The role of frontopolar cortex in subgoal processing during working memory

Neuroimaging studies have implicated the anterior-most or frontopolar regions of prefrontal cortex (FP-PFC, e.g., Brodmann's Area 10) as playing a central role in higher cognitive functions such as planning, problem solving, reasoning, and episodic memory retrieval. The current functional magnetic resonance imaging (fMRI) study tested the hypothesis that FP-PFC subserves processes related to the monitoring and management of subgoals, while maintaining information in working memory (WM). Subjects were scanned while performing two variants of a simple delayed response WM task. In the control WM condition, subjects monitored for the presence of a specific concrete probe word (LIME) occurring following a specific abstract cue word (FATE). In the subgoal WM condition, subjects monitored for the presence of any concrete probe word immediately following any abstract cue word. Thus, the task required semantic classification of the probe word (the subgoal task), while the cue was simultaneously maintained in WM, so that both pieces of information could be integrated into a target determination. In a second control condition, subjects performed abstract/concrete semantic classification without WM demands. A region within right FP-PFC was identified which showed significant activation during the subgoal WM condition, but no activity in either of the two control conditions. However, this FP-PFC region was not modulated by direct manipulation of active maintenance demands. In contrast, left dorsolateral PFC was affected by active maintenance demands, but the effect did not interact with the presence of a subgoal task. Finally, left ventral PFC regions showed activation in response to semantic classification, but were not affected by WM demands. These results suggest a triple dissociation of function within PFC regions, and further indicate that FP-PFC is selectively engaged by the requirement to monitor and integrate subgoals during WM tasks.     

Neuroimaging a single thought: dorsolateral PFC activity associated with refreshing just-activated information.

Neuroimaging studies of human working memory (WM) show conflicting results regarding whether dorsolateral prefrontal cortex (PFC) contributes to maintaining information in consciousness or is recruited primarily when information must be manipulated. Using functional magnetic resonance imaging (fMRI), we looked at a minimal maintenance process--thinking back to a single, just-seen stimulus (refreshing). We found greater activity in left dorsolateral PFC (BA9) when participants refreshed a word compared to reading a word once or a second time. Furthermore, recognition memory was subsequently more accurate and faster for items that had been refreshed, demonstrating that a single thought that maintains activation can have consequences for long-term memory. Our fMRI results call into question any class of models of the functional organization of PFC and WM that associates simple and/or maintenance processes only with ventrolateral PFC or that associates dorsolateral PFC only with more complex processes such as manipulation.     

The role of precuneus and left inferior frontal cortex during source memory episodic retrieval

The posterior medial parietal cortex and left prefrontal cortex (PFC) have both been implicated in the recollection of past episodes. In a previous study, we found the posterior precuneus and left lateral inferior frontal cortex to be activated during episodic source memory retrieval. This study further examines the role of posterior precuneal and left prefrontal activation during episodic source memory retrieval using a similar source memory paradigm but with longer latency between encoding and retrieval. Our results suggest that both the precuneus and the left inferior PFC are important for regeneration of rich episodic contextual associations and that the precuneus activates in tandem with the left inferior PFC during correct source retrieval. Further, results suggest that the left ventro-lateral frontal region/frontal operculum is involved in searching for task-relevant information (BA 47) and subsequent monitoring or scrutiny (BA 44/45) while regions in the dorsal inferior frontal cortex are important for information selection (BA 45/46).     

Hemispheric specialization of the lateral prefrontal cortex for strategic processing during spatial and shape working memory

OBJECTIVE: We investigated whether spatial working memory (WM) is associated with functional specialization of the right prefrontal cortex (PFC) relative to WM for shapes. We designed spatial and shape WM tasks that are relatively easy to perform and that minimize both task-switching and manipulation demands. The tasks use identical stimuli and require the same motor response. METHODS: We presented 12 subjects with target shapes that appeared in particular locations. Subjects maintained either the location or the shape of the targets in WM and responded to each probe by indicating whether it was a target. During a non-WM control task, subjects indicated whether the probe appeared on the right or left side of the screen. Subjects were scanned with a 3.0 T Siemens scanner and data were analyzed using SPM99. The WM tasks were compared to identify PFC activation that was different for spatial versus shape WM. Each WM task was also compared to the control task. RESULTS: compared with shape WM, spatial WM performance was faster and more accurate and was associated with increased right ventrolateral and frontopolar PFC activation. In contrast, compared to spatial WM, shape WM was associated with increased left ventrolateral PFC activity. CONCLUSIONS: These findings demonstrate hemispheric specialization for spatial versus shape WM in the ventrolateral PFC. The increased activity in the right PFC for spatial WM cannot be attributed to increased task difficulty, the stimuli used, or the response requirements. Rather, we propose that differences in performance and activation reflect the use of configural processing strategies for spatial WM.     

