Monkey lateral prefrontal cortex subregions differentiate between perceptual exposure to visual stimuli.

Each day, humans must parse visual stimuli with varying amounts of perceptual experience, ranging from incredibly familiar to entirely new. Even when choosing a novel to buy at a bookstore, one sees covers they have repeatedly experienced intermixed with recently released titles. Visual exposure to stimuli has distinct neural correlates in the lateral prefrontal cortex (LPFC) of nonhuman primates. However, it is currently unknown if this function may be localized to specific subregions within LPFC. Specifically, we aimed to determine whether the posterior fundus of area 46 (p46f), an area that responds to deviations from learned sequences, also responds to less frequently presented stimuli outside of the sequential context. We compare responses in p46f to the adjacent subregion, posterior ventral area 46 (p46v), which we propose may be more likely to show exposure-dependent responses due to its proximity to novelty responsive regions. To test whether p46f or p46v represent perceptual exposure, we performed awake functional magnetic resonance imaging (fMRI) on three male monkeys as they observed visual stimuli that varied in their number of daily presentations. Here we show that p46v, but not p46f, shows preferential activation to stimuli with low perceptual exposure, further localizing exposure-dependent effects in monkey LPFC. These results align with previous research that has found novelty responses in ventral LPFC and are consistent with the proposal that p46f performs a sequence-specific function. Further, they expand on our knowledge of the specific role of LPFC subregions and localize perceptual exposure processing within this broader brain region.

Cognitive sequences in obsessive-compulsive disorder are supported by frontal cortex ramping activity and mediated by symptom severity.

Completing sequences is part of everyday life. Many such sequences can be considered abstract - that is, defined by a rule that governs the order but not the identity of individual steps (e.g., getting dressed for work). Over-engagement in ritualistic and repetitive behaviors seen in obsessive-compulsive disorder (OCD) suggests that abstract sequences may be disrupted in this disorder. Previous work has shown the necessity of the rostrolateral prefrontal cortex (RLPFC) for abstract sequence processing and that neural activity increases (ramps) in this region across sequences (Desrochers et al., 2015, 2019). Neurobiological models of the cortico-striatal-thalamo-cortical (CSTC) loops describe prefrontal circuitry connected to RLPFC and that is believed to be dysfunctional in OCD. As a potential extension of these models, we hypothesized that neural dynamics of RLPFC could be disrupted in OCD during abstract sequence engagement. We found that neural dynamics in RLPFC did not differ between OCD and healthy controls (HCs), but that increased ramping in pregenual anterior cingulate cortex (rACC), and superior frontal sulcus (SFS) dissociates these two groups in an abstract sequence paradigm. Further, we found that anxiety and depressive symptoms mediated the relationship between observed neural activity and behavioral differences observed in the task. This study highlights the importance of investigating ramping as a relevant neural dynamic during sequences and suggests expansion of current neurobiological models to include regions that support sequential behavior in OCD. Further, our results may point to novel regions to consider for neuromodulatory treatments of OCD in the future. Significance Statement: Completing sequences of tasks is crucial for functional day-to-day living. The possible disruption of this cognitive process in obsessive-compulsive disorder (OCD) urges the investigation of such behavior and its neural underpinnings in this disorder. Our findings elucidate novel cortical regions that support abstract sequential behavior in OCD, highlighting the potential contribution of ramping dynamics to pathology. Further, our results may refine models of dysfunctional neural circuits in OCD, which could inform future treatments and diagnostic criteria.

Abstract task sequence initiation deficit dissociates anxiety disorders from obsessive-compulsive disorder and healthy controls.

In everyday life, humans perform sequences of tasks. These tasks may be disrupted in people with obsessive-compulsive disorder (OCD). Symptoms, such as compulsions, can be considered sequential and often cause repetitions of tasks that disrupt daily living (e.g., checking the stove while cooking). Motor sequences have been used to study behavioral deficits in OCD. However, not all sequences are motor sequences. Some are more "abstract" in that they are composed of a series of tasks (e.g., chopping and stirring) rather than being dependent on individual actions or stimuli. These abstract task sequences require cognitive control mechanisms for their execution. Although theory has proposed deficits in these sequences in OCD as well, they have not been directly investigated. We tested the hypotheses that OCD participants exhibit deficits in the control mechanisms specific to abstract task sequences and more general flexible behavior (measured with task switching within the sequences), relative to health controls (HCs) and clinical controls (participants with anxiety disorders [ANX]). A total of 112 participants completed abstract task sequences consisting of simple categorization tasks. Surprisingly, participants with OCD did not perform worse than HCs or ANX. However, ANX participants showed impairments specific to sequential control that did not extend to more general flexible control. Thus, we showed a novel behavioral dissociation between OCD and ANX specific to abstract task sequential control. These results also implicate deficits in specific frontal sequential control neural circuitry in ANX and not in OCD, where implicit sequential deficits may more closely align with striatal circuits.

