The present experiment tested three hypotheses regarding the function and organization of lateral prefrontal cortex (PFC). The first account (the information cascade hypothesis) suggests that the anterior-posterior organization of lateral PFC is based on the timing with which cue stimuli reduce uncertainty in the action selection process. The second account (the levels-of-abstraction hypothesis) suggests that the anterior-posterior organization of lateral PFC is based on the degree of abstraction of the task goals. The current study began by investigating these two hypotheses, and identified several areas of lateral PFC that were predicted to be active by both the information cascade and levels-of-abstraction accounts. However, the pattern of activation across experimental conditions was inconsistent with both theoretical accounts. Specifically, an anterior area of mid-dorsolateral PFC exhibited sensitivity to experimental conditions that, according to both accounts, should have selectively engaged only posterior areas of PFC. We therefore investigated a third possible account (the adaptive context maintenance hypothesis) that postulates that both posterior and anterior regions of PFC are reliably engaged in task conditions requiring active maintenance of contextual information, with the temporal dynamics of activity in these regions flexibly tracking the duration of maintenance demands. Activity patterns in lateral PFC were consistent with this third hypothesis: regions across lateral PFC exhibited transient activation when contextual information had to be updated and maintained in a trial-by-trial manner, but sustained activation when contextual information had to be maintained over a series of trials. These findings prompt a reconceptualization of current views regarding the anterior-posterior organization of lateral PFC, but do support other findings regarding the active maintenance role of lateral PFC in sequential working memory paradigms.

Funding: This research was supported in part by grants MH069597 and 2 RO1 MH66078 from the National Institute of Mental Health, and a National Research Service Award (5F32MH07530002). No additional external funding received for this study. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Introduction

During the past decade, considerable attention has been given to understanding the processes associated with various areas of lateral prefrontal cortex (PFC). This work has consistently suggested that areas of lateral PFC are organized in some fashion along an anterior-posterior gradient [1]–[7]. However, despite apparent agreement on the presence of such a gradient, there is substantial controversy regarding the representational and/or processing demands that underlie this organization. Two strongly formulated hypotheses have received considerable attention:

1. The information cascade hypothesis: The anterior-posterior gradient of lateral PFC is organized according to when cue stimuli reduce uncertainty in (i.e. provide information useful for) the action selection process [4], [5], [8]. Anterior areas of lateral PFC are postulated to respond selectively to task cues that are temporally remote from the action selection process, and therefore must be maintained for extended durations (i.e., across multiple trials). In contrast, posterior areas are postulated to be responsive to cues that appear in close temporal proximity to the action selection process (i.e., in the same trial) in addition to cues that are relevant across trials. Because this hypothesis relies upon information theory to quantify the cascading contributions of multiple control signals, we subsequently refer to it as the information cascade hypothesis.

2. The levels-of-abstraction hypothesis: The anterior-posterior gradient of PFC is organized according to the level of abstraction (or hierarchical nesting) of cues required to guide action selection [1], [9]. Anterior areas of lateral PFC are associated selectively with the processing of more abstract information regarding actions (e.g. sets of stimulus-response mappings), whereas posterior areas of PFC are postulated to be associated with the processing of more concrete information regarding actions (e.g. individual stimulus-response mappings).

These two hypotheses make similar predictions under many circumstances, since abstract information may systematically need to be maintained for long durations, and concrete information may systematically need to be updated frequently [10]. However, in principle, they can be experimentally dissociated. The first goal of the current study was to investigate which, if either, of these two hypotheses accurately characterizes the recruitment of areas of lateral PFC in a sequential working memory (WM) paradigm. In order to accomplish this goal, we developed an experimental paradigm that orthogonally manipulated two factors. First, we manipulated maintenance duration, which was defined as the timing of when information-carrying cues were presented and consequently, how long such cue-related information needed to be maintained. Cues were presented either on a trial-by-trial basis or at the beginning of a block of trials (termed single-trial and multiple-trial conditions, respectively). Second, we manipulated level of abstraction, which was defined as the degree of nesting, or the number of task-relevant cues that must be processed in order to determine the appropriate action (termed baseline, low abstraction, and high abstraction; see Figures 1 and 2).

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larger image TIFF original image Download: Figure 1. Nesting task structure. In the baseline condition (bottom row), participants were required to select a response to a particular letter stimulus (illustrated in black). One indicates index finger response, and two indicates a middle finger response. In the low abstraction conditions (middle row), participants must use a prior number cue (illustrated in green) in order to appropriately interpret the subsequent probe letter. In the high abstraction conditions, participants must use an additional color cue (illustrated in red) to interpret the number cue that will then allow them to respond to the final probe letter. Dashed blue lines separate the 3 different nesting conditions. The degree of nesting increases as additional relevant cues are added (compare with Figure 2 of Badre & D'Esposito, 2007 [9]). The low abstraction conditions require the control processes in the baseline condition plus those involved with processing the number cue. The high abstraction conditions require the processes in the low abstraction conditions plus those involved with processing the color cue. https://doi.org/10.1371/journal.pone.0030284.g001

