Monkey dorsolateral prefrontal cortex shows anatomically and functionally specific responses to sequential but not temporal or image changes.

Sequential information permeates our daily lives, such as when listening to music. These sequences are potentially abstract in that they do not depend on the exact identity of the stimuli (pitch of the notes), but on the rule that they follow (interval between them). Previously, we showed that a subregion of monkey lateral prefrontal cortex (LPFC), area 46, responds to abstract visual sequences in a manner that parallels human responses. However, area 46 has several mapped subregions and abstract sequences require of multiple stimulus features (such as stimulus and time), leaving open questions as to the specificity of responses in the LPFC. To determine the anatomical and functional specificity of abstract visual sequence responses within area 46 subregions, we used awake functional magnetic resonance imaging in three male macaque monkeys during two no-report visual tasks. One task presented images in an abstract visual sequence; the other used the same timing properties and image variation, but no sequential information. We found, using subdivisions from a multimodal parcellation of area 46, that responses to abstract visual sequences were unique to the posterior fundus of area 46, which did not respond to changes in timing or image alone. In contrast, posterior shoulder regions of area 46 showed selectivity to more concrete stimulus changes (i.e., timing and image). These results align with organizational hierarchies observed in monkeys and humans, and suggest that interactions between adjacent LPFC subregions is 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.

Optimal habits can develop spontaneously through sensitivity to local cost.

Habits and rituals are expressed universally across animal species. These behaviors are advantageous in allowing sequential behaviors to be performed without cognitive overload, and appear to rely on neural circuits that are relatively benign but vulnerable to takeover by extreme contexts, neuropsychiatric sequelae, and processes leading to addiction. Reinforcement learning (RL) is thought to underlie the formation of optimal habits. However, this theoretic formulation has principally been tested experimentally in simple stimulus-response tasks with relatively few available responses. We asked whether RL could also account for the emergence of habitual action sequences in realistically complex situations in which no repetitive stimulus-response links were present and in which many response options were present. We exposed naïve macaque monkeys to such experimental conditions by introducing a unique free saccade scan task. Despite the highly uncertain conditions and no instruction, the monkeys developed a succession of stereotypical, self-chosen saccade sequence patterns. Remarkably, these continued to morph for months, long after session-averaged reward and cost (eye movement distance) reached asymptote. Prima facie, these continued behavioral changes appeared to challenge RL. However, trial-by-trial analysis showed that pattern changes on adjacent trials were predicted by lowered cost, and RL simulations that reduced the cost reproduced the monkeys' behavior. Ultimately, the patterns settled into stereotypical saccade sequences that minimized the cost of obtaining the reward on average. These findings suggest that brain mechanisms underlying the emergence of habits, and perhaps unwanted repetitive behaviors in clinical disorders, could follow RL algorithms capturing extremely local explore/exploit tradeoffs.