sensitivity to nonspatial content. We propose that dorsal-"where"/ventral-"what" frameworks that have been applied to WM maintenance also apply to executive processes of WM. Hence, WM can largely be simplified to a dual selection model.

The lateral frontal cortex (LFC) is thought to represent contextual and rule-based information that allows adaptive behavior according to circumstance. Recent progress has suggested that the representations of the LFC vary along its rostral-caudal axis with more abstract, higher level representations associated with rostral areas of the LFC and more concrete, lower level representations associated with caudal areas of the LFC. Here, we investigated this proposal. Subjects responded to stimuli based upon a nested series of contextual cues stored in working memory (WM) while being scanned with fMRI. Higher level context cues denoted an abstract rule set while lower level context cues provided more concrete information. Using multi-variate pattern analysis (MVPA), we found varying forms of representation along the rostral-caudal axis of the LFC depending on the type of information stored in WM. Rostral areas of frontal cortex in the lateral orbitofrontal cortex (OFC) represented the higher level context, but not more concrete information, and only when more concrete information was unavailable. Mid-level areas in the mid-dorsolateral prefrontal cortex (DLPFC) and inferior frontal junction (IFJ) represented more concrete rules, but only when the forthcoming response could not be anticipated. By contrast, the dorsal premotor cortex (PMd) and primary motor cortex (M1) represented contextual and response information when the forthcoming response could be anticipated on the basis of context. Collectively, these data indicate that representations dedicated to higher levels of abstraction become less discriminating when more concrete information becomes available. These patterns are consistent with rostral-caudal abstraction proposals of the LFC., (Copyright © 2012 Elsevier Inc. All rights reserved.)

The sixth meeting of the Cognitive Neuroscience Treatment Research to Improve Cognition in Schizophrenia (CNTRICS) consortium was focused on selecting promising imaging biomarker measures for each of the cognitive constructs selected in the first CNTRICS meeting. In the domain of working memory (WM), the 2 constructs of interest were "goal maintenance" and "interference control." CNTRICS received 7 task nominations for goal maintenance and 3 task nominations for interference control. For goal maintenance, the breakout group for WM recommended the AX Continuous Performance Test/Dot Pattern Expectancy (DPX) and the Switching Stroop task for translation and further development for use in clinical trial contexts in schizophrenia research. Notably, these same 2 paradigms were recommended for "rule generation and selection" in executive control, a highly related construct. For interference control, the breakout group recommended the Suppress Task and the Sternberg Item Recognition Paradigm for translation for use in clinical trials. This manuscript describes the ways in which each of these tasks met the criteria used by the breakout group to recommend tasks for further development. In addition, the group revisited the construct of WM capacity. Since the initial CNTRICS meeting, a growing body of work has emerged on the neurobiological substrates of WM capacity, making measure of this construct ready for translation. The group suggested a promising imaging biomarker measure for capacity, a version of the change detection task that measures delay activity over posterior parietal and occipital cortex.

A key feature of human intelligence is the ability to predict the outcomes of one's own actions prior to executing them. Action values are thought to be represented in part in the dorsal and ventral medial prefrontal cortex (mPFC), yet current studies have focused on the value of executed actions rather than the anticipated value of a planned action. Thus, little is known about the neural basis of how individuals think (or fail to think) about their actions and the potential consequences before they act. We scanned individuals with fMRI while they thought about performing actions that they knew would likely be rewarded or unrewarded. Here we show that merely imagining an unrewarded action, as opposed to imagining a rewarded action, increases activity in the dorsal anterior cingulate cortex, independently of subsequent actions. This activity overlaps with regions that respond to actual unrewarded actions. The findings show a distinct network that signals the prospective outcomes of one's possible actions. A number of clinical disorders such as schizophrenia and drug abuse involve a failure to take the potential consequences of an action into account prior to acting. Our results thus suggest how dysfunctions of the mPFC may contribute to such failures.

Major depressive disorder (MDD) has been characterized by excessive default-network activation and connectivity with the subgenual cingulate. These hyper-connectivities are often interpreted as reflecting rumination, where MDDs perseverate on negative, self-referential thoughts. However, the relationship between connectivity and rumination has not been established. Furthermore, previous research has not examined how connectivity with the subgenual cingulate differs when individuals are engaged in a task or not. The purpose of the present study was to examine connectivity of the default network specifically in the subgenual cingulate both on- and off-task, and to examine the relationship between connectivity and rumination. Analyses using a seed-based connectivity approach revealed that MDDs show more neural functional connectivity between the posterior-cingulate cortex and the subgenual-cingulate cortex than healthy individuals during rest periods, but not during task engagement. Importantly, these rest-period connectivities correlated with behavioral measures of rumination and brooding, but not reflection.