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larger image TIFF original image Download: Figure 2. Task Design. Panel A corresponds to the structure of each task within a single BOLD run. Panel B illustrates the 5 conditions. In the low abstraction conditions, participants responded to an imperative stimulus on the basis of a single previously encountered number stimulus (see Figure 1). In the high abstraction conditions, participants responded to an imperative stimulus on the basis of two previously encountered cues (a number and a colored circle). In the multiple-trial conditions, participants received one relevant piece of information at the beginning of a block, and were required to use that information on multiple trials. In the single-trial conditions, participants received every piece of information they needed on a trial-by-trial basis. Italic letters below each stream of stimuli correspond to the appropriate responses: L: left index finger, I: Right index finger, M: Right middle finger. Solid lines over stimuli indicate the maintenance duration of the number cue, whereas the dotted lines over stimuli indicate the maintenance duration of the colored circle. The dashed lines on the right represent conditions in which the trial structure, the number of possible stimuli, and stimulus-response mappings are matched. Taken together, these two contrasts are equivalent to the episodic control contrast (see Figure 3A). https://doi.org/10.1371/journal.pone.0030284.g002

When decomposed into these two dimensions of maintenance duration and level of abstraction, the two hypotheses make different predictions regarding the engagement of lateral PFC. The information cascade hypothesis predicts that anterior areas such as mid-dorsolateral PFC (mid-DLPFC; see Materials and Methods for the empirical demarcation of the different areas of PFC under consideration) should be recruited selectively by task cues that are presented at the beginning of a block of multiple trials, and are relevant over the entire block (i.e. the multiple-trial conditions). This type of temporally distant, block-oriented control has been termed episodic control [4], [5]. Conversely, the information cascade hypothesis predicts that more posterior areas of PFC will be recruited by task cues that are presented on a trial-by-trial basis (i.e. single-trial conditions). This type of immediate, trial-oriented control has been termed contextual control [4], [5] and, as with episodic control, we adopt this term for consistency with the existing literature. In the current paradigm, these two types of control form a clear 2 (low vs. high contextual control)×2 (low vs. high episodic control) factorial design that can be used to test predictions of the information cascade hypothesis (see Figure 3A): The information cascade hypothesis predicts that more anterior areas such as mid-DLPFC should be sensitive to only episodic control, whereas posterior areas of PFC should be sensitive to contextual control as well as episodic control. The latter effect is predicted from the hypothesized projection from mid-DLPFC to posterior PFC, and thus reflects an anterior-to-posterior cascade of episodic control.

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larger image TIFF original image Download: Figure 3. Analysis Approaches. Panel A reflects the analysis that is consistent with the information cascade hypothesis suggested by Koechlin and colleagues [4], [5]. Conditions with information maintained across a block of trials require episodic control and should selectively recruit mid-DLPFC. Conditions with a cue that is updated on each trial require contextual control and should recruit posterior PFC. The white cells correspond to a 2×2 factorial design. The high abstraction, single-trial condition is under constrained in this theoretical framework, and could depend on different levels of contextual control, depending on one's definition of task-set (see Materials and Methods). Panel B reflects the analysis consistent with the levels of abstraction hypothesis suggested by Badre and D'Esposito [9]. As the degree of nesting increases (see Figure 1), increasingly anterior areas of PFC should be recruited. The low abstraction conditions should recruit posterior PFC, whereas the high abstraction conditions should recruit mid-DLPFC. This analysis suggests a different 2×2 factorial ANOVA, as indicated by the white cells. In both panels, the contrast of underlined conditions was used to identify regions of interest, because both hypothesis predict that it should activate both mid-DLPFC and posterior PFC. https://doi.org/10.1371/journal.pone.0030284.g003

To test the levels of abstraction hypothesis, we used an alternate analysis strategy, and focused on a different set of predictions. The abstraction hypothesis predicts that the critical organizing factor for lateral PFC is the degree of nesting (see Figure 1 and 3B). Specifically, the hierarchical level of task cues should map onto the anterior-posterior gradient of PFC activation, with low-abstraction conditions selectively engaging posterior PFC relative to baseline, and high-abstraction conditions further engaging more anterior regions of PFC relative to the low-abstraction conditions (i.e. mid-DLPFC; see Figure 1 and 3B). Posterior PFC regions are thus predicted to be active in both high and low-abstraction conditions relative to baseline, while mid-DLPFC regions should be engaged only in the high-abstraction conditions. In contrast to the information cascade hypothesis, the levels-of-abstraction hypothesis suggests that the degree of nesting is the relevant factor, irrespective of when contextual cues are presented (see Figure 3B). Thus, the levels-of-abstraction hypothesis predicts the maintenance duration factor should be irrelevant.

