Analogical reasoning and prefrontal cortex: evidence for separable retrieval and integration mechanisms

The present study examined the contributions of prefrontal cortex (PFC) subregions to two component processes underlying verbal analogical reasoning: semantic retrieval and integration. Event-related functional magnetic resonance imaging data were acquired while subjects performed propositional analogy and semantic decision tasks. On each trial, subjects viewed a pair of words (pair 1), followed by an instructional cue and a second word pair (pair 2). On analogy trials, subjects evaluated whether pair 2 was semantically analogous to pair 1. On semantic trials, subjects indicated whether the pair 2 words were semantically related to each other. Thus, analogy--but not semantic--trials required integration across multiple retrieved relations. To identify regions involved in semantic retrieval, we manipulated the associative strength of pair 1 words in both tasks. Anterior left inferior PFC (aLIPC) was modulated by associative strength, consistent with a role in controlled semantic retrieval. Left frontopolar cortex was insensitive to associative strength, but was more sensitive to integration demands than was aLIPC, consistent with a role in integrating the products of semantic retrieval to evaluate whether distinct representations are analogous. Right dorsolateral PFC exhibited a profile consistent with a role in response selection rather than retrieval or integration. These findings indicate that verbal analogical reasoning depends on multiple, PFC-mediated computations.     

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.     

A direct comparison of anterior prefrontal cortex involvement in episodic retrieval and integration

Retrieval of information from episodic memory reliably engages regions within the anterior prefrontal cortex (aPFC). This observation has led researchers to suggest that these regions may subserve processes intimately tied to episodic retrieval. However, the aPFC is also recruited by other complex tasks not requiring episodic retrieval. One hypothesis concerning these results is that episodic retrieval recruits a general cognitive process that is subserved by the aPFC. The current study tested a specific version of this hypothesis--namely, that the integration of internally represented information is this process. Event-related fMRI was employed in a 2 (memory task: encoding versus retrieval) x 2 (level of integration: low versus high) factorial within-subjects design. A functional dissociation was observed, with one aPFC subregion uniquely sensitive to level of integration and another jointly sensitive to level of integration and memory task. Analysis of event-related activation latencies indicated that level of integration and memory task effects occurred with significantly different timing. The results provide the first direct evidence regarding the functional specialization within lateral aPFC and the nature of its recruitment during complex cognitive tasks. Moreover, the study highlights the benefits of activation latency analysis for understanding functional contributions and dissociations between closely linked brain regions.     

Where Is ELSA? The Early to Late Shift in Aging

Studies of cognitive and neural aging have recently provided evidence of a shift from an early- to late-onset cognitive control strategy, linked with temporally extended activity in the prefrontal cortex (PFC). It has been uncertain, however, whether this age-related shift is unique to PFC and executive control tasks or whether the functional location might vary depending on the particular cognitive processes that are altered. The present study tested whether an early-to-late shift in aging (ELSA) might emerge in the medial temporal lobes (MTL) during a protracted context memory task comprising both anticipatory cue (retrieval preparation) and retrieval probe (retrieval completion) phases. First, we found reduced MTL activity in older adults during the early retrieval preparation phase coupled with increased MTL activity during the late retrieval completion phase. Second, we found that functional connectivity between MTL and PFC regions was higher during retrieval preparation in young adults but higher during retrieval completion in older adults, suggesting an important interactive relationship between the ELSA pattern in MTL and PFC. Taken together, these results critically suggest that aging results in temporally lagged activity even in regions not typically associated with cognitive control, such as the MTL.     

Learning-related neuronal responses in prefrontal cortex studied with functional neuroimaging

We assessed time-dependent neuronal activity accompanying learning using functional magnetic resonance imaging (fMRI). An artificial grammar learning paradigm enabled us to dissociate activations associated with individual item learning from those involved in learning the underlying grammar system. We show that a localized region of right prefrontal cortex (PFC) is preferentially sensitive to individual item learning during the early stages of the experiment, while the left PFC region is sensitive to grammar learning which occurred across the entire course of the experiment. In addition to dissociating these two types of learning, we were able to characterize the effect of rule acquisition on neuronal responses associated with explicit learning of individual items. This effect was expressed as modulation of the time-dependent right PFC activations such that the early increase in activation associated with item learning was attenuated as the experiment progressed. In a further analysis we used structural equation modelling to explore time-dependent changes in inter-regional connectivity as a function of both item and grammar rule learning. Although there were no significant effects of item learning on the measured path strengths, rule learning was associated with a decrease in right fronto-parietal connectivity and an increase in connectivity between left and right PFC. Further fronto-parietal path strengths were observed to change, with an increase in left fronto-parietal and a decrease in right fronto-parietal connectivity path strength from right PFC to left parietal cortex. We interpret our findings in terms of a left frontal system mediating the semantic analysis of study items and directly influencing a right fronto-parietal system associated with episodic memory retrieval.     

