Cingulo-Opercular Subnetworks Motivate Frontoparietal Subnetworks during Distinct Cognitive Control Demands.

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.

Hippocampal activity supporting working memory is contingent upon specific task demands.

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.

Generalizing the control architecture of the lateral prefrontal cortex.

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.

Manipulating Reward Sensitivity Using Reward Circuit-Targeted Transcranial Magnetic Stimulation.

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.

Integrative frontal-parietal dynamics supporting cognitive control.

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.

Evidence for Hierarchical Cognitive Control in the Human Cerebellum.

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.

Benchmarks for models of short-term and working memory.

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

Benchmarks provide common ground for model development: Reply to Logie (2018) and Vandierendonck (2018).

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

Hippocampal-targeted Theta-burst Stimulation Enhances Associative Memory Formation.

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.

The Representational Basis of Working Memory.

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.

Frontal Cortex and the Hierarchical Control of Behavior.

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.

Causal evidence for lateral prefrontal cortex dynamics supporting cognitive control.

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.

Distinct Regions within Medial Prefrontal Cortex Process Pain and Cognition.

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.

Causal evidence for frontal cortex organization for perceptual decision making.

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.

The hierarchical organization of the lateral prefrontal cortex.

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.

Frontal-medial temporal interactions mediate transitions among representational states in short-term memory.

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.

Distinct regions of anterior cingulate cortex signal prediction and outcome evaluation.

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.

Prefrontal cortex organization: dissociating effects of temporal abstraction, relational abstraction, and integration with FMRI.

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.

Neural correlates of impaired cognitive control over working memory in schizophrenia.

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.