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.     

Complex span tasks and hippocampal recruitment during working memory

The working memory (WM) system is vital to performing everyday functions that require attentive, non-automatic processing of information. However, its interaction with long term memory (LTM) is highly debated. Here, we used fMRI to examine whether a popular complex WM span task, thought to force the displacement of to-be-remembered items in the focus of attention to LTM, recruited medial temporal regions typically associated with LTM functioning to a greater extent and in a different manner than traditional neuroimaging WM tasks during WM encoding and maintenance. fMRI scans were acquired while participants performed the operation span (OSPAN) task and an arithmetic task. Results indicated that performance of both tasks resulted in significant activation in regions typically associated with WM function. More importantly, significant bilateral activation was observed in the hippocampus, suggesting it is recruited during WM encoding and maintenance. Right posterior hippocampus activation was greater during OSPAN than arithmetic. Persitimulus graphs indicate a possible specialization of function for bilateral posterior hippocampus and greater involvement of the left for WM performance. Recall time-course activity within this region hints at LTM involvement during complex span.     

Dissociating a common working memory network from different neural substrates of phonological and spatial stimulus processing.

Positron emission tomography was used to investigate common versus specific cortical regions for the maintenance of spatial versus phonological information in working memory (WM). Group and single-subject analyses of regional cerebral blood flow during a new 2 x 2 factorial n-back task were performed. Eight subjects had to memorize either phonological features or the location of serially presented syllables. Brain activation during phonological judgment and spatial judgment (0-back) was compared with that during two corresponding WM conditions (2-back). We observed a common network associated with the requirement of maintaining and sequencing items in WM. Seven or more subjects activated (posterior) superior frontal sulcus (pSFS, BA 6/8, global maximum) and/or adjacent gyri, posterior parietal cortex, and precuneus (BA 7). Less consistently, bilateral middle frontal gyrus (BA 9/46) was involved. Bilateral anterior (BA 39/40) and posterior (BA 7) intraparietal sulcus, as well as right pSFS, exhibited dominance for spatial WM. Although underlying stimulus processing pathways for both types of information were different, no region specific for phonological WM was found. Robust activation within the left inferior frontal gyrus (BA 44 and 45) was present, during both phonological WM and phonological judgment. We conclude that the controversial left prefrontal lateralization for verbal WM reflects more general phonological processing strategies, not necessarily required by tasks using letters. We propose a stimulus-independent role for the bilateral pSFS and its vicinity for maintenance and manipulation of different context-dependent information within working memory.     

Trial-by-trial coupling between EEG and BOLD identifies networks related to alpha and theta EEG power increases during working memory maintenance

PET and fMRI experiments have previously shown that several brain regions in the frontal and parietal lobe are involved in working memory maintenance. MEG and EEG experiments have shown parametric increases with load for oscillatory activity in posterior alpha and frontal theta power. In the current study we investigated whether the areas found with fMRI can be associated with these alpha and theta effects by measuring simultaneous EEG and fMRI during a modified Sternberg task This allowed us to correlate EEG at the single trial level with the fMRI BOLD signal by forming a regressor based on single trial alpha and theta power estimates. We observed a right posterior, parametric alpha power increase, which was functionally related to decreases in BOLD in the primary visual cortex and in the posterior part of the right middle temporal gyrus. We relate this finding to the inhibition of neuronal activity that may interfere with WM maintenance. An observed parametric increase in frontal theta power was correlated to a decrease in BOLD in regions that together form the default mode network. We did not observe correlations between oscillatory EEG phenomena and BOLD in the traditional WM areas. In conclusion, the study shows that simultaneous EEG-fMRI recordings can be successfully used to identify the emergence of functional networks in the brain during the execution of a cognitive task.     

