Anatomical Connectivity Constrains Dynamic Functional Connectivity among Neural Systems: Implications for Cognition and Behavior.

Leslie Ungerleider had a tremendous impact across many different areas of cognitive neuroscience. Her ideas and her approach, as well as her findings, will continue to impact the field for generations to come. One of the most impactful aspects of her approach was her focus on the ways that anatomical connections constrain functional communications among brain regions. Furthermore, she emphasized that changes in these functional communications, whether from lesions to the anatomical connections or temporary modulations of the efficacy of information transmission resulting from selective attention, have consequences for cognition and behavior. By necessity, this short review cannot cover the vast amount of research that contributed to or benefited from Leslie's work. Rather, we focus on one line of research that grew directly from some of Leslie's early work and her mentoring on these important concepts. This research and the many other lines of research that arose from these same origins has helped develop our understanding of the visual system, and cognitive systems more generally, as collections of highly organized, specialized, dynamic, and interacting subsystems.

Spontaneous Fluctuations in the Flexible Control of Covert Attention.

Spontaneous fluctuations in cognitive flexibility are characterized by moment-to-moment changes in the efficacy of control over attentional shifts. We used fMRI to investigate the neural correlates in humans of spontaneous fluctuations in readiness to covertly shift attention between two peripheral rapid serial visual presentation streams. Target detection response time (RT) after a shift or hold of covert spatial attention served as a behavioral index of fluctuations in attentional flexibility. In particular, the cost associated with shifting attention compared with holding attention varied as a function of pretrial brain activity in key regions of the default mode network (DMN), but not the dorsal attention network. High pretrial activity within the DMN was associated with a greater increase in shift trial RT relative to hold trial RT, revealing that these areas are associated with a state of attentional stability. Conversely, high pretrial activity within bilateral anterior insula and the presupplementary motor area/supplementary motor area was associated with a greater decrease in shift trial RT relative to hold trial RT, reflecting increased flexibility. Our results importantly clarify the roles of the precuneus, medial prefrontal cortex, and lateral parietal cortex, indicating that reduced activity may not simply indicate greater task engagement, but also, specifically, a readiness to update the focus of attention. Investigation of the neural correlates of spontaneous changes in attentional flexibility may contribute to our understanding of disorders of cognitive control as well as healthy variability in the control of spatial attention. SIGNIFICANCE STATEMENT: Individuals regularly experience fluctuations in preparatory cognitive control that affect performance in everyday life. For example, individuals are able to more quickly initiate a spatial shift of attention at some moments than at others. The current study revealed that pretrial brain activity in specific cortical regions predicted trial-by-trial changes in participants' abilities to flexibly shift the focus of attention. Intrinsically generated fluctuations in brain activity within several key default mode network regions, as well as within the anterior insula and presupplementary/supplementary motor areas, carried behavioral consequences for preparatory attentional control beyond lapses of attentional engagement. Our results are the first to link intrinsic variation in pretrial brain activity to moment-by-moment changes in preparatory attentional control over spatial selection.

Linking dopaminergic reward signals to the development of attentional bias: A positron emission tomographic study.

The attention system is shaped by reward history, such that learned reward cues involuntarily draw attention. Recent research has begun to uncover the neural mechanisms by which learned reward cues compete for attention, implicating dopamine (DA) signaling within the dorsal striatum. How these elevated priority signals develop in the brain during the course of learning is less well understood, as is the relationship between value-based attention and the experience of reward during learning. We hypothesized that the magnitude of the striatal DA response to reward during learning contributes to the development of a learned attentional bias towards the cue that predicted it, and examined this hypothesis using positron emission tomography with [11C]raclopride. We measured changes in dopamine release for rewarded versus unrewarded visual search for color-defined targets as indicated by the density and distribution of the available D2/D3 receptors. We then tested for correlations of individual differences in this measure of reward-related DA release to individual differences in the degree to which previously reward-associated but currently task-irrelevant stimuli impair performance in an attention task (i.e., value-driven attentional bias), revealing a significant relationship in the right anterior caudate. The degree to which reward-related DA release was right hemisphere lateralized was also predictive of later attentional bias. Our findings provide support for the hypothesis that value-driven attentional bias can be predicted from reward-related DA release during learning.

Density of available striatal dopamine receptors predicts trait impulsiveness during performance of an attention-demanding task.

