Functional specializations in lateral prefrontal cortex associated with the integration and segregation of information in working memory

Control processes are thought to play an important role in working memory (WM), by enabling the coordination, transformation, and integration of stored information. Yet little is known about the neural mechanisms that subserve such control processes. This study examined whether integration operations within WM involve the activation of distinct neural mechanisms within lateral prefrontal cortex (PFC). Event-related functional magnetic resonance imaging was used to monitor brain activity while participants performed a mental arithmetic task. In the integration (IN) condition, a WM preload item had to be mentally inserted into the last step of the math problem. This contrasted with the segregation (SG) condition, which also required maintenance of the WM preload while performing mental arithmetic but had no integration requirement. Two additional control conditions involved either ignoring the preload (math only condition) or ignoring the math problem (recall only condition). Left anterior PFC (Brodmann's Area [BA] 46/10) was selectively engaged by integration demands, with activation increasing prior to, as well as during the integration period. A homologous right anterior PFC region showed selectively increased activity in the SG condition during the period in which the math problem and preload digit were reported. Left middorsolateral PFC regions (BA 9/46) showed increased, but equivalent, activity in both the SG and IN conditions relative to both control conditions. These results provide support for the selective role of lateral PFC in cognitive control over WM and suggest more specific hypotheses regarding dissociable PFC mechanisms involved during the integration and segregation of stored WM items.     

Common and dissociable activation patterns associated with controlled semantic and phonological processing: evidence from FMRI adaptation

Recent evidence suggests specialization of anterior left inferior prefrontal cortex (aLIPC; approximately BA 45/47) for controlled semantics and of posterior LIPC (pLIPC; approximately BA 44/6) for controlled phonology. However, the more automated phonological tasks commonly used raise the possibility that some of the typically extensive aLIPC activation during semantic tasks may relate to controlled language processing beyond the semantic domain. In the present study, an event-related fMRI adaptation paradigm was employed that used a standard controlled semantic task and a phonological task that also emphasized controlled processing. When compared with letter (baseline) processing, significant fMRI task and adaptation effects in the aLIPC and pLIPC regions ( approximately BA 45/47, approximately BA 44) were observed during both semantic and phonological processing, with aLIPC showing the strongest effects during semantic processing. A left frontal region ( approximately BA 6) showed task and relative adaptation effects preferential for phonological processing, and a left temporal region ( approximately BA 21) showed task and relative adaptation effects preferential for semantic processing. Our results demonstrate that aLIPC and pLIPC regions are involved in controlled processing across multiple language domains, arguing against a domain-specific LIPC model and for domain-preferentiality in left posterior frontal and temporal regions.     

The role of the lateral frontal cortex in causal associative learning: exploring preventative and super-learning

Prediction error--a mismatch between expected and actual outcome--is critical to associative accounts of inferential learning. However, it has proven difficult to explore the effects of prediction error using functional magnetic resonance imaging (fMRI) while excluding the confounding effects of stimulus novelty and incorrect responses. In this event-related fMRI study we used a three-stage experiment generating preventative- and super-learning conditions. In both cases, it was possible to generate prediction error within a causal associative learning experiment while subtracting the effects of novelty and error. We show that right lateral prefrontal cortex (PFC) activation is sensitive to the magnitude of prediction error. Furthermore, super-learning activation in this region of PFC correlates, across subjects, with the amount learned. We thus provide direct evidence for a brain correlate of the surprise-dependent mechanisms proposed by associative accounts of causal learning. We show that activity in right lateral PFC is sensitive to the magnitude, though not the direction, of the prediction error. Furthermore, its activity is not directly explicable in terms of novelty or response errors and appears directly related to the learning that arises out of prediction error.     