How does the brain accommodate to increased task difficulty in word finding? A functional MRI study

In functional imaging of the brain, the difficulty of a task may be critical for the pattern of activation. Increased task difficulty could lead to increased activation in task-specific regions or to activation of additional, "compensatory" regions. A previous study with functional transcranial Doppler sonography (fTCD) showed no evidence that increased difficulty in word retrieval leads to a recruitment of areas homologous to language-related regions. The question remains how the brain accommodates increasing task difficulty. Because of limitations of fTCD method, we used functional magnetic resonance imaging (fMRI) in this study. We manipulated word retrieval difficulty in healthy subjects (n = 14) to determine whether the classical language-related brain regions are activated with increasing difficulty in word retrieval. fMRI demonstrated that with increased task difficulty (I) the lateralization of language-associated brain activation remained constant, (II) no additional activation of language-related regions of the dominant hemisphere, nor of homologous regions of the subdominant hemisphere, was evident, (III) additional activation was found in right posterior parietal cortex--typically associated with sustained attention and executive control. Thus, increased difficulty in word retrieval leads to coactivation of distinct brain areas, working together in a large cognitive network, rather than to increased activation of typically language-related areas.     

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.     

Delayed verbal memory retrieval: a functional MRI study in epileptic patients with structural lesions of the left medial temporal lobe.

In a previous functional magnetic resonance imaging (fMRI) study, we suggested that in left medial temporal lobe epilepsy (LTLE) poor verbal episodic memory performances were sustained by abnormal neocortical and mesiotemporal activations. In the present study, we attempted to examine the evolution of these abnormal neocortical and mesiotemporal activations over 24 h. We thus observed the fMRI brain regions activated during the 24-h-delayed retrieval of a word list in the same sample of healthy control subjects and LTLE patients. In control subjects, a similar left occipitotemporofrontal network was activated during both immediate and 24-h-delayed retrieval conditions. In addition, the 24-h-delayed retrieval also activated a larger parietal region and the right hippocampus. This distributed neocortical and mesiotemporal network was very poorly activated during the 24-h-delayed retrieval in LTLE patients, suggesting the inability to reactivate areas that are keys to retrieving stored information.     

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.     

Neural system for updating object working memory from different sources: sensory stimuli or long-term memory

Working memory (WM) is the active maintenance of currently relevant information so that it is available for use. A crucial component of WM is the ability to update the contents when new information becomes more relevant than previously maintained information. New information can come from different sources, including from sensory stimuli (SS) or from long-term memory (LTM). Updating WM may involve a single neural system regardless of source, distinct systems for each source, or a common network with additional regions involved specifically in sensory or LTM processes. The current series of experiments indicates that a single fronto-parietal network (including supplementary motor area, parietal, left inferior frontal junction, middle frontal gyrus) is active in updating WM regardless of the source of information. Bilateral cuneus was more active during updating WM from LTM than updating from SS, but the activity in this region was attributable to recalling information from LTM regardless of whether that information was to be entered into WM for future use or not. No regions were found to be more active during updating from SS than updating from LTM. Functional connectivity analysis revealed that different regions within this common update network were differentially more correlated with visual processing regions when participants updated from SS, and more correlated with LTM processing regions when participants updated from the contents of LTM. These results suggest that a single neural mechanism is responsible for controlling the contents of WM regardless of whether that information originates from a sensory stimulus or from LTM. This network of regions involved in updating WM interacts with the rest of the brain differently depending on the source of newly relevant information.     

Methylphenidate enhances brain activation and deactivation responses to visual attention and working memory tasks in healthy controls

Methylphenidate (MPH) is a stimulant drug that amplifies dopamineric and noradrenergic signaling in the brain, which is believed to underlie its cognition enhancing effects. However, the neurobiological effects by which MPH improves cognition are still poorly understood. Here, functional magnetic resonance imaging (fMRI) was used together with working memory (WM) and visual attention (VA) tasks to test the hypothesis that 20mg oral MPH would increase activation in the dorsal attention network (DAN) and deactivation in the default mode network (DMN) as well as improve performance during cognitive tasks in healthy men. The group of subjects that received MPH (MPH group; N=16) had higher activation than the group of subjects who received no medication (control group: N=16) in DAN regions (parietal and prefrontal cortex, regions increasingly activated with increased cognitive load) and had increased deactivation in the insula and posterior cingulate cortex (regions increasingly deactivated with increased cognitive load) and these effects did not differ for the VA and the WM tasks. These findings provide the first evidence that MPH enhances activation of the DAN whereas it alters DMN deactivation. This suggests that MPH (presumably by amplifying dopamine and noradrenergic signaling) modulates cognition in part through its effects on DAN and DMN.     