The density (measured at binding potential) of available striatal D2/D3 receptors has been shown to predict trait impulsiveness. This relationship is highly robust and well replicated. In each case, however, the availability of dopamine receptors was measured at rest. More broadly, the extent to which relationships between dopamine receptor availability and behavioral traits hold when participants perform a cognitive task is unclear. Furthermore, the performance of a cognitive task engages fundamentally different neural networks than are maximally engaged during the resting state. This complicates interpretation of previously observed correlations, which could be influenced by two distinct factors. The first is variation in available receptor density, which reflects a stable trait of the individual. The second is variation in context-specific dopamine release, which differentially displaces some dopamine radiotracers (such as raclopride) across individuals. Using an existing data set, we related trait impulsiveness, as measured using the Barratt Impulsiveness Scale (BIS-11), to the density (binding potential) of available striatal D2/D3 receptors as measured using positron emission tomography (PET) with [11C]raclopride. Importantly, the PET scan was completed while participants performed an attention-demanding visual search task. We replicate robust correlations between this measure of receptor availability and trait impulsiveness previously demonstrated during the resting state, extending this relationship to periods of active task engagement. Our results support the idea that this relationship depends on striatal D2/D3 receptor density and not on context-dependent dopamine release.NEW & NOTEWORTHY Several studies have demonstrated a relationship between the density of available striatal D2/D3 receptors and trait impulsiveness. However, in each case, the availability of dopamine receptors was measured during the resting state. This complicates interpretation of previously observed correlations, which could be influenced by either stable variation in receptor density or context-dependent dopamine release. We present evidence uniquely consistent with the former interpretation, providing clarity to the nature of this brain-behavior relationship.

The role of alpha oscillations in deriving and maintaining spatial relations in working memory.

Previous research has demonstrated distinct neural correlates for maintenance of abstract, relational versus concrete, sensory information in working memory (WM). Storage of spatial relations in WM results in suppression of posterior sensory regions, which suggests that sensory information is task-irrelevant when relational representations are maintained in WM. However, the neural mechanisms by which abstract representations are derived from sensory information remain unclear. Here, using electroencephalography, we investigated the role of alpha oscillations in deriving spatial relations from a sensory stimulus and maintaining them in WM. Participants encoded two locations into WM, then after an initial maintenance period, a cue indicated whether to convert the spatial information to another sensory representation or to a relational representation. Results revealed that alpha power increased over posterior electrodes when sensory information was converted to a relational representation, but not when the information was converted to another sensory representation. Further, alpha phase synchrony between posterior and frontal regions increased for relational compared to sensory trials during the maintenance period. These results demonstrate that maintaining spatial relations and locations in WM rely on distinct neural oscillatory patterns.

A signal detection theory analysis of behavioral pattern separation paradigms.

Behavioral pattern separation (BPS) paradigms ask participants to discriminate previously encoded (old) stimuli from highly similar (lure) and categorically distinct (novel) stimuli. The lure-old discrimination, thought to uniquely reflect pattern separation in the hippocampal formation, is typically pitted against the traditional novel-old discrimination. However, BPS paradigms have measured lure-old discrimination neither consistently across studies nor in such a way that allows for accurate comparison to novel-old discrimination. Therefore, we advocate for signal detection theory (SDT) as a unified framework. Moreover, we compare SDT with previously used measures of lure-old discrimination, indicating how other formulas' inaccuracies can lead to erroneous conclusions.

Maintenance of relational information in working memory leads to suppression of the sensory cortex.

Working memory (WM) for sensory-based information about individual objects and their locations appears to involve interactions between lateral prefrontal and sensory cortexes. The mechanisms and representations for maintenance of more abstract, nonsensory information in WM are unknown, particularly whether such actively maintained information can become independent of the sensory information from which it was derived. Previous studies of WM for individual visual items found increased electroencephalogram (EEG) alpha (8-13 Hz) power over posterior electrode sites, which appears to correspond to the suppression of cortical areas that represent irrelevant sensory information. Here, we recorded EEG while participants performed a visual WM task that involved maintaining either concrete spatial coordinates or abstract relational information. Maintenance of relational information resulted in higher alpha power in posterior electrodes. Furthermore, lateralization of alpha power due to a covert shift of attention to one visual hemifield was marginally weaker during storage of relational information than during storage of concrete information. These results suggest that abstract relational information is maintained in WM differently from concrete, sensory representations and that during maintenance of abstract information, posterior sensory regions become task irrelevant and are thus suppressed.