Prefrontal cortex asymmetry for memory encoding of words and abstract shapes

Previous work suggested a differential contribution of prefrontal cortex (PFC) to successful encoding depending on the stimulus material. Here, we tested the hypothesis that encoding of words preferentially involves the left PFC, while encoding of nonverbal items (abstract shapes) relies on the right PFC. We used an experimental design that evaluated encoding of both words and abstract shapes in the same healthy volunteers. A transient virtual lesion of the left or the right PFC was elicited with transcranial magnetic stimulation (TMS) while subjects memorized verbal and nonverbal items. We found that encoding of verbal material was disrupted by left PFC stimulation, whereas encoding of nonverbal material was disrupted by right PFC stimulation. These results demonstrate a functionally relevant lateralization of prefrontal contribution for verbal and nonverbal memory encoding.     

Keeping memory for intentions: a cTBS investigation of the frontopolar cortex

The present study aimed to investigate the role of frontopolar cortex in prospective memory (PM) by means of inhibitory theta-burst stimulation (cTBS). "Experiment 1"-8 volunteers were evaluated after inhibitory cTBS over left Brodmann area (BA) 10, right BA10, and Cz. In the PM procedure, sequences of 4 words each were presented. During the intersequence delay, subjects had to repeat the sequence in the observed order (ongoing task forward) or in the reverse order (backward). At the occurrence of a target word, subjects had to press a key on the keyboard (PM task). Recall and recognition of the target words were also tested. PM accuracy was lower after cTBS over left BA10 compared with Cz (P = 0.012), whereas it was comparable in right BA10 and Cz conditions. No other significant differences between the 3 conditions were found. "Experiment 2"-8 subjects were administered the same experimental PM procedure as above after inhibitory cTBS over left BA46 and Cz. In this case, none of the tested effects were significant. Our findings corroborate the hypothesis that within the prefrontal cortex, the left BA10 is specifically involved in the mediation of processes related to the execution of delayed intentions.     

Maintaining and shifting attention within left or right hemifield

Positron emission tomography (PET) was used to examine two questions: (i) which structures of the intact human brain change their activity with the direction of attention to left or right visual field; and (ii) how does activity in these structures, and in parietal cortex in particular, depend on the frequency of attentional shifts? Subjects were required to discriminate the orientation of peripheral gratings. The two main experimental variables were the attended hemifield (left or right) and the proportion of trials requiring a shift within that hemifield (20% or 80%). A detection control condition was also included. Behaviourally, subjects were less accurate and significantly slower when a trial required a shift than when it did not. Ventral and lateral occipital areas showed significantly higher blood flow levels contralateral to the direction of attention. Replicating previous work, there was also a significant main effect of the direction of attention in left lateral prefrontal cortex: blood flow levels were higher during leftward attention in comparison both to baseline and to rightward attention. This left frontal effect reached significance in single subjects in whom several activation sites could be distinguished within left middle and inferior frontal gyrus. Right and left parietal cortex were activated during both left- and right-field attention conditions, with a tendency for higher activity levels when attention was directed contralaterally. Contrary to the experimental hypothesis, however, parietal regions were not activated differentially by high versus low numbers of attentional shifts. The current experiment confirms that left frontal convexity is sensitive to manipulations of the direction of visuospatial attention. The results do not indicate a specific role of parietal cortex in attentional shifting.     

Modulation of ventral prefrontal cortex functional connections reflects the interplay of cognitive processes and stimulus characteristics

Emerging ideas of brain function emphasize the context-dependency of regional contributions to cognitive operations, where the function of a particular region is constrained by its pattern of functional connectivity. We used functional magnetic resonance imaging to examine how modality of input (auditory or visual) affects prefrontal cortex (PFC) functional connectivity for simple working memory tasks. The hypothesis was that PFC would show contextually dependent changes in functional connectivity in relation to the modality of input despite similar cognitive demands. Participants were presented with auditory or visual bandpass-filtered noise stimuli, and performed 2 simple short-term memory tasks. Brain activation patterns independently mapped onto modality and task demands. Analysis of right ventral PFC functional connectivity, however, suggested these activity patterns interact. One functional connectivity pattern showed task differences independent of stimulus modality and involved ventromedial and dorsolateral prefrontal and occipitoparietal cortices. A second pattern showed task differences that varied with modality, engaging superior temporal and occipital association regions. Importantly, these association regions showed nonzero functional connectivity in all conditions, rather than showing a zero connectivity in one modality and nonzero in the other. These results underscore the interactive nature of brain processing, where modality-specific and process-specific networks interact for normal cognitive operations.     

