Flexible behavior depends on the ability to shift an internal cognitive set as soon as external demand changes. According to neuropsychological studies in human and nonhuman primates, selective lesion to the PFC impairs flexible behavioral shifting. Our previous fMRI study demonstrated that the prefrontal regions showed transient activation related to set shifting in humans and monkeys. To investigate the underlying neural processing, we recorded single-unit activities while monkeys performed a cognitive-set-shifting task, which required shifting between shape-matching and color-matching behaviors. We identified a group of neurons in the inferior arcuate region that exhibited selective activity when the monkeys were required to shift their cognitive set. These shift-related neurons were localized in the focal area along the posterior bank of the inferior arcuate sulcus. Reversible inactivation of this area ipsilateral to the response hand with a small volume of muscimol (even with 0.5 μl) selectively impaired the performance of behavioral shifting. Moreover, this selective behavioral impairment strongly correlated with the dose of muscimol. These results demonstrated localized neural processing for cognitive set shifting and its causal role for behavioral flexibility in primates.

Cognitive flexibility arises from our ability to shift behaviors depending on demand changes. Behavioral shifting recruits both a preparatory process for an upcoming behavior and an execution process for the actual behavior. Although neuroimaging studies have shown that several brain regions, including posterior parietal cortex (PPC) participated in each component process, it remains unresolved how such processes are implemented at the single-cell level or even whether these processes are distinctively carried out across microstructures in such regions. By recording single-unit activity from PPC of two monkeys performing an analog of the Wisconsin Card Sorting Test, we found that, in the execution process, two types of neurons exhibited activity modulation depending on whether shift was (shift trial) or was not required (nonshift trial): one type showing larger activity and the other showing smaller activity in the shift trial than in the nonshift trial. In the preparatory process, in contrast, the population activity of both types became larger in the shift trial than in the nonshift trial. The majority of both types exhibited shift-related activity modulation in both processes, whereas the remaining was specialized in the execution process. The former and the latter neurons were spatially intermingled within PPC. Significantly, when the animals performed set shifting spontaneously in prospect of a demand change, the shift-related activity modulation still emerged in both processes. We suggest that both execution and preparation signals are represented within PPC, and that these signals reflect behavioral shifting mechanisms that can be driven by either internal or external triggers.

Proactive interference (PI), which is formed through repetition of certain behavior and lasts for a while, needs to be inhibited in order for subsequent behavior to prevail over the antecedent one. Although the inhibitory mechanisms in the pFC have been reported that are recruited long after one behavior is updated to another, very little is known about the inhibitory mechanisms that are recruited immediately after the update. The WCST was modified in the present fMRI study such that inhibition of PI could be examined both immediately after and long after update of behavior. Use of “dual-match” stimuli allowed us to compare two types of trials where inhibition of PI was and was not required (control and release trials, respectively). Significant activation was observed in the left pre-SMA during control versus release trials. The pre-SMA activation was selective to PI inhibition required immediately after update of behavior, which exhibited marked contrast to the left anterior prefrontal activation selective to PI inhibition required long after the update. These results reveal dissociable inhibitory mechanisms in these two regions that are recruited in the different temporal contexts of the inhibitory demands imposed during performance of the task.

One of the most prevailing views on the functional localization of human cognition is the hemispheric specialization, wherein the left and right hemispheres are implicated primarily in verbal and nonverbal functions, respectively. Cognitive control is known to involve the lateral prefrontal cortex. However, it remains unclear whether the hemispheric specialization in the lateral prefrontal cortex can be observed in cognitive control per se, independent of sensory aspects of stimulus materials. In this functional magnetic resonance imaging study, we tested whether the verbal/nonverbal hemispheric specialization applies to the lateral prefrontal activation by investigating interference suppression, the ability to filter out irrelevant information in the environment. The flanker task was employed using a compound stimulus that contained a target and a flanker. The flanked stimulus was either a color word flanked by a colored patch or a colored patch flanked by a color word, which allowed us to manipulate the modality of the presented flanker stimulus from which interference originates, keeping the total stimulus modality balanced. The inferior frontal gyrus (IFG) showed prominent Modality-by-Hemisphere interaction in interference suppression, the left IFG being activated when a word flanker (plus a patch target) was presented and the right IFG being activated when a patch flanker (plus a word target) was presented. These results suggest that the verbal/nonverbal hemispheric specialization in the IFG can be explained by cognitive control processes per se, independent of sensory aspects of presented materials.

The go/no-go task, which effectively taps the ability to inhibit prepotent response tendency, has consistently activated the lateral prefrontal cortex, particularly the right inferior frontal gyrus (rIFG). On the other hand, rIFG activation has rarely been reported in the antisaccade task, seemingly an oculomotor version of the manual go/no-go task. One possible explanation for the variable IFG activation is the modality difference of the two tasks: The go/no-go task is performed manually, whereas the antisaccade task is performed in the oculomotor modality. Another explanation is that these two tasks have different task structures that require different cognitive processes: The traditional antisaccade task requires (i) configuration of a preparatory set prior to antisaccade execution and (ii) response inhibition at the time of antisaccade execution, whereas the go/no-go task requires heightened response inhibition under a minimal preparatory set. To test these possibilities, the traditional antisaccade task was modified in the present functional magnetic resonance imaging study such that it required heightened response inhibition at the time of antisaccade execution under a minimal preparatory set. Prominent activation related to response inhibition was observed in multiple frontoparietal regions, including the rIFG. Moreover, meta-analyses revealed that the rIFG activation in the present study was observed in the go/no-go tasks but not in the traditional antisaccade task, indicating that the rIFG activation was sensitive to the task structure difference, but not to the response modality difference. These results suggest that the rIFG is part of a network active during response inhibition across different response modalities.