Development of orthogonal task designs in fMRI studies of higher cognition: the NIMH experience.

This paper chronicles one researcher's journey at the National Institute of Mental Health, exploring ways to understand the neural systems responsible for the cognitive sub-processes of working memory tasks. Both the opportunities and the pitfalls with applying the idea of cognitive subtraction to neuroimaging data were well-known from studies using positron emission tomography. We took advantage of the improved temporal resolution of fMRI with a delayed-recognition task and identified the time-courses of the different stages of the task (encoding, memory delay, and recognition test) as predictor variables in a multiple regression analysis. Because these signals were temporally independent, individual components of tasks could be contrasted with one another, rather than entire tasks, reducing the problem of violations of pure insertion in cognitive subtraction. This approach enabled us to draw more detailed conclusions about the neural systems of higher cognition and the organization of prefrontal cortex than had been possible before fMRI. Further enhancements and innovations over the last 20 years by a multitude of researchers across the field have greatly expanded this knowledge, but this approach called "orthogonal task design" has remained a fundamental component of many of these modern studies.

Spatial relations and spatial locations are dissociated within prefrontal and parietal cortex.

Item-specific spatial information is essential for interacting with objects and for binding multiple features of an object together. Spatial relational information is necessary for implicit tasks such as recognizing objects or scenes from different views but also for explicit reasoning about space such as planning a route with a map and for other distinctively human traits such as tool construction. To better understand how the brain supports these two different kinds of information, we used functional MRI to directly contrast the neural encoding and maintenance of spatial relations with that for item locations in equivalent visual scenes. We found a double dissociation between the two: whereas item-specific processing implicates a frontoparietal attention network, including the superior frontal sulcus and intraparietal sulcus, relational processing preferentially recruits a cognitive control network, particularly lateral prefrontal cortex (PFC) and inferior parietal lobule. Moreover, pattern classification revealed that the actual meaning of the relation can be decoded within these same regions, most clearly in rostrolateral PFC, supporting a hierarchical, representational account of prefrontal organization.

'Working memory is a distributed dynamic process'.

I propose working memory be considered, not as a process for static maintenance in a particular set of brain regions, but rather as a dynamic process unfolding to serve future needs. Brain regions such as the hippocampus, or sensory and motor regions, may be necessarily recruited during this process, depending on task demands. Information stored in working memory is thus a distributed representation reflected in the structural and functional state of multiple brain areas and the trajectory of that state over time. Recent research is discussed in support of this view.

Object recognition in Williams syndrome: uneven ventral stream activation.

Williams syndrome (WS) is a genetic disorder associated with severe visuospatial deficits, relatively strong language skills, heightened social interest, and increased attention to faces. On the basis of the visuospatial deficits, this disorder has been characterized primarily as a deficit of the dorsal stream, the occipitoparietal brain regions that subserve visuospatial processing. However, some evidence indicates that this disorder may also affect the development of the ventral stream, the occipitotemporal cortical regions that subserve face and object recognition. The present studies examined ventral stream function in WS, with the hypothesis that faces would produce a relatively more mature pattern of ventral occipitotemporal activation, relative to other objects that are also represented across these visual areas. Using functional magnetic imaging, we compared activation patterns during viewing of human faces, cat faces, houses and shoes in individuals with WS (age 14-27), typically developing 6-9-year-olds (matched approximately on mental age), and typically developing 14-26-year-olds (matched on chronological age). Typically developing individuals exhibited changes in the pattern of activation over age, consistent with previous reports. The ventral stream topography of individuals with WS differed from both control groups, however, reflecting the same level of activation to face stimuli as chronological age matches, but less activation to house stimuli than either mental age or chronological age matches. We discuss the possible causes of this unusual topography and implications for understanding the behavioral profile of people with WS.

Understanding cognitive dysfunction in multiple sclerosis: integrating a first-person perspective with neuropsychological testing, neuroimaging, and cognitive neuroscience research.

This paper gives perspectives on a companion article, the case history of a professional writer who has multiple sclerosis. The patient's first-person account of her illness is combined with clinical summaries about her care. The discussion of this case illustrates the value of combining such subjective and objective reports in evaluating a patient. Furthermore, considering these reports in the context of current research findings on the organization and function of cognitive neural systems can shed light on patients' seemingly contradictory clinical findings. For this patient, a deficit in the ability to select the most important information to achieve her current goals reflected her neuropsychological test results and neuroradiologic findings, and helped to explain her difficulties with her job and her activities of daily living. Because the patient's cognitive impairments have been her primary manifestations of multiple sclerosis, she illustrates the importance of physicians attending to and helping patients manage their cognitive deficits.