Cognitive control, goal maintenance, and prefrontal function in healthy aging

Cognitive control impairments in healthy older adults may partly reflect disturbances in the ability to actively maintain goal-relevant information, a function that depends on the engagement of lateral prefrontal cortex (PFC). In 2 functional magnetic resonance imaging studies, healthy young and older adults performed versions of a task in which contextual cues provide goal-relevant information used to bias processing of subsequent ambiguous probes. In Study 1, a blocked design and manipulation of the cue-probe delay interval revealed a generalized pattern of enhanced task-related brain activity in older adults but combined with a specific delay-related reduction of activity in lateral PFC regions. In Study 2, a combined blocked/event-related design revealed enhanced sustained (i.e., across-trial) activity but a reduction in transient trial-related activation in lateral PFC among older adults. Further analyses of within-trial activity dynamics indicated that, within these and other lateral PFC regions, older adults showed reduced activation during the cue and delay period but increased activation at the time of the probe, particularly on high-interference trials. These results are consistent with the hypothesis that age-related impairments in goal maintenance abilities cause a compensatory shift in older adults from a proactive (seen in young adults) to a reactive cognitive control strategy.     

Hippocampal and brain stem activation during word retrieval after repeated and semantic encoding

Repeated word presentation during learning and the use of a semantic encoding task both increase the accuracy of subsequent word retrieval. Previous neuroimaging studies have shown that successful word retrieval depends on the recruitment of the hippocampus, whereas the effort of retrieval is linked to activation of prefrontal cortex modules. We studied the effects of repetition (4x versus 1x presentation) and encoding task (semantic versus perceptual) on hippocampal and prefrontal cortex activation during word-stem cued recall using positron emission tomography. Repeated and semantic encoding resulted in increased recall accuracy, with word repetition showing a greater effect when using a semantic encoding task. The more successful retrieval of words presented repeatedly compared with words presented once was associated with activation of the left anterior hippocampus. The more successful retrieval of words encoded using a semantic compared with a perceptual task was associated with activation of the right posterior and, less significantly, the left anterior hippocampus. The greater benefit of repeated learning when using the semantic task was linked to activation of the right brainstem, in the region of the ventral tegmentum. Our results suggest that word repetition and semantic encoding increase recall accuracy during subsequent word retrieval via distinct hippocampal mechanisms and that ventral tegmentum activation is relevant for word retrieval after semantic encoding. These findings confirm the importance of hippocampal recruitment during word retrieval and provide novel evidence for a role of brainstem neurons in word retrieval after semantic encoding.     

Domain-general and domain-sensitive prefrontal mechanisms for recollecting events and detecting novelty

Recollecting the past and discriminating novel from familiar memoranda depend on poorly understood prefrontal cortical (PFC) mechanisms hypothesized to vary according to memory task (e.g. recollection versus novelty detection) and domain of targeted memories (e.g. perceptual versus conceptual). Using event-related fMRI, we demonstrate that recollecting conceptual or perceptual details surrounding object encounters similarly recruits left frontopolar and posterior PFC compared with detecting novel stimuli, suggesting that a domain-general control network is engaged during contextual remembering. In contrast, left anterior ventrolateral PFC coactivated with a left middle temporal region associated with semantic representation, and right ventrolateral PFC with bilateral occipito-temporal cortices associated with representing object form, depending on whether recollections were conceptual or perceptual. These PFC/posterior cortical dissociations suggest that during recollection, lateralized ventrolateral PFC mechanisms bias posterior conceptual or perceptual feature representations as a function of memory relevance, potentially improving the gain of bottom-up memory signals. Supporting this domain-sensitive biasing hypothesis, novelty detection also recruited right ventrolateral PFC and bilateral occipito-temporal cortices compared with conceptual recollection, suggesting that searching for novel objects heavily relies upon perceptual feature processing. Collectively, these data isolate task- from domain-sensitive PFC control processes strategically recruited in the service of episodic memory.     