Spatiotemporal characteristics of hemodynamic changes in the human lateral prefrontal cortex during working memory tasks

The prefrontal cortex (PFC) is widely believed to subserve mental manipulation and monitoring processes ascribed to the central executive (CE) of working memory (WM). We attempted to examine and localize the CE by functional imaging of the frontal cortex during tasks designed to require the CE. Using near-infrared spectroscopy, we studied the spatiotemporal dynamics of oxygenated hemoglobin (oxy-Hb), an indicator of changes in regional cerebral blood flow, in both sides of lateral PFC during WM intensive tasks. In most participants, increases in oxy-Hb were localized within one subdivison during performance of the n-back task, whereas oxy-Hb increased more diffusely during the random number generation (RNG) task. Activation of the ventrolateral PFC (VLPFC) was prominent in the n-back task; both sustained and transient dynamics were observed. Transient dynamics means that oxy-Hb first increases but then decreases to less than 50% of the peak value or below the baseline level before the end of the task. For the RNG task sustained activity was also observed in the dorsolateral PFC (DLPFC), especially in the right hemisphere. However, details of patterns of activation varied across participants: subdivisions commonly activated during performance of the two tasks were the bilateral VLPFCs, either side of the VLPFC, and either side of the DLPFC in 4, 2, and 4 of the 12 participants, respectively. The remaining 2 of the 12 participants had no regions commonly activated by these tasks. These results suggest that although the PFC is implicated in the CE, there is no stereotyped anatomical PFC substrate for the CE.     

Working memory dysfunction in schizophrenia compared to healthy controls and patients with depression: evidence from event-related fMRI

Studies on working memory (WM) dysfunction in schizophrenia have reported several functionally aberrant brain areas including the lateral prefrontal cortex, superior temporal areas and the striatum. However, less is known about the relationship of WM-dysfunction, cerebral activation, task-accuracy and diagnostic specificity. Using a novel WM-task and event-related functional magnetic resonance imaging (fMRI), we studied healthy control subjects (n=17) and partially remitted, medicated inpatients meeting DSM-IV criteria for schizophrenia (n=19) and major depressive disorder (n=12). Due to the event-related technique, we excluded incorrectly performed trials, thus controlling for accuracy-related activation confounds. Compared with controls, patients with schizophrenia showed less activation in frontoparietal and subcortical regions at high cognitive load levels. Compared with patients with depression, schizophrenic patients showed less prefrontal activation in left inferior frontal cortex and right cerebellum. In patients with schizophrenia, a lack of deactivation of the superior temporal cortex was found compared to both healthy controls and patients with depression. Thus, we could not confirm previous findings of impaired lateral prefrontal activation during WM performance in schizophrenic patients after the exclusion of incorrectly performed or omitted trials in our functional analysis. However, superior temporal cortex dysfunction in patients with schizophrenia may be regarded as schizophrenia-specific finding in terms of psychiatric diagnosis specificity.     

Task constraints modulate activation in right ventral lateral prefrontal cortex

Lesion data suggest that right prefrontal cortex (PFC) plays a critical role in open-ended problem solving. To test this hypothesis, we scanned fifteen normal subjects with fMRI as they completed three types of anagram problems varying in the level of constraints placed on the search space. On unconstrained trials, they rearranged letters to generate solutions (e.g., Can you make a "Word with ZJAZ?"). On semantically constrained trials, they rearranged letters to generate solutions within particular semantic categories (e.g., Can you make a type of "Music with ZJAZ?"). On baseline trials, they rearranged letters to make specific words (e.g., Can you make the word "JAZZ with ZJAZ?"). As predicted, the critical comparison of unconstrained vs. semantically constrained trials revealed significant activation in right ventral lateral PFC, as well as left superior frontal gyrus, frontopolar cortex, right superior parietal lobe, right post central gyrus, and the occipital-parietal sulcus. Furthermore, activation in right ventral lateral PFC (BA 47) increased as the constraints placed on the anagram search space were reduced. We argue that the activation in right ventral lateral PFC is related to hypothesis generation in unconstrained settings, whereas activation in other structures is related to additional processes linked to anagram problems such as semantic retrieval, semantic categorization, and cognitive monitoring. These results extend the lesion data and imaging studies by demonstrating that a relative absence of constraints on the solution space is sufficient to engage right ventral lateral PFC in hypothesis generation tasks.     