Dissociating state and item components of recognition memory using fMRI

Cognitive functions such as memory retrieval involve a combination of state- and item-related processes. State-related processes are sustained throughout a task (e.g., "retrieval mode" associated with ongoing goals), whereas item-related processes are transient and allied to individual stimuli (e.g., "retrieval success" associated with the recovery of information from memory). The present study employed a mixed "blocked and event-related" experimental design to identify neural mechanisms that support state- and item-related processes during a recognition memory task. Subjects alternated between blocks of fixation and recognition memory (discriminating between old and new words). Critically, event-related procedures were embedded within the recognition blocks, including the jittering of sequential trials. This design ensures that the temporal profiles of state- and item-related activity differ and consequently renders them separable; without this procedure item-related activity would summate to produce a state-like response. Results suggest three classes of brain region support recognition memory, exhibiting: (1) predominantly transient activity (including regions in medial parietal, lateral parietal, and anterior left frontal cortex) reflecting item-related processing associated with "retrieval success," (2) predominantly sustained activity (including decreased activity in bilateral parahippocampal cortex) reflecting state-related processing associated with "retrieval mode," (3) concurrent sustained and transient activity (including regions in left middle frontal gyrus, bilateral frontal operculum, and medial frontal gyrus), reflecting a combination of state- and item-related processing. The present findings support the idea that recognition memory tasks are dependent upon a combination of state- and item-related processes that have dissociable neural correlates identifiable using fMRI. Moreover, the mixed "blocked and event-related" design employed here provides a general procedure for separating state- and item-related processes.     

Temporal dynamics of basal ganglia response and connectivity during verbal working memory

Research on the neural basis of working memory (WM) has generally focused on neocortical regions; comparatively little is known about the role of subcortical structures. There is growing evidence that the basal ganglia are involved in WM, but their contribution to different component processes of WM is poorly understood. We examined the temporal dynamics of basal ganglia response and connectivity during the encoding, maintenance and response phases of a Sternberg WM task. During the encoding and maintenance phases, WM-load-dependent activation was observed in the left anterior caudate, anterior putamen and globus pallidus; activation in the right anterior caudate was observed only during the maintenance phase. During the response phase, the basal ganglia were equally active in both the high-load and low-load WM conditions. Caudate and putamen activations were primarily localized to the (rostral) associative parts of the basal ganglia, consistent with the putative role of these regions in cognitive processing. Effective connectivity analyses revealed increased WM-load-dependent interaction of the left anterior caudate with the left posterior parietal cortex during all three phases of the task; with the visual association cortex, including the fusiform gyrus and inferior temporal gyrus, only during the encoding phase; with the ventrolateral prefrontal cortex during the encoding and maintenance phases; with the pre-supplementary motor area during the maintenance and response phases; and with the dorsolateral prefrontal and anterior cingulate cortices only during the response phase. Taken together with known neuroanatomy of the basal ganglia, these results suggest that the anterior caudate helps to link signals in distinct functional networks during different phases of the WM task. Our study offers new insight into the integrative and adaptive role of the basal ganglia in higher cognitive function.     

fMRI evidence of brain reorganization during attention and memory tasks in multiple sclerosis

Functional magnetic resonance imaging (fMRI) data on motor function have shown adaptive functional changes related to brain injury in multiple sclerosis (MS). We investigated whether patients with MS have altered fMRI activation patterns during attention and memory tasks, and whether functional changes in the brain correlate with the extent of overall tissue damage on conventional MRI. Twenty-two right-handed patients with relapsing-remitting MS (RRMS) and no or only mild deficits at neuropsychological testing and 22 matched healthy subjects were scanned during the Paced Auditory Serial Addition Test (PASAT) and a recall task. fMRI data were analyzed using Statistical Parametric Mapping (SPM99). The relation between fMRI changes during both tasks and T2 lesion load was investigated. During both tasks, patients exhibited significantly greater brain activation than controls and recruited additional brain areas. Task-related functional changes were more significant in patients whose performance matched that of controls than in patients with a lower performance. During the PASAT, brain functional changes involved the right supplementary motor area and cingulate, the bilateral prefrontal, temporal and parietal areas, whereas during the recall task they involved the prefrontal and temporal cortex and basal ganglia bilaterally, and the left thalamus. In patients, activation in specific brain areas during performance of both tasks positively correlated with T2 brain lesions. Patients with RRMS exhibit altered patterns of activation during tasks exploring sustained attention, information processing and memory. During these tasks, fMRI activity is greater in patients with better cognitive function than in those with lower cognitive function. Functional changes in specific brain areas increase with increasing tissue damage suggesting that they may also represent adaptive mechanisms that reflect underlying neural disorganization or disinhibition, possibly associated with MS.     