Mechanisms of top-down facilitation in perception of visual objects studied by FMRI

Prior knowledge regarding the possible identity of an object facilitates its recognition from a degraded visual input, though the underlying mechanisms are unclear. Previous work implicated ventral visual cortex but did not disambiguate whether activity-changes in these regions are causal to or merely reflect an effect of facilitated recognition. We used functional magnetic resonance imaging to study top-down influences on processing of gradually revealed objects, by preceding each object with a name that was congruent or incongruent with the object. Congruently primed objects were recognized earlier than incongruently primed, and this was paralleled by shifts in activation profiles for ventral visual, parietal, and prefrontal cortices. Prior to recognition, defined on a trial-by-trial basis, activity in ventral visual cortex rose gradually but equivalently for congruently and incongruently primed objects. In contrast, prerecognition activity was greater with congruent priming in lateral parietal, retrosplenial, and lateral prefrontal cortices, whereas functional coupling between parietal and ventral visual (and also left lateral prefrontal and parietal) cortices was enhanced in the same context. Thus, when controlling for recognition point and stimulus information, activity in ventral visual cortex mirrors recognition success, independent of condition. Facilitation by top-down cues involves lateral parietal cortex interacting with ventral visual areas, potentially explaining why parietal lesions can lead to deficits in recognizing degraded objects even in the context of top-down knowledge.     

Right prefrontal activation during encoding, but not during retrieval, in a non-verbal paired-associates task

Brain imaging studies have shown that episodic encoding into long-term memory preferentially activates the left prefrontal cortex and retrieval activates the right prefrontal cortex. However, it is unclear to what degree verbal analysis contributes to the left prefrontal activation during encoding. The present study was designed to avoid verbal analysis during encoding by using abstract pictures and computer- generated sounds which were difficult to code verbally. Sounds and pictures were grouped into six stimulus-stimulus pairs. When the sound from a pair was presented, the subjects were instructed to recall and visualize the associated picture. After 2.0 s the associated picture and another picture appeared on the screen and the subjects were required to identify the associated picture. Feedback about the choice was then given. Regional cerebral blood flow (rCBF) was measured with [15O]butanol and positron emission tomography (PET) in 10 subjects during initial training on the paired-associates task (encoding scan) and after 35 min of training (retrieval scan). Performance during the encoding scan was 59% correct and during the retrieval scan 98% correct, with a mean reaction time of 709 ms during retrieval. The rCBF was also measured during a control condition without any instruction to encode or retrieve. Compared with retrieval, encoding showed significant activation of the posterior part of the right middle frontal gyrus, the right inferior parietal cortex, the cingulate cortex, the left inferior parietal cortex and the left inferior and middle temporal gyri. The rCBF increase during encoding was strongly correlated with the rate of encoding. Retrieval was compared with both encoding and control. In none of these comparisons was there any prefrontal activation. The lack of prefrontal activation during near- perfect performance of the retrieval task suggests that the prefrontal cortex is not necessarily active when retrieval is fast and accurate, or what might be called automatic. Encoding was not associated with more activation of the left than the right prefrontal cortex. This result presents a limitation to the generality of left prefrontal activation during episodic encoding, which has been found in several previous brain imaging studies. Differences between studies in the relative activation of left and right prefrontal cortex during encoding and retrieval might be due to differences in paradigms, the type of stimulus used, and the demand for working memory and verbal analysis.      

Striatal dopamine and working memory

Recent studies have emphasized the importance of dopamine projections to the prefrontal cortex (PFC) for working memory (WM) function, although this system has rarely been studied in humans in vivo. However, dopamine and PFC activity can be directly measured with positron emission tomography (PET) and functional magnetic resonance imaging (fMRI), respectively. In this study, we examined WM capacity, dopamine, and PFC function in healthy older participants in order to test the hypothesis that there is a relationship between these 3 factors. We used the PET tracer 6-[18F]fluoro-L-m-tyrosine to measure dopamine synthesis capacity in the striatum (caudate, putamen), and event-related fMRI to measure brain activation during different epochs (cue, delay, probe) of a WM task. Caudate (but not putamen) dopamine correlated positively with WM capacity, whereas putamen (but not caudate) dopamine correlated positively with motor speed. In addition, delay-related fMRI activation in a left inferior prefrontal region was related to both caudate dopamine and task accuracy, suggesting that this may be a critical site for the integration of WM maintenance processes. These results provide new evidence that striatal dopaminergic function is related to PFC-dependent functions, particularly brain activation and behavioral performance during WM tasks.     