Individuals diagnosed with major depressive disorder (MDD) often ruminate about their depression and their life situations, impairing their concentration and performance on daily tasks. We examined whether rumination might be due to a deficit in the ability to expel negative information from short-term memory (STM), and fMRI was used to examine the neural structures involved in this ability. MDD and healthy control (HC) participants were tested using a directed-forgetting procedure in a short-term item recognition task. As predicted, MDD participants had more difficulty than did HCs in expelling negative, but not positive, words from STM. Overall, the neural networks involved in directed forgetting were similar for both groups, but the MDDs exhibited more spatial variability in activation in the left inferior frontal gyrus (a region critical for inhibiting irrelevant information), which may contribute to their relative inability to inhibit negative information.

Behavioral research has yielded conflicting results regarding the architecture of short-term memory (STM). Whereas a consensus has emerged that within STM a single chunk within the focus of attention (FA) has a privileged status, it is unclear whether further distinctions exist. One proposal is that outside of FA, memory is all of one sort with a continuous progression from STM to long-term memory (LTM). On the other hand, sharp performance drop-offs when STM is loaded with more than 4±1 items suggest distinctions between STM and LTM. We use functional magnetic resonance imaging (fMRI) to adjudicate between these theories. A neural triple dissociation provided evidence for a 3-state model of memory. Critically, prefrontal cortex was selectively enhanced to retrieval from activated portions of LTM whereas the hippocampus was associated with retrieval of items within putative 4±1 capacity limits. We hypothesize that the associative properties of the hippocampus serve to inter-relate information actively maintained in STM which not only promotes strong STM, but also lays the foundations for subsequent LTM. By contrast, information not actively maintained in mind requires top-down retrieval processes mediated by the prefrontal cortex. These data provide key insights into the architecture of STM and its relationship to LTM., (Copyright © 2010 Elsevier Inc. All rights reserved.)

The last decade has seen considerable discussion regarding a theoretical account of medial prefrontal cortex (mPFC) function with particular focus on the anterior cingulate cortex. The proposed theories have included conflict detection, error likelihood prediction, volatility monitoring, and several distinct theories of error detection. Arguments for and against particular theories often treat mPFC as functionally homogeneous, or at least nearly so, despite some evidence for distinct functional subregions. Here we used functional magnetic resonance imaging (fMRI) to simultaneously contrast multiple effects of error, conflict, and task-switching that have been individually construed in support of various theories. We found overlapping yet functionally distinct subregions of mPFC, with activations related to dominant error, conflict, and task-switching effects successively found along a rostral-ventral to caudal-dorsal gradient within medial prefrontal cortex. Activations in the rostral cingulate zone (RCZ) were strongly correlated with the unexpectedness of outcomes suggesting a role in outcome prediction and preparing control systems to deal with anticipated outcomes. The results as a whole support a resolution of some ongoing debates in that distinct theories may each pertain to corresponding distinct yet overlapping subregions of mPFC., (Copyright © 2010 Elsevier Inc. All rights reserved.)

In two experiments, we investigated individual differences in the ability to resolve interference in participants diagnosed with major depressive disorder (MDD). Participants were administered the "Ignore/Suppress" task, a short-term memory task composed of two steps. In Step 1 ("ignore"), participants were instructed to memorize a set of stimuli while ignoring simultaneously presented irrelevant material. In Step 2 ("suppress"), participants were instructed to forget a subset of the previously memorized material. The ability to resolve interference was indexed by response latencies on two recognition tasks in which participants decided whether a probe was a member of the target set. In Step 1, we compared response latencies to probes from the to-be-ignored list with response latencies to nonrecently presented items. In Step 2, we compared response latencies to probes from the to-be-suppressed list with response latencies to nonrecently presented items. The results indicate that, compared with control participants, depressed participants exhibited increased interference in the "suppress" but not in the "ignore" step of the task, when the stimuli were negative words. No group differences were obtained when we presented letters instead of emotional words. These findings indicate that depression is associated with difficulty in removing irrelevant negative material from short-term memory.

The aim of this article is to develop a spatial model for multi-subject fMRI data. There has been extensive work on univariate modeling of each voxel for single and multi-subject data, some work on spatial modeling of single-subject data, and some recent work on spatial modeling of multi-subject data. However, there has been no work on spatial models that explicitly account for inter-subject variability in activation locations. In this article, we use the idea of activation centers and model the inter-subject variability in activation locations directly. Our model is specified in a Bayesian hierarchical framework which allows us to draw inferences at all levels: the population level, the individual level, and the voxel level. We use Gaussian mixtures for the probability that an individual has a particular activation. This helps answer an important question that is not addressed by any of the previous methods: What proportion of subjects had a significant activity in a given region. Our approach incorporates the unknown number of mixture components into the model as a parameter whose posterior distribution is estimated by reversible jump Markov chain Monte Carlo. We demonstrate our method with a fMRI study of resolving proactive interference and show dramatically better precision of localization with our method relative to the standard mass-univariate method. Although we are motivated by fMRI data, this model could easily be modified to handle other types of imaging data.