Different subregions of monkey lateral prefrontal cortex respond to abstract sequences and their components.

Sequential information permeates daily activities, such as when watching for the correct series of buildings to determine when to get off the bus or train. These sequences include periodicity (the spacing of the buildings), the identity of the stimuli (the kind of house), and higher-order more abstract rules that may not depend on the exact stimulus (e.g. house, house, house, business). Previously, we found that the posterior fundus of area 46 in the monkey lateral prefrontal cortex (LPFC) responds to rule changes in such abstract visual sequences. However, it is unknown if this region responds to other components of the sequence, i.e., image periodicity and identity, in isolation. Further, it is unknown if this region dissociates from other, more ventral LPFC subregions that have been associated with sequences and their components. To address these questions, we used awake functional magnetic resonance imaging in three male macaque monkeys during two no-report visual tasks. One task contained abstract visual sequences, and the other contained no visual sequences but maintained the same image periodicity and identities. We found the fundus of area 46 responded only to abstract sequence rule violations. In contrast, the ventral bank of area 46 responded to changes in image periodicity and identity, but not changes in the abstract sequence. These results suggest a functional specialization within anatomical substructures of LPFC to signal different kinds of stimulus regularities. This specialization may provide key scaffolding to identify abstract patterns and construct complex models of the world for daily living. Significance Statement: Daily tasks, such as a bus commute, require tracking or monitoring your place (same, same, same, different building) until your stop. Sequence components such as rule, periodicity (timing), and item identity are involved in this process. While prior work located responses to sequence rule changes to area 46 of monkey lateral prefrontal cortex (LPFC) using awake monkey fMRI, less was known about other components. We found that LPFC subregions differentiated between sequence components. Area 46 posterior fundus responded to abstract visual sequence rule changes, but not to changes in image periodicity or identity. The converse was true for the more ventral, adjacent shoulder region. These results suggest that interactions between adjacent LPFC subregions provide key scaffolding for complex daily behaviors.

Monkey Dorsolateral Prefrontal Cortex Represents Abstract Visual Sequences during a No-Report Task.

Monitoring sequential information is an essential component of our daily lives. Many of these sequences are abstract, in that they do not depend on the individual stimuli, but do depend on an ordered set of rules (e.g., chop then stir when cooking). Despite the ubiquity and utility of abstract sequential monitoring, little is known about its neural mechanisms. Human rostrolateral prefrontal cortex (RLPFC) exhibits specific increases in neural activity (i.e., "ramping") during abstract sequences. Monkey dorsolateral prefrontal cortex (DLPFC) has been shown to represent sequential information in motor (not abstract) sequence tasks, and contains a subregion, area 46, with homologous functional connectivity to human RLPFC. To test the prediction that area 46 may represent abstract sequence information, and do so with parallel dynamics to those found in humans, we conducted functional magnetic resonance imaging (fMRI) in three male monkeys. When monkeys performed no-report abstract sequence viewing, we found that left and right area 46 responded to abstract sequential changes. Interestingly, responses to rule and number changes overlapped in right area 46 and left area 46 exhibited responses to abstract sequence rules with changes in ramping activation, similar to that observed in humans. Together, these results indicate that monkey DLPFC monitors abstract visual sequential information, potentially with a preference for different dynamics in the two hemispheres. More generally, these results show that abstract sequences are represented in functionally homologous regions across monkeys and humans.SIGNIFICANCE STATEMENT Daily, we complete sequences that are "abstract" because they depend on an ordered set of rules (e.g., chop then stir when cooking) rather than the identity of individual items. Little is known about how the brain tracks, or monitors, this abstract sequential information. Based on previous human work showing abstract sequence related dynamics in an analogous area, we tested whether monkey dorsolateral prefrontal cortex (DLPFC), specifically area 46, represents abstract sequential information using awake monkey functional magnetic resonance imaging (fMRI). We found that area 46 responded to abstract sequence changes, with a preference for more general responses on the right and dynamics similar to humans on the left. These results suggest that abstract sequences are represented in functionally homologous regions across monkeys and humans.

Caught in the ACTS: Defining Abstract Cognitive Task Sequences as an Independent Process.