Working memory component processes: Isolating BOLD signal changes

The chronology of the component processes subserving working memory (WM) and hemodynamic response lags has hindered the use of fMRI for exploring neural substrates of WM. In the present study, however, participants completed full trials that involved encoding two or six letters, maintaining the memory set over a delay, and then deciding whether a probe was in the memory set or not. Additionally, they completed encode-only, encode-and-maintain, and encode-and-decide partial trials intermixed with the full trials. The inclusion of partial trials allowed for the isolation of BOLD signal changes to the different trial periods. The results showed that only lateral and medial prefrontal cortex regions differentially responded to the 2- and 6-letter memory sets over the trial periods, showing greater activation to 6-letter sets during the encode and maintain trial periods. Thus, the data showed the differential involvement of PFC in the encoding and maintenance of supra- and sub-capacity memory sets and show the efficacy of using fMRI partial trial methods to study WM component processes.     

Age-related changes in neural activity during performance matched working memory manipulation

A long-standing assumption in the cognitive aging literature is that performance on working memory (WM) tasks involving serial recall is relatively unaffected by aging, whereas tasks that require the rearrangement of items prior to recall are more age-sensitive. Previous neuroimaging studies of WM have found age-related increases in neural activity in frontoparietal brain regions during simple maintenance tasks, but few have examined whether there are age-related differences that are specific to rearranging WM items. In the current study, older and younger adults' brain activity was monitored using functional magnetic resonance imaging (fMRI) as they performed WM tasks involving either maintenance or manipulation (letter–number sequencing). The paradigm was developed so that performance was equivalent across age groups in both tasks, and the manipulation condition was not more difficult than the maintenance condition. In younger adults, manipulation-related increases in activation occurred within a very focal set of regions within the canonical brain WM network, including left posterior prefrontal cortex and bilateral inferior parietal cortex. In contrast, older adults showed a much wider extent of manipulation-related activation within this WM network, with significantly increased activity relative to younger adults found within bilateral PFC. The results suggest that activation and age-differences in lateral PFC engagement during WM manipulation conditions may reflect strategy use and controlled processing demands rather than reflect the act of manipulation per se.     

The Role of Prefrontal Cortex in Sensory Memory and Motor Preparation: An Event-Related fMRI Study

Delayed-response tasks are behavioral paradigms in which subjects must remember stimulus attributes across a delay to subsequently perform the appropriate motor response. Quintana and Fuster (1992), reported that there exist subpopulations of neurons in monkey lateral prefrontal cortex (PFC) whose firing rates during the delay are tuned to either sensorial attributes of the stimulus (i.e., involved in sensory memory) or the direction of a postdelay motor response associated with the stimulus (i.e., involved in motor preparation). We studied human subjects with an event-related fMRI method that would allow us to test the hypothesis that there are regions within the PFC that are recruited during both motor preparation and sensory memory. Subjects performed a delayed-response task with two types of trials that either (1) allowed subjects to prepare during a delay period for a specific motor response or (2) required that subjects maintain a sensory attribute (specifically, color) during a delay period for correct performance postdelay. It was assumed that during the delay periods, the delayed-response trials would engage motor preparation while delayed-match trials would engage sensory memory. Behavioral data supported this assumption. Imaging results support the hypothesis that the PFC is involved in both motor preparation and sensory memory. Furthermore, no selectivity (in terms of intensity of neural representation on the spatial scale of the voxel size <5 mm³) for motor preparation over sensory memory (or vice-versa) was detected within the PFC. This latter result fails to support a gross anatomical segregation within the PFC with respect to involvement in these two cognitive processes.     