Hemispheric specialization in human prefrontal cortex for resolving certain and uncertain inferences

Uncertainty is a fact of life that must be accommodated in real-world decision making. Although it has been suggested that the right prefrontal cortex (PFC) has a special role to play in decision making under uncertainty, there is very little hard data to support this hypothesis. To better understand the roles of left and right PFCs in reasoning and decision making in situations with complete and incomplete information, we administered simple inference problems to 18 patients with lateralized focal lesions to PFC (9 right hemisphere, 9 left hemisphere) and 22 age- and education-matched normal controls. The stimuli were systematically manipulated for completeness of information regarding the status of the conclusion. Our results demonstrated a 2-way interaction such that patients with left PFC lesions were selectively impaired in trials with complete information, whereas patients with right PFC lesions were selectively impaired in trials with incomplete information. These results provide compelling evidence for hemispheric specialization for reasoning in PFC and suggest that the right PFC has a critical role to play in reasoning about incompletely specified situations. We postulate this role involves the maintenance of ambiguous mental representations that temper premature overinterpretation by the left hemisphere.     

Neural evidence for dissociable components of task-switching

The ability to retrieve and flexibly switch between task rules is seen as an important component of cognitive control. It is often assumed that lateral prefrontal cortex (latPFC) is important for switching between rules. However, activation associated with rule-switching is less reliably observed in latPFC than in medial PFC (specifically, pre-supplementary motor area). In this study, we tested the hypothesis that medial PFC is important for reconfiguration of task sets, whereas latPFC is important for retrieving, maintaining and implementing relevant rules (i.e. rule representation). Twenty young adults participated in a functional magnetic resonance imaging study in which they determined the correct response to a target stimulus on the basis of an instructional cue. For bivalent targets, the appropriate response depended on the currently relevant rule. In contrast, univalent targets were always associated with the same response. Brain regions of interest were characterized according to their responsiveness to bivalent and univalent targets, on both rule-switch and rule-repetition trials. The data support the hypothesis that rule representation and task-set reconfiguration are separable cognitive processes, associated with dissociable neural activation in latPFC and medial PFC, respectively. Activation profiles of posterior parietal cortex, basal ganglia and rostrolateral PFC are also examined and discussed.     

The neural correlates of declining performance with age: evidence for age-related changes in cognitive control

The neural system involved in cognitive control includes the anterior cingulate cortex (ACC) and the lateral prefrontal cortex (PFC). Neural activity within these structures is sensitive to aging. We investigated the hypothesis that decline in performance with age results in increased cognitive control, as indexed by greater activity within the ACC and lateral PFC. Using positron emission tomography we measured neural activity during a range of verbal decision-making tasks in 16 subjects aged 37-83 years. Conditions were separated behaviorally on the basis of their sensitivity to aging. This allowed the comparison of age-dependent and age-independent conditions, revealing the neural correlates of age-dependent decline in performance. We then modeled the relationship between age, decision type, performance, and frontal lobe activity. ACC activity was independently predicted by age and decision-making accuracy, indicating that in older individuals ACC response is more sensitive to declining performance. We also found strong functional connectivity between the ACC and lateral PFC and observed that activation of the lateral PFC was qualitatively different over time in different age groups. Thus, the ACC and lateral PFC show distinct responses to age-related decline in decision-making performance. This suggests that greater cognitive control is employed as individuals age and their performance declines.     