Cognitive neuroscience currently conflates the study of serial responses (e.g., delay match to sample/nonsample, n-back) with the study of sequential operations. In this essay, our goal is to define and disentangle the latter, termed abstract cognitive task sequences (ACTS). Existing literatures address tasks requiring serial events, including procedural learning of implicit motor responses, statistical learning of predictive relationships, and judgments of attributes. These findings do not describe the behavior and underlying mechanism required to succeed at remembering to evaluate color, then shape; or to multiply, then add. A new literature is needed to characterize these sorts of second-order cognitive demands of studying a sequence of operations. Our second goal is to characterize gaps in knowledge related to ACTS that merit further investigation. In the following sections, we define more precisely what we mean by ACTS and suggest research questions that further investigation would be positioned to address.

Unpacking self-ordered sequences.

In this issue of Neuron, Chiang et al. examine population coding of self-ordered sequences in prefrontal cortex. They find better decoding, more distributed information, and less variability when order is consistent. Consistent ordering produces reliable population response patterns that may aid planning and memory.

Reward Value Enhances Sequence Monitoring Ramping Dynamics as Ending Rewards Approach in the Rostrolateral Prefrontal Cortex.

Many fundamental human behaviors contain multiple sequences performed to reach a desired outcome, such as cooking. Reward is inherently associated with sequence completion and has been shown to generally enhance cognitive control. However, the impact of reward on cognitive sequence processing remains unexplored. To address this key question, we focused on the rostrolateral prefrontal cortex (RLPFC). This area is necessary and exhibits increasing ("ramping") activation during sequences, a dynamic that may be related to reward processing in other brain regions. To separate these dynamics, we designed a task where reward was only provided after multiple four-item sequences ("iterations"), rather than each individual sequence. Using fMRI in humans, we investigated three possible interactions of reward and sequential control signals in RLPFC: (1) with the visibility of sequential cues, i.e., memory; (2) equally across individual sequence iterations; and (3) differently across individual sequence iterations (e.g., increasing as reward approaches). Evidence from previous, nonsequential cognitive control experiments suggested that reward would uniformly change RLPFC activity across iterations and may depend on the visibility of cues. However, we found the influence of reward on RLPFC ramping increased across sequence iterations and did not interact with memory. These results suggest an active, predictive, and distinctive role for RLPFC in sequence monitoring and integration of reward information, consistent with extant literature demonstrating similar accelerating reward-related dopamine dynamics in regions connected to RLPFC. These results have implications for understanding sequential behavior in daily life, and when they go awry in disorders such as addiction.

Abstract sequential task control is facilitated by practice and embedded motor sequences.

Everyday task sequences, such as cooking, contain overarching goals (completing the meal), subgoals (prepare vegetables), and motor actions (chopping). Such tasks generally are considered hierarchical because superordinate levels (e.g., goals) affect performance at subordinate levels (e.g., subgoals and motor actions). However, there is debate as to whether this hierarchy is "strict" with unidirectional, top-down influences, and it is unknown if and how practice affects performance at the superordinate levels. To investigate these questions, we manipulated practice with sequences at the goal and motor action levels using an abstract, or nonmotor, task sequence paradigm (Desrochers et al., 2015; Schneider & Logan, 2006). In three experiments, participants performed memorized abstract task sequences composed of simple tasks (e.g., color/shape judgements), where some contained embedded motor response sequences. We found that practice facilitated performance and reduced control costs for abstract task sequences and subordinate tasks. The interrelation was different between the hierarchical levels, demonstrating a strict relationship between abstract task sequence goals and subgoals and a nonstrict relationship between subgoal and motor response levels. Under some conditions, the motor response level influenced the abstract task sequence level in a nonstrict manner. Further, manipulating the presence or absence of a motor sequence after learning indicated that these effects were not the result of an integrated representation produced by practice. These experiments provide evidence for a mixed hierarchical model of task sequences and insight into the distinct roles of practice and motor processing in efficiently executing task sequences in daily life. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Addressing the Gender Gap in Research: Insights from a Women in Neuroscience Conference.

There has been growing interest in quantifying the proportion of women participating in scientific conferences, publications, and committees. Numbers reveal persistent disparities, but offer few cures to the root causes of the gender gaps in research. Toward remediation, we outline five lessons learned through organizing two conferences for Women in Neuroscience (WiN). These recommendations build on participants' comments, and aim to better support women in their scientific paths and help provide equal opportunity.

A role for visual areas in physics simulations.