Local landmark-based mapping of human auditory cortex

Mammalian sensory cortex is functionally partitioned into cortical fields that are specialized for different processing operations. In theory, averaging functional and anatomical images across subjects can reveal both the average anatomy and the mean functional organization of sensory regions. However, this averaging process must overcome at least two obstacles: (1) the relative locations and sizes of cortical sensory areas vary in different subjects so that across-subject averaging introduces spatial smearing; (2) the relative locations and sizes of cortical areas vary between hemispheres, making it difficult to compare activations between hemispheres or to combine activations across hemispheres. These difficulties are particularly acute for small cortical regions such as auditory cortex. In whole-brain averaging procedures, considerable intersubject variance in the location and orientation of auditory cortex is introduced by variance of the size and shape of structures outside auditory cortex. Here, we compared these global methods with local landmark-based methods (LLMs) that use warping based on local anatomical landmarks. In comparison to maps made with global methods, LLMs produced anatomical maps of auditory cortex with clearer gyral and sulcal structure, and produce functional maps with improved resolution. These results suggest that LLMs have significant advantages over global mapping procedures in studying the details of auditory cortex organization.     

A gateway system in rostral PFC? Evidence from biasing attention to perceptual information and internal representations

Some situations require us to be highly sensitive to information in the environment, whereas in other situations, our attention is mainly focused on internally represented information. It has been hypothesized that a control system located in the rostral prefrontal cortex (PFC) acts as gateway between these two forms of attention. Here, we examined the neural underpinnings of this 'gateway system' using fMRI and functional connectivity analysis. We designed different tasks, in which the demands for attending to external or internal information were manipulated, and tested 1) whether there is a functional specialization within the rostral PFC along a medial-lateral dimension, and 2) whether these subregions can influence attentional weighting processes by specifically interacting with other parts of the brain. Our results show that lateral aspects of the rostral PFC are preferentially activated when attention is directed to internal representations, whereas anterior medial aspects are activated when attention is directed to sensory events. Furthermore, the rostrolateral subregion was preferentially connected to regions in the prefrontal and parietal cortex during internal attending, whereas the rostromedial subregion was connected to the basal ganglia, thalamus, and sensory association cortices during external attending. Finally, both subregions interacted with another important prefrontal region involved in cognitive control, the inferior frontal junction, in a task-specific manner, depending on the current attentional demands. These findings suggest that the rostrolateral and rostromedial part of the anterior PFC have dissociable roles in attentional control, and that they might, as part of larger networks, be involved in dynamically adjusting the contribution of internal and external information to current cognition.     

Quantification of serotonin transporter availability with [11C]MADAM--a comparison between the ECAT HRRT and HR systems

The five-factor model organizes personality traits into five factors: Neuroticism, Extraversion, Openness to Experience, Agreeableness, and Conscientiousness. Measures of these personality traits predict people's behaviors and important outcomes of their lives. Therefore, understanding the neural correlates of these personality traits is important. This study assessed the relationships between white matter (WM) integrity and personality traits among 51 healthy participants using diffusion tensor imaging (DTI) and the revised NEO Personality Inventory (NEO-PI-R). Neuroticism correlated positively while Openness and Agreeableness correlated negatively with DTI mean diffusivity (MD) in the corona radiata and superior longitudinal fasciculus, tracts that interconnect prefrontal cortex (PFC), parietal cortex, and subcortical structures. Furthermore, Neuroticism correlated positively with MD in the anterior cingulum and uncinate fasciculus, tracts interconnecting PFC and amygdala. Openness correlated negatively with MD of WM adjacent to the dorsolateral PFC in both hemispheres. These findings suggest that greater Neuroticism associates with worse integrity of WM interconnecting extensive cortical and subcortical structures including the PFC and amygdala and that greater Openness associates with better integrity of WM interconnecting extensive cortical and subcortical structures including the dorsolateral PFC.     

Functional MRI investigation of verbal selection mechanisms in lateral prefrontal cortex

Response selection activates appropriate response representations to task-relevant environmental stimuli. Research implicates dorsolateral prefrontal cortex (dlPFC) for this process. On the other hand, studies of semantic selection, which activates verbal responses based on the semantic requirements of a task, implicate ventrolateral PFC (vlPFC). Despite this apparent dissociation, the neurocognitive distinction between response and semantic selection is controversial. The current functional MRI study attempts to resolve this controversy by investigating verbal response and semantic selection in the same participants. Participants responded vocally with a word to a visually presented noun, either from a memorized list of paired associates (response selection task), or by generating a semantically related verb (semantic selection task). We found a dissociation in left lateral PFC. Activation increased significantly in dlPFC with response selection difficulty, but not semantic selection difficulty. Conversely, semantic, but not response, selection difficulty increased activity significantly in vlPFC. Activity in left parietal cortex, on the other hand, was affected by difficulty increases in both selection tasks. These results suggest that response and semantic selection may be distinct cognitive processes mediated by different regions of lateral PFC; but both of these selection processes rely on cognitive mechanisms mediated by parietal cortex.     