The ability to mitigate interference is of central importance to cognition. Previous research has provided conflicting accounts about whether operations that resolve interference are singular in character or form a family of functions. Here, the authors examined the relationship between interference-resolution processes acting on working memory representations versus responses. The authors combined multiple forms of interference into a single paradigm by merging a directed-forgetting task, which induces proactive interference, with a stop-signal task, which taps response inhibition processes. The results demonstrated that proactive interference and response inhibition produced distinct behavioral signatures that did not interact. By contrast, combining two different measures of response inhibition by merging a go/no-go task variant and a stop signal produced overadditive behavioral interference, demonstrating that different forms of response inhibition tap the same processes. However, not all forms of response conflict interacted, suggesting that inhibition-related functions acting on response selection are dissociable from those acting on response inhibition. These results suggest that inhibition-related functions for memory and responses are dissociable., ((c) 2009 APA, all rights reserved.)

A critical aspect of cognitive control is the ability to select goal-relevant information in the face of competing distraction. A popular account is that common top-down selection processes underlie the ability to select among competing percepts and memories. We test the degree to which selective attention and memorial selection recruit the same neural resources. We demonstrate that both functions elicit largely overlapping networks within the dorsolateral prefrontal cortex (DLPFC), frontal eye fields (FEF), premotor cortex, and superior parietal lobule (SPL). Despite the close commonalities of selective attention and memorial selection, our results demonstrate that the SPL and FEF show preferential involvement in selective attention, whereas left ventrolateral prefrontal cortex (VLPFC) is uniquely associated with memorial selection. Thus, the two sorts of selection are not identical. We show further that variations in shared selection circuits are associated with differences in behavioral performance, suggesting that economy of control is beneficial to performance.

The third meeting of the Cognitive Neuroscience Treatment Research to Improve Cognition in Schizophrenia (CNTRICS) was focused on selecting promising measures for each of the cognitive constructs selected in the first CNTRICS meeting. In the domain of working memory, the 2 constructs of interest were goal maintenance and interference control. CNTRICS received 3 task nominations for each of these constructs, and the breakout group for working memory evaluated the degree to which each of these tasks met prespecified criteria. For goal maintenance, the breakout group for working memory recommended the AX-Continuous Performance Task/Dot Pattern Expectancy task for translation for use in clinical trial contexts in schizophrenia research. For interference control, the breakout group recommended the recent probes and operation/symmetry span tasks for translation for use in clinical trials. This article describes the ways in which each of these tasks met the criteria used by the breakout group to recommend tasks for further development.

Behavioral research has led to the view that items in short-term memory can be parsed into two categories: a single item in the focus of attention that is available for immediate cognitive processing and a small set of other items that are in a heightened state of activation but require retrieval for further use. We examined this distinction by using an item-recognition task. The results show that the item in the focus of attention is represented by increased activation in inferior temporal representational cortices relative to other information in short-term memory. Functional connectivity analyses suggest that activation of these inferior temporal regions is maintained via frontal- and posterior-parietal contributions. By contrast, other items in short-term memory demand retrieval mechanisms that are represented by increased activation in the medial temporal lobe and left mid-ventrolateral prefrontal cortex. These results show that there are two distinctly different sorts of access to information in short-term memory, and that access by retrieval operations makes use of neural machinery similar to that used in long-term memory retrieval.

Control over interference is a pervasive feature of cognitive life. Central to research on interference control has been the identification of its underlying mechanisms. Investigations have focused on processes that filter out distracting perceptual information, leading to negative priming, and processes that discard intruding memories that cause proactive interference. Theories differ regarding whether or not a single process during episodic retrieval underlies both negative priming and the resolution of proactive interference. Using functional magnetic resonance imaging, we combined both phenomena into a single paradigm and found that occipital cortex shows activation uniquely related to negative priming, whereas activation increases in left lateral prefrontal cortex are uniquely associated with proactive interference. This pattern of results contradicts theories that rely on a single process to account for both phenomena. However, results also showed common recruitment of right dorsolateral prefrontal cortex and parietal regions and therefore suggest that some control processes are shared.

What have neuroscientific techniques contributed to the development of psychological theory about short- and long-term memory? We argue that the contributions have been varied: In some cases, data about brain mechanisms have been vital to the advancement of psychological theory; in other cases, neuroscientific data and behavioral data from normal participants have made equal contributions; and in yet other cases, the data from neuroscientific approaches have actually led psychological theory astray. We illustrate these various contributions by focusing on the relationship of short- to long-term memory.