Dissociating the roles of the rostral anterior cingulate and the lateral prefrontal cortices in performing two tasks simultaneously or successively

A fundamental question about the nature of cognitive control is whether performing two tasks successively or simultaneously activates distinct brain regions. To investigate this question, we designed a functional magnetic resonance imaging (fMRI) study that compared task-switching and dual-task performance. The results showed that performing two tasks successively or simultaneously activated a common prefronto-parietal neural network relative to performing each task separately. More importantly, we found that the anterior cingulate and the lateral prefrontal cortices were differently activated in dual-task and task-switching situations. When performing two tasks simultaneously, as compared to performing them in succession, activation was found in the rostral anterior cingulate cortex. In contrast, switching between two tasks, relative to performing them simultaneously, activated the left lateral prefrontal cortex and the bilateral intra-parietal sulcus region. We interpret these results as indicating that the rostral anterior cingulate cortex serves to resolve conflicts between stimulus-response associations when performing two tasks simultaneously, while the lateral prefrontal cortex dynamically selects the neural pathways needed to perform a given task during task switching.     

FMRI evidence for an organization of prefrontal cortex by both type of process and type of information

Neuroimaging evidence is conflicting regarding whether human prefrontal cortex (PFC) shows functional organization by type of processes engaged or type of information processed. Most studies use complex working or long-term memory tasks requiring multiple processes and the combinations of processes recruited for different materials may vary. Using functional magnetic resonance imaging (fMRI) and simple tasks suggested by a component process approach, we found activity in left PFC when participants thought about (refreshed) a just-seen item and in right PFC when participants noted whether an item had been presented previously. Furthermore, the distribution of activation in left or right PFC varied with type of information. Thus, at the component process level, PFC shows functional organization by both process and type of information.     

Aβ Deposition in aging is associated with increases in brain activation during successful memory encoding

To investigate early effects of beta-amyloid (Aβ) on neuronal function, elderly normal controls (NCs, age range 58-97) were scanned with Pittsburgh Compound-B (PIB) positron emission tomography (a measure of Aβ) as well as functional magnetic resonance imaging (a measure of brain activation) while performing an episodic memory-encoding task of natural scenes (also performed by young NCs; age range 18-30). Relationships between Aβ and activation were assessed across task-positive (regions that activate for subsequently remembered vs. forgotten scenes) and task-negative regions (regions that deactivate for subsequently remembered vs. forgotten scenes). Significant task-related activation was present in a distributed network spanning ventrolateral prefrontal, lateral occipital, lateral parietal, posterior inferior temporal cortices, and the right parahippocampal/hippocampus, whereas deactivation was present in many default mode network regions (posteromedial, medial prefrontal, and lateral temporoparietal cortices). Task-positive activation was higher in PIB+ compared with PIB- subjects, and this activation was positively correlated with memory measures in PIB+ subjects. Although task deactivation was not impaired in PIB+ NCs, deactivation was reduced in old versus young subjects and was correlated with worse task memory performance among old subjects. Overall, these results suggest that heightened activation during episodic memory encoding is present in NC elderly subjects with high Aβ.     

Evidence of left inferior frontal-premotor structural and functional connectivity deficits in adults who stutter

The neurophysiological basis for stuttering may involve deficits that affect dynamic interactions among neural structures supporting fluid speech processing. Here, we examined functional and structural connectivity within corticocortical and thalamocortical loops in adults who stutter. For functional connectivity, we placed seeds in the left and right inferior frontal Brodmann area 44 (BA44) and in the ventral lateral nucleus (VLN) of the thalamus. Subject-specific seeds were based on peak activation voxels captured during speech and nonspeech tasks using functional magnetic resonance imaging. Psychophysiological interaction (PPI) was used to find brain regions with heightened functional connectivity with these cortical and subcortical seeds during speech and nonspeech tasks. Probabilistic tractography was used to track white matter tracts in each hemisphere using the same seeds. Both PPI and tractrography supported connectivity deficits between the left BA44 and the left premotor regions, while connectivity among homologous right hemisphere structures was significantly increased in the stuttering group. No functional connectivity differences between BA44 and auditory regions were found between groups. The functional connectivity results derived from the VLN seeds were less definitive and were not supported by the tractography results. Our data provide strongest support for deficient left hemisphere inferior frontal to premotor connectivity as a neural correlate of stuttering.