Age-related changes in working memory during sentence comprehension: an fMRI study.

Sentence comprehension declines with age, but the neural basis for this change is unclear. We monitored regional brain activity in 13 younger subjects and 11 healthy seniors matched for sentence comprehension accuracy while they answered a simple probe about written sentences. The sentences varied in their grammatical features (subject-relative vs object-relative subordinate clause) and their verbal working memory (WM) demands (short vs long antecedent noun-gap linkage). We found that young and senior subjects both recruit a core written sentence processing network, including left posterolateral temporal and bilateral occipital cortex for all sentences, and ventral portions of left inferior frontal cortex for object-relative sentences with a long noun-gap linkage. Differences in activation patterns for seniors compared to younger subjects were due largely to changes in brain regions associated with a verbal WM network. While seniors had less left parietal recruitment than younger subjects, left premotor cortex, and dorsal portions of left inferior frontal cortex showed greater activation in seniors compared to younger subjects. Younger subjects recruited right posterolateral temporal cortex for sentences with a long noun-gap linkage. Seniors additionally recruited right parietal cortex for this sentence-specific form of WM. Our findings are consistent with the hypothesis that the neural basis for sentence comprehension includes dissociable but interactive large-scale neural networks supporting core written sentence processes and related cognitive resources involved in WM. Seniors with good comprehension appear to up-regulate portions of the neural substrate for WM during sentence processing to achieve comprehension accuracy that equals young subjects.     

Common neural substrates for visual working memory and attention

Humans are severely limited in their ability to memorize visual information over short periods of time. Selective attention has been implicated as a limiting factor. Here we used functional magnetic resonance imaging to test the hypothesis that this limitation is due to common neural resources shared by visual working memory (WM) and selective attention. We combined visual search and delayed discrimination of complex objects and independently modulated the demands on selective attention and WM encoding. Participants were presented with a search array and performed easy or difficult visual search in order to encode one or three complex objects into visual WM. Overlapping activation for attention-demanding visual search and WM encoding was observed in distributed posterior and frontal regions. In the right prefrontal cortex and bilateral insula blood oxygen-level-dependent activation additively increased with increased WM load and attentional demand. Conversely, several visual, parietal and premotor areas showed overlapping activation for the two task components and were severely reduced in their WM load response under the condition with high attentional demand. Regions in the left prefrontal cortex were selectively responsive to WM load. Areas selectively responsive to high attentional demand were found within the right prefrontal and bilateral occipital cortex. These results indicate that encoding into visual WM and visual selective attention require to a high degree access to common neural resources. We propose that competition for resources shared by visual attention and WM encoding can limit processing capabilities in distributed posterior brain regions.     

Cortical capacity constraints for visual working memory: dissociation of fMRI load effects in a fronto-parietal network

Working memory (WM) capacity limitations and their neurophysiological correlates are of special relevance for the understanding of higher cognitive functions. Evidence from behavioral studies suggests that restricted attentional resources contribute to these capacity limitations. In an event-related functional magnetic resonance imaging (fMRI) study, we probed the capacity of the human visual WM system for up to four complex nonnatural objects using a delayed discrimination task. A number of prefrontal and parietal areas bilaterally showed increased blood oxygen level-dependent activity, relative to baseline, throughout the task when more than one object had to be held in memory. Monotonic increases in response to memory load were observed bilaterally in the dorsolateral prefrontal cortex (DLPFC) and the presupplementary motor area (pre-SMA). Conversely, activity in the frontal eye fields (FEFs) and in areas along the intraparietal sulcus (IPS) peaked when subjects had to maintain only two or three objects and decreased in the highest load condition. This dissociation of memory load effects on cortical activity suggests that the cognitive operations subserved by the IPS and FEF, which are most likely related to attention, fail to support visual WM when the capacity limit is approached. The correlation of brain activity with performance implies that only the operations performed by the DLPFC and pre-SMA, which support an integrated representation of visual information, helped subjects to maintain a reasonable level of performance in the highest load condition. These results indicate that at least two distinct cortical subsystems are recruited for visual WM, and that their interplay changes when the capacity limit is reached.     