Dissociable correlates of two classes of retrieval processing in prefrontal cortex

Although substantial evidence suggests that the prefrontal cortex (PFC) implements processes that are critical for accurate episodic memory judgments, the specific roles of different PFC subregions remain unclear. Here, we used event-related functional magnetic resonance imaging to distinguish between prefrontal activity related to operations that (1) influence processing of retrieval cues based on current task demands, or (2) are involved in monitoring the outputs of retrieval. Fourteen participants studied auditory words spoken by a male or female speaker and completed memory tests in which the stimuli were unstudied foil words and studied words spoken by either the same speaker at study, or the alternate speaker. On "general" test trials, participants were to determine whether each word was studied, regardless of the voice of the speaker, whereas on "specific" test trials, participants were to additionally distinguish between studied words that were spoken in the same voice or a different voice at study. Thus, on specific test trials, participants were explicitly required to attend to voice information in order to evaluate each test item. Anterior (right BA 10), dorsolateral prefrontal (right BA 46), and inferior frontal (bilateral BA 47/12) regions were more active during specific than during general trials. Activation in anterior and dorsolateral PFC was enhanced during specific test trials even in response to unstudied items, suggesting that activation in these regions was related to the differential processing of retrieval cues in the two tasks. In contrast, differences between specific and general test trials in inferior frontal regions (bilateral BA 47/12) were seen only for studied items, suggesting a role for these regions in post-retrieval monitoring processes. Results from this study are consistent with the idea that different PFC subregions implement distinct, but complementary processes that collectively support accurate episodic memory judgments.     

Human medial intraparietal cortex subserves visuomotor coordinate transformation

In the macaque, the posterior parietal cortex (PPC) integrates multimodal sensory information for planning and coordinating complex movements. In particular, the areas around the intraparietal sulcus (IPS) serve as an interface between the sensory and motor systems to allow for coordinated movements in space. Because recent imaging studies suggest a comparable functional and anatomical organization of human and monkey IPS, we hypothesized that in humans, as in macaques, the medial intraparietal cortex (area MIP) subserves visuomotor transformations. To test this hypothesis, changes of neural activity were measured using functional magnetic resonance imaging (fMRI) while healthy subjects performed a joystick paradigm similar to the ones previously employed in macaques for studying area MIP. As hypothesized, visuomotor coordinate transformation subserving goal-directed hand movements activated superior parietal cortex with the local maximum of increased neural activity lying in the medial wall of IPS. Compared to the respective visuomotor control conditions, goal-directed hand movements under predominantly proprioceptive control activated a more anterior part of medial IPS, whereas posterior medial IPS was more responsive to visually guided hand movements. Contrasting the two coordinate transformation conditions, changing the modality of movement guidance (visual/proprioceptive) did not significantly alter the BOLD signal within IPS but demonstrated differential recruitment of modality specific areas such as V5/MT and sensorimotor cortex/area 5, respectively. The data suggest that the human medial intraparietal cortex subserves visuomotor transformation processes to control goal-directed hand movements independently from the modality-specific processing of visual or proprioceptive information.     

Similarities and differences in the neural correlates of episodic memory retrieval and working memory

Functional neuroimaging studies have shown that different cognitive functions activate overlapping brain regions. An activation overlap may occur because a region is involved in operations tapped by different cognitive functions or because the activated area comprises subregions differentially involved in each of the functions. To investigate these issues, we directly compared brain activity during episodic retrieval (ER) and working memory (WM) using event-related functional MRI (fMRI). ER was investigated with a word recognition test, and WM was investigated with a word delayed-response test. Two-phase trials distinguished between retrieval mode and cue-specific aspects of ER, as well as between encoding/maintenance and retrieval aspects of WM. The results revealed a common fronto-parieto-cerebellar network for ER and WM, as well as subregions differentially involved in each function. Specifically, there were two main findings. First, the results differentiated common and specific subregions within the prefrontal cortex: (i) left dorsolateral areas were recruited by both functions, possibly reflecting monitoring operations; (ii) bilateral anterior and ventrolateral areas were more activated during ER than during WM, possibly reflecting retrieval mode and cue-specific ER operations, respectively; and (iii) left posterior/ventral (Broca's area) and bilateral posterior/dorsal areas were more activated during WM than during ER, possibly reflecting phonological and generic WM operations, respectively. Second, hippocampal and parahippocampal regions were activated not only for ER but also for WM. This result suggests that indexing operations mediated by the medial temporal lobes apply to both long-term and short-term memory traces. Overall, our results show that direct cross-function comparisons are critical to understand the role of different brain regions in various cognitive functions.     