Binding serial order to representations in working memory: a spatial/verbal dissociation.

Verbal information is coded naturally as ordered representations in working memory (WM). However, this may not be true for spatial information. Accordingly, we used memory span tasks to test the hypothesis that serial order is more readily bound to verbal than to spatial representations. Removing serial-order requirements improved performance more for spatial locations than for digits. Furthermore, serial order was freely reproduced twice as frequently for digits as for locations. When participants reordered spatial sequences, they minimized the mean distance between items. Participants also failed to detect changes in serial order more frequently for spatial than for verbal sequences. These results provide converging evidence for a dissociation in the binding of serial order to spatial versus verbal representations. There may be separable domain-specific control processes responsible for this binding. Alternatively, there may be fundamental differences in how effectively temporal information can be bound to different types of stimulus features in WM.

Modulation of Peak Alpha Frequency Oscillations During Working Memory Is Greater in Females Than Males.

Peak alpha frequency is known to vary not just between individuals, but also within an individual over time. While variance in this metric between individuals has been tied to working memory performance, less understood are how short timescale modulations of peak alpha frequency during task performance may facilitate behavior. This gap in understanding may be bridged by consideration of a key difference between individuals: sex. Inconsistent findings in the literature regarding the relationship between peak alpha frequency and cognitive performance, as well as known sex-related-differences in peak alpha frequency and its modulation motivated our hypothesis that cognitive and neural processes underlying working memory-modulation of peak alpha frequency in particular-may differ based upon sex. Targeting sex as a predictive factor, we analyzed the EEG data of participants recorded while they performed four versions of a visual spatial working memory task. A significant difference between groups was present: females modulated peak alpha frequency more than males. Task performance did not differ by sex, yet a relationship between accuracy and peak alpha frequency was present in males, but not in females. These findings highlight the importance of considering sex as a factor in the study of oscillatory activity, particularly to further understanding of the neural mechanisms that underlie working memory.

Selective involvement of superior frontal cortex during working memory for shapes.

A spatial/nonspatial functional dissociation between the dorsal and ventral visual pathways is well established and has formed the basis of domain-specific theories of prefrontal cortex (PFC). Inconsistencies in the literature regarding prefrontal organization, however, have led to questions regarding whether the nature of the dissociations observed in PFC during working memory are equivalent to those observed in the visual pathways for perception. In particular, the dissociation between dorsal and ventral PFC during working memory for locations versus object identities has been clearly present in some studies but not in others, seemingly in part due to the type of objects used. The current study compared functional MRI activation during delayed-recognition tasks for shape or color, two object features considered to be processed by the ventral pathway for perceptual recognition. Activation for the shape-delayed recognition task was greater than that for the color task in the lateral occipital cortex, in agreement with studies of visual perception. Greater memory-delay activity was also observed, however, in the parietal and superior frontal cortices for the shape than for the color task. Activity in superior frontal cortex was associated with better performance on the shape task. Conversely, greater delay activity for color than for shape was observed in the left anterior insula and this activity was associated with better performance on the color task. These results suggest that superior frontal cortex contributes to performance on tasks requiring working memory for object identities, but it represents different information about those objects than does the ventral frontal cortex.

Knowledge of objects' physical properties implicitly guides attention during visual search.

Our interactions with the world are guided by our understanding of objects' physical properties. When packing groceries, we place fragile items on top of more durable ones and position sharp corners so they will not puncture the bags. However, physical properties are not always readily observable, and we often must rely on our knowledge of attributes such as weight, hardness, and slipperiness to guide our actions on familiar objects. Here, we asked whether our knowledge of physical properties not only shapes our actions but also guides our attention to the visual world. In a series of four visual search experiments, participants viewed arrays of everyday objects and were tasked with locating a specified object. The target was sometimes differentiated from the distractors based on its hardness, while a host of other visual and semantic attributes were controlled. We found that observers implicitly used the hardness distinction to locate the target more quickly, even though none reported being aware that hardness was relevant. This benefit arose from fixating fewer distractors overall and spending less time interrogating each distractor when the target was distinguished by hardness. Progressively more stringent stimulus controls showed that surface properties and curvature cues to hardness were not necessary for the benefit. Our findings show that observers implicitly recruit their knowledge of objects' physical properties to guide how they attend to and engage with visual scenes. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Age-related differences in the structural and effective connectivity of cognitive control: a combined fMRI and DTI study of mental arithmetic.