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).     

Distinct neural correlates of associative working memory and long-term memory encoding in the medial temporal lobe

Increasing evidence suggests a role for the hippocampus not only in long-term memory (LTM) but also in relational working memory (WM) processes, challenging the view of the hippocampus as being solely involved in episodic LTM. However, hippocampal involvement reported in some neuroimaging studies using "classical" WM tasks may at least partly reflect incidental LTM encoding. To disentangle WM processing and LTM formation we administered a delayed-match-to-sample associative WM task in an event-related fMRI study design. Each trial of the WM task consisted of four pairs of faces and houses, which had to be maintained during a delay of 10s. This was followed by a probe phase consisting of three consecutively presented pairs; for each pair participants were to indicate whether it matched one of the pairs of the encoding phase. After scanning, an unexpected recognition-memory (LTM) task was administered. Brain activity during encoding was analyzed based on WM and LTM performance. Hence, encoding-related activity predicting WM success in the absence of successful LTM formation could be isolated. Furthermore, regions critical for successful LTM formation for pairs previously correctly processed in WM were analyzed. Results showed that the left parahippocampal gyrus including the fusiform gyrus predicted subsequent accuracy on WM decisions. The right anterior hippocampus and left inferior frontal gyrus, in contrast, predicted successful LTM for pairs that were previously correctly classified in the WM task. Our results suggest that brain regions associated with higher-level visuo-perceptual processing are involved in successful associative WM encoding, whereas the anterior hippocampus and left inferior frontal gyrus are involved in successful LTM formation during incidental encoding.     

Content-specific activation during associative long-term memory retrieval

We tested whether visual stimulus material that is assumed to be processed in different cortical networks during perception (i.e., faces and spatial positions) is also topographically dissociable during long-term memory recall. With an extensive overlearning procedure, 12 participants learned paired associates of words and faces and words and spatial positions. Each word was combined with either one or two positions or one or two faces. fMRI was recorded several days later during a cued recall test, in which two words were presented and the participants had to decide whether these were linked to each other via a common mediator, i.e., a face or a position. This paradigm enforces retrieval from long-term memory without confounding recall with perceptual processes. A network of cortical areas was found to be differently activated during recall of positions and faces, including regions along the dorsal and ventral visual pathways, such as the parietal and precentral cortex for positions and the left prefrontal, temporal (including fusiform gyrus) and posterior cingulate cortex for faces. In a subset of these areas, the BOLD response was found to increase monotonically with the number of the to-be-re-activated associations. These results show that material-specific cortical networks are systematically activated during long-term memory retrieval that overlap with areas also activated by positions and faces during perceptual and working memory tasks.     

Defining functional SMA and pre-SMA subregions in human MFC using resting state fMRI: Functional connectivity-based parcellation method

Noninvasive parcellation of the human cerebral cortex is an important goal for understanding and examining brain functions. Recently, the patterns of anatomical connections using diffusion tensor imaging (DTI) have been used to parcellate brain regions. Here, we present a noninvasive parcellation approach that uses “functional fingerprints” obtained by correlation measures on resting state functional magnetic resonance imaging (fMRI) data to parcellate brain regions. In other terms, brain regions are parcellated based on the similarity of their connection – as reflected by correlation during resting state – to the whole brain. The proposed method was used to parcellate the medial frontal cortex (MFC) into supplementary motor areas (SMA) and pre-SMA subregions. In agreement with anatomical landmark-based parcellation, we find that functional fingerprint clustering of the MFC results in anterior and posterior clusters. The probabilistic maps from 12 subjects showed that the anterior cluster is mainly located rostral to the vertical commissure anterior (VCA) line, whereas the posterior cluster is mainly located caudal to VCA line, suggesting the homologues of pre-SMA and SMA. The functional connections from the putative pre-SMA cluster were connected to brain regions which are responsible for complex/cognitive motor control, whereas those from the putative SMA cluster were connected to brain regions which are related to the simple motor control. These findings demonstrate the feasibility of the functional connectivity-based parcellation of the human cerebral cortex using resting state fMRI.