Distraction modulates connectivity of the cingulo-frontal cortex and the midbrain during pain--an fMRI analysis

Neuroimaging studies with positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) have delineated a human pain network in vivo. Despite the recognition of cerebral structures engaged in pain transmission, the cerebral mechanisms involved in pain modulation are still not well understood. Here, we investigated healthy volunteers using fMRI during experimental heat pain and distraction induced by a visual incongruent color-word Stroop task. A factorial design permitted categorical and covariation analysis of four conditions, namely innocuous and noxious heat; with and without distraction. Pain without distraction evoked an activation pattern similar to that observed in previous neuroimaging pain studies. Distraction was associated with a significant reduction of the visual analogue scale (VAS) ratings for pain intensity and unpleasantness and a reduction of pain-related activation in multiple brain areas, particularly in the so-called 'medial pain system'. Distraction significantly increased the activation of the cingulo-frontal cortex including the orbitofrontal and perigenual anterior cingulate cortex (ACC), as well as the periaquaeductal gray (PAG) and the posterior thalamus. Covariation analysis revealed functional interaction between these structures during pain stimulation and distraction, but not during pain stimulation per se. According to our results, the cingulo-frontal cortex may exert top-down influences on the PAG and posterior thalamus to gate pain modulation during distraction.     

Visual short-term memory: Activity supporting encoding and maintenance in retinotopic visual cortex

Recent studies have demonstrated that retinotopic cortex maintains information about visual stimuli during retention intervals. However, the process by which transient stimulus-evoked sensory responses are transformed into enduring memory representations is unknown. Here, using fMRI and short-term visual memory tasks optimized for univariate and multivariate analysis approaches, we report differential involvement of human retinotopic areas during memory encoding of the low-level visual feature orientation. All visual areas show weaker responses when memory encoding processes are interrupted, possibly due to effects in orientation-sensitive primary visual cortex (V1) propagating across extrastriate areas. Furthermore, intermediate areas in both dorsal (V3a/b) and ventral (LO1/2) streams are significantly more active during memory encoding compared with non-memory (active and passive) processing of the same stimulus material. These effects in intermediate visual cortex are also observed during memory encoding of a different stimulus feature (spatial frequency), suggesting that these areas are involved in encoding processes on a higher level of representation. Using pattern-classification techniques to probe the representational content in visual cortex during delay periods, we further demonstrate that simply initiating memory encoding is not sufficient to produce long-lasting memory traces. Rather, active maintenance appears to underlie the observed memory-specific patterns of information in retinotopic cortex.     

A regulation role of the prefrontal cortex in the fist-edge-palm task: evidence from functional connectivity analysis

The Fist-Edge-Palm (FEP) task is a motor sequencing task that is widely used in neurological examination. Deficits in this task are believed to reflect impairment in the frontal lobe regions. However, two recent functional brain imaging studies of the FEP task using conventional subtraction analysis failed to demonstrate FEP-induced activation in the prefrontal cortex (PFC), which contradicts existing neuropsychological literature. In this study, psychophysiological interaction (PPI) analysis was used to reanalyze our previous neuroimaging dataset from 10 healthy subjects in order to evaluate the changes of functional connectivity between the sensorimotor cortex and the prefrontal regions during the performances of the FEP task relative to simple motor control tasks. The PPI analysis revealed significantly increased functional connectivity between bilateral sensorimotor cortex and the right inferior and middle frontal cortex during the performance of the FEP task compared with the control tasks. However, regional signal changes showed no significant activation differences in these prefrontal regions. These results provide evidence supporting the involvement of the frontal lobe in the performance of the FEP task, and suggest a role of regulation, rather than direct participation, of the prefrontal cortex in the execution of complex motor sequence tasks such as the FEP task.