Cognitive changes with aging are highly variable across individuals. This study investigated whether cognitive control performance might depend on preservation of structural and effective connectivity in older individuals. Specifically, we tested inhibition following working memory (WM) updating and maintenance. We analyzed diffusion tensor imaging and functional magnetic resonance imaging data in thirty-four young adults and thirty-four older adults, who performed an arithmetic verification task during functional magnetic resonance imaging. Results revealed larger arithmetic interference in older adults relative to young adults after WM updating, whereas both groups showed similar interference after WM maintenance. In both groups, arithmetic interference was associated with larger activations and stronger effective connectivity among bilateral anterior cingulate, bilateral inferior frontal gyrus, and left angular gyrus, with larger activations of frontal regions in older adults than in younger adults. In older adults, preservation of frontoparietal structural microstructure, especially involving the inferior frontaloccipital fasciculus, was associated with reduced interference, and stronger task-related effective connectivity. These results highlight how both structural and functional changes in the cognitive control network contribute to individual variability in performance during aging.

Transient neural activity in human parietal cortex during spatial attention shifts.

Observers viewing a complex visual scene selectively attend to relevant locations or objects and ignore irrelevant ones. Selective attention to an object enhances its neural representation in extrastriate cortex, compared with those of unattended objects, via top-down attentional control signals. The posterior parietal cortex is centrally involved in this control of spatial attention. We examined brain activity during attention shifts using rapid, event-related fMRI of human observers as they covertly shifted attention between two peripheral spatial locations. Activation in extrastriate cortex increased after a shift of attention to the contralateral visual field and remained high during sustained contralateral attention. The time course of activity was substantially different in posterior parietal cortex, where transient increases in activation accompanied shifts of attention in either direction. This result suggests that activation of the parietal cortex is associated with a discrete signal to shift spatial attention, and is not the source of a signal to continuously maintain the current attentive state.

Information processing biases in the brain: Implications for decision-making and self-governance.

To make behavioral choices that are in line with our goals and our moral beliefs, we need to gather and consider information about our current situation. Most information present in our environment is not relevant to the choices we need or would want to make and thus could interfere with our ability to behave in ways that reflect our underlying values. Certain sources of information could even lead us to make choices we later regret, and thus it would be beneficial to be able to ignore that information. Our ability to exert successful self-governance depends on our ability to attend to sources of information that we deem important to our decision-making processes. We generally assume that, at any moment, we have the ability to choose what we pay attention to. However, recent research indicates that what we pay attention to is influenced by our prior experiences, including reward history and past successes and failures, even when we are not aware of this history. Even momentary distractions can cause us to miss or discount information that should have a greater influence on our decisions given our values. Such biases in attention thus raise questions about the degree to which the choices that we make may be poorly informed and not truly reflect our ability to otherwise exert self-governance.

Binding of what and where during working memory maintenance.

Prefrontal cortex (PFC) supports the maintenance of currently relevant information in working memory (WM). How the PFC is organized for the maintenance of disparate information, how this information is conjoined into a unified whole, and how the representation may change with task demands is still debated. The pattern of neural activity during maintenance of either abstract visual patterns, locations, or their "conjunction" was measured in two experiments using functional magnetic resonance imaging (fMRI). During delays, common regions in PFC were active, but a dorsal-ventral/spatial-nonspatial functional topography distinguished among the three delay types. During conjunction delays, no additional neural architecture was recruited. Instead, conjunction delays were characterized by a significant reduction compared to the response of that cortical region while maintaining its "preferred" information. A model is presented, extending the principles of "biased competition" to the PFC and the dynamic maintenance of information in WM, that accounts for current and seemingly contradictory previous results from both imaging and physiological studies. In this schema, the PFC is not only the source of biasing signals targeting earlier processing regions, but is also the target of these signals. This model stands as an alternative to traditional "domain specific" and "domain general" models of frontal organization of WM, and as an extension of earlier models of PFC mechanisms related to the cognitive control of goal directed behavior.