To engage with the world, we must regularly make predictions about the outcomes of physical scenes. How do we make these predictions? Recent computational evidence points to simulation-the idea that we can introspectively manipulate rich, mental models of the world-as one explanation for how such predictions are accomplished. However, questions about the potential neural mechanisms of simulation remain. We hypothesized that the process of simulating physical events would evoke imagery-like representations in visual areas of those same events. Using functional magnetic resonance imaging, we find that when participants are asked to predict the likely trajectory of a falling ball, motion-sensitive brain regions are activated. We demonstrate that this activity, which occurs even though no motion is being sensed, resembles activity patterns that arise while participants perceive the ball's motion. This finding thus suggests that mental simulations recreate sensory depictions of how a physical scene is likely to unfold.

Hierarchical cognitive control and the frontal lobes.

Cognitive control refers to our ability to choose courses of thought and action that achieve our goals over habitual but contextually inappropriate ones. Hierarchical control problems are those in which multiple goals or contextual contingency must be managed at once and related to one another. In the open-ended complexity of the real world, hierarchical control arguably characterizes most of the problems faced by our control systems. And, it is these cases of hierarchical control where patients with damage to executive systems are most apt to fail, even those that perform well on simplified laboratory tasks. In this chapter, we consider the functional organization of frontal brain systems that support hierarchical cognitive control. We focus on two particular cases of hierarchical control. First, we discuss a line of work testing how managing multiple contingencies en route to a response relates to processing along the rostrocaudal axis of frontal cortex. Second, we consider cases of sequential tasks that require monitoring and behaving according to a series of tasks performed in time. In this latter case, we focus on the particular role of rostrolateral prefrontal cortex. We conclude with considerations of future directions of basic and clinically relevant research in this domain.

Need-based prioritization of behavior.

When presented with a choice, organisms need to assimilate internal information with external stimuli and past experiences to rapidly and flexibly optimize decisions on a moment-to-moment basis. We hypothesized that increasing hunger intensity would curb expression of social behaviors such as mating or territorial aggression; we further hypothesized social interactions, reciprocally, would influence food consumption. We assessed competition between these motivations from both perspectives of mice within a resident-intruder paradigm. We found that as hunger state escalated, resident animal social interactions with either a female or male intruder decreased. Furthermore, intense hunger states, especially those evoked via AgRP photoactivation, fundamentally altered sequences of behavioral choice; effects dependent on food availibility. Additionally, female, but not male, intrusion attenuated resident mouse feeding. Lastly, we noted environmental context-dependent gating of food intake in intruding mice, suggesting a dynamic influence of context cues on the expression of feeding behaviors.

Sequential Control Underlies Robust Ramping Dynamics in the Rostrolateral Prefrontal Cortex.

An essential human skill is our capacity to monitor and execute a sequence of tasks in the service of an overarching goal. Such a sequence can be as mundane as making a cup of coffee or as complex as flying a fighter plane. Previously, we showed that, during sequential control, the rostrolateral prefrontal cortex (RLPFC) exhibits activation that ramps steadily through the sequence and is necessary for sequential task execution using fMRI in humans (Desrochers et al., 2015). It remains unknown what computations may underlie this ramping dynamic. Across two independent fMRI experiments, we manipulated three features that were unique to the sequential control task to determine whether and how they modulated ramping activity in the RLPFC: (1) sequence position uncertainty, (2) sequential monitoring without external position cues (i.e., from memory), and (3) sequential monitoring without multilevel decision making (i.e., task execution). We replicated the ramping activation in RLPFC and found it to be remarkably robust regardless of the level of task abstraction or engagement of memory functions. Therefore, these results both replicate and extend previous findings regarding the function of the RLPFC. They suggest that sequential control processes are integral to the dynamics of RLPFC activity. Advancing knowledge of the neural bases of sequential control is crucial for our understanding of the sequential processes that are necessary for daily living.SIGNIFICANCE STATEMENT We perform sequences of tasks every day, but little is known about how they are controlled in the brain. Previously we found that ramping activity in the rostrolateral prefrontal cortex (RLPFC) was necessary to perform a sequence of tasks. We designed two independent fMRI experiments in human participants to determine which features of the previous sequential task potentially engaged ramping in the RLPFC. We found that any demand to monitor a sequence of state transitions consistently elicited ramping in the RLPFC, regardless of the level of the decisions made at each step in the sequence or engagement of memory functions. These results provide a framework for understanding RLPFC function during sequential control, and consequently, daily life.