The two theoretical accounts make distinct predictions regarding which experimental factors should engage mid-DLPFC and posterior PFC. Thus, the first goal of the current study was to determine whether either hypothesis accurately predicted the activation patterns observed in posterior and anterior PFC regions. In light of this goal, it is important to note that the experimental conditions used in the current study enabled separate tests of the predictions from each theoretical account, because the manipulations used here strongly parallel the manipulations used in prior studies. For example, the baseline and low abstraction, multiple-trial conditions correspond to blocks in prior “motor” experiments used to examine episodic control in tests of the information cascade hypothesis [4], [8]: Each individual trial consists of only an imperative stimulus that requires a decision, but the stimulus-response (S-R) mapping of that decision can be varied across blocks (e.g., in one block, an “R” stimulus maps to an index finger response, and in another, it maps to a middle finger response; see Figure 2). Similarly, the low abstraction, single-trial and high abstraction, multiple-trial conditions correspond to blocks in prior “task” experiments used to examine both contextual and episodic control [4], [8]: Each individual trial includes a cue that provides contextual information regarding the appropriate S-R mapping, but the appropriate S-R mapping can be varied across blocks (e.g. in one block, a “0” stimulus indicates that one should respond to an “X” with an index finger and a “Y” with a middle finger, but in another block, a “0” indicates the reverse mapping; see Figure 2). The additional fifth condition used here (the high abstraction, single-trial condition) does not correspond to a condition used in prior information cascade studies, but does parallel prior “dimension” manipulations used in studies of the levels-of-abstraction hypothesis to create high-abstraction conditions [9]. In such cases, there are three relevant stimuli on each trial, one of which specifies the S-R mapping rule (i.e., dimension) to apply when evaluating the other two.

An additional goal of the experiment was to test a third, qualitatively distinct alternative account of lateral PFC function that relates not to anterior-posterior organization, but rather to the temporal dynamics of PFC engagement:

3. The adaptive context maintenance hypothesis: The temporal dynamics of both anterior and posterior PFC adjust dynamically according to strategic and task-dependent maintenance demands. Areas of both mid-DLPFC and posterior PFC are predicted to show sustained activity dynamics when information must be maintained across multiple trials and more transient activity patterns when information must be updated frequently.

This hypothesis synthesizes a large literature demonstrating that the internal representation and active maintenance of contextual information can engage areas of anterior and posterior PFC, even under conditions that involve neither a high level of abstraction nor maintenance demands that span multiple trials [11]–[18]. Here we suggest that the maintenance duration manipulation used in the current study might influence the temporal dynamics of PFC activation, rather than the anatomical location of the PFC regions engaged. Specifically, the adaptive context maintenance hypothesis predicts that lateral PFC activity would be transient in nature (i.e., event-related) under conditions in which a contextual cue is presented and utilized promptly (i.e., single-trial conditions). Conversely, the adaptive context maintenance hypothesis predicts that lateral PFC activity – in the same regions – should be sustained (rather than transient) under conditions in which contextual information was presented at a point in time temporally distal to when it was used, and thus had to be maintained over multiple sequential trials (i.e. multiple-trial conditions). The flexible nature of PFC activation dynamics accords well with the recent Dual Mechanisms of Control framework [19], which postulates that the temporal dynamics of PFC activity flexibly adapts to the relevant control demands. In prior work testing this framework, shifts from transient to sustained PFC dynamics have been observed in relationship to shifts in task control demands or participant control strategy [11], [19]–[21]. Thus, the framework would also predict that a shift in the nature of context maintenance demands (i.e., from single-trial to multiple-trial), would also lead to a shift in PFC activation dynamics.

The focus on PFC temporal dynamics is a strong departure from both the information cascade and levels-of-abstraction hypotheses, which have primarily identified PFC regions either through the use of blocked contrasts or identification of event-related activation. Instead, the adaptive context maintenance account requires analyses that can simultaneously assess and decompose transient and sustained activation dynamics. With such an analysis approach, two testable predictions can be made. First, both posterior and anterior PFC regions should have increased activity in the four experimental conditions that require the internal representation and maintenance of context information (relative to the baseline condition that does not involve context information). Second, this increased activity should have a specific temporal profile. The single-trial conditions that require only transient, within-trial context maintenance should be associated with primarily event-related, rather than sustained, increases in PFC activation. In contrast, the multiple-trial conditions that require maintenance of contextual signals across a block of trials should be associated with sustained, rather than event-related, increases in PFC activation. In other words, PFC activity dynamics should change as a function of maintenance duration. It is important to note that the adaptive context maintenance hypothesis does not postulate that these effects will show a specific anterior-posterior gradient, as previous studies have associated context maintenance with both posterior and anterior regions of PFC. Further, the adaptive context maintenance hypothesis does not differentiate between types of contextual information (such as high vs. low abstraction), and therefore the effects are predicted to be present for both high and low abstraction contexts. In order to investigate the adaptive context maintenance hypothesis, all conditions were run using a mixed block/event-related approach that permits appropriate decomposition of task-related activity into sustained and event-related components (see Methods and Materials) [22].

We next describe the results of analyses testing the predictions made by the three hypotheses concerning the organization and temporal dynamics of lateral PFC. To preview, the observed results regarding the location and pattern of activated lateral PFC regions were not consistent with predictions made by either the information cascade or levels-of-abstraction accounts. However, the temporal dynamics observed in large areas of lateral PFC were in strong accord with predictions made by the adaptive context maintenance hypothesis.