The Necessity of Rostrolateral Prefrontal Cortex for Higher-Level Sequential Behavior.

Frontal neocortex is thought to support our highest intellectual abilities, including our ability to plan and enact a sequence of tasks toward a desired goal. In everyday life, such task sequences are abstract in that they do not require consistent movement sequences and are often assembled "on the fly." Yet, remarkably little is known about the necessity of frontal sub-regions for such control. Participants repeatedly completed sequences of simple tasks during fMRI scanning. Rostrolateral prefrontal cortex (RLPFC) activation ramped over sequence position and reset at the initiation of each new sequence. To establish the necessity and function of RLPFC in this task, participants performed the sequential task while undergoing transcranial magnetic stimulation (TMS) of the RLPFC versus two prefrontal control regions. Across two independent experiments, only RLPFC stimulation increasingly disrupted task performance as each sequence progressed. These data establish RLPFC as necessary for uncertainty resolution during sequence-level control.

Habit Learning by Naive Macaques Is Marked by Response Sharpening of Striatal Neurons Representing the Cost and Outcome of Acquired Action Sequences.

Over a century of scientific work has focused on defining the factors motivating behavioral learning. Observations in animals and humans trained on a wide range of tasks support reinforcement learning (RL) algorithms as accounting for the learning. Still unknown, however, are the signals that drive learning in naive, untrained subjects. Here, we capitalized on a sequential saccade task in which macaque monkeys acquired repetitive scanning sequences without instruction. We found that spike activity in the caudate nucleus after each trial corresponded to an integrated cost-benefit signal that was highly correlated with the degree of naturalistic untutored learning by the monkeys. Across learning, neurons encoding both cost and outcome gradually acquired increasingly sharp phasic trial-end responses that paralleled the development of the habit-like, repetitive saccade sequences. Our findings demonstrate an integrated cost-benefit signal by which RL and its neural correlates could drive naturalistic behaviors in freely behaving primates.

The Monitoring and Control of Task Sequences in Human and Non-Human Primates.

Our ability to plan and execute a series of tasks leading to a desired goal requires remarkable coordination between sensory, motor, and decision-related systems. Prefrontal cortex (PFC) is thought to play a central role in this coordination, especially when actions must be assembled extemporaneously and cannot be programmed as a rote series of movements. A central component of this flexible behavior is the moment-by-moment allocation of working memory and attention. The ubiquity of sequence planning in our everyday lives belies the neural complexity that supports this capacity, and little is known about how frontal cortical regions orchestrate the monitoring and control of sequential behaviors. For example, it remains unclear if and how sensory cortical areas, which provide essential driving inputs for behavior, are modulated by the frontal cortex during these tasks. Here, we review what is known about moment-to-moment monitoring as it relates to visually guided, rule-driven behaviors that change over time. We highlight recent human work that shows how the rostrolateral prefrontal cortex (RLPFC) participates in monitoring during task sequences. Neurophysiological data from monkeys suggests that monitoring may be accomplished by neurons that respond to items within the sequence and may in turn influence the tuning properties of neurons in posterior sensory areas. Understanding the interplay between proceduralized or habitual acts and supervised control of sequences is key to our understanding of sequential task execution. A crucial bridge will be the use of experimental protocols that allow for the examination of the functional homology between monkeys and humans. We illustrate how task sequences may be parceled into components and examined experimentally, thereby opening future avenues of investigation into the neural basis of sequential monitoring and control.

Finding parallels in fronto-striatal organization.

Evidence suggests that lateral frontal cortex is hierarchically organized such that rostral frontal regions support more abstract representations than caudal regions. A recent fMRI study of language processing proposes that striatum may exhibit an analogous organization. We consider this hypothetical correspondence at both the cognitive and anatomical levels.

A system for recording neural activity chronically and simultaneously from multiple cortical and subcortical regions in nonhuman primates.

A major goal of neuroscience is to understand the functions of networks of neurons in cognition and behavior. Recent work has focused on implanting arrays of ∼100 immovable electrodes or smaller numbers of individually adjustable electrodes, designed to target a few cortical areas. We have developed a recording system that allows the independent movement of hundreds of electrodes chronically implanted in several cortical and subcortical structures. We have tested this system in macaque monkeys, recording simultaneously from up to 127 electrodes in 14 brain regions for up to one year at a time. A key advantage of the system is that it can be used to sample different combinations of sites over prolonged periods, generating multiple snapshots of network activity from a single implant. Used in conjunction with microstimulation and injection methods, this versatile system represents a powerful tool for studying neural network activity in the primate brain.