Disturbing visual working memory: electrophysiological evidence for a role of the prefrontal cortex in recovery from interference

Single cell recordings in monkeys support the notion that the lateral prefrontal cortex (PFC) controls reactivation of visual working memory representations when rehearsal is disrupted. In contrast, recent fMRI findings yielded a double dissociation for PFC and the medial temporal lobe (MTL) in a letter working memory task. PFC was engaged in interference protection during reactivation while MTL was prominently involved in the retrieval of the letter representations. We present event-related potential data (ERP) that support PFC involvement in the top-down control of reactivation during a visual working memory task with endogenously triggered recovery after visual interference. A differentiating view is proposed for the role of PFC in working memory with respect to endogenous/exogenous control and to stimulus type. General implications for binding and retention mechanisms are discussed.     

The effects of aging on material-independent and material-dependent neural correlates of source memory retrieval

Age-related declines in source memory have been observed for various stimuli and associated details. These impairments may be related to alterations in brain regions contributing to source memory via material-independent processes and/or regions specialized for processing specific materials. Using event-related functional magnetic resonance imaging, we investigate the effects of aging on source memory and associated neural activity for words and objects. Source accuracy was equally impaired in older adults for both materials. Imaging data revealed both groups recruited similar networks of regions to support source memory accuracy irrespective of material, including parietal and prefrontal cortices (PFC) and the hippocampus. Age-related decreases in material-independent activity linked to postretrieval monitoring were observed in right lateral PFC. Additionally, age-related increases in source accuracy effects were shown in perirhinal cortex, which were positively correlated with performance in older adults, potentially reflecting functional compensation. In addition to group differences in material-independent regions, age-related crossover interactions for material-dependent source memory effects were observed in regions selectively engaged by objects. These results suggest that older adults' source memory impairments reflect alterations in regions making material-independent contributions to source memory retrieval, primarily the lateral PFC, but may be further impacted by changes in regions sensitive to particular materials.     

Role of prefrontal and anterior cingulate regions in decision-making processes shared by memory and nonmemory tasks

In the episodic retrieval (ER) domain, activations in right dorsolateral prefrontal cortex (DLPFC) are often attributed to postretrieval monitoring. Yet, right DLPFC activations are also frequently found during nonmemory tasks. To investigate the role of this region across different cognitive functions, we directly compared brain activity during ER and visual perception (VP) using event-related functional magnetic resonance imaging. In the ER task, participants decided whether words were old or new, whereas in the VP task, they decided which of the two colored screen areas was larger. In both tasks, each decision was followed by a confidence rating. The main finding was that right DLPFC (Brodmann area 46/10) activity was greater for low- than for high-confidence decisions in both tasks, demonstrating a general role in decision making. Even when reaction times (RTs) were included in the model, confidence remained the significant predictor of activity, suggesting that right DLPFC is involved in discontinuous evaluation rather than in continuous monitoring. In contrast, activity in anterior cingulate cortex was not only greater for low-confidence decisions but also increased with RT, reflecting a role in continuous conflict monitoring. Overall, the results demonstrate how direct cross-function comparisons clarify the generality and specificity of the functions of various brain regions.     

Brain activity underlying encoding and retrieval of source memory

Neural activity elicited during the encoding and retrieval of source information was investigated with event-related functional magnetic resonance imaging (efMRI). During encoding, 17 subjects performed a natural/artificial judgement on pictures of common objects which were presented randomly in one of the four quadrants of the display. At retrieval, old pictures were mixed with new ones and subjects judged whether each picture was new or old and, if old, indicated in which quadrant it was presented at encoding. During encoding, study items that were later recognized and assigned a correct source judgement elicited greater activity than recognized items given incorrect judgements in a variety of regions, including right lateral occipital and left prefrontal cortex. At retrieval, regions showing greater activity for recognized items given correct versus incorrect source judgements included the right hippocampal formation and the left prefrontal cortex. These findings indicate a role for these regions in the encoding and retrieval of episodic information beyond that required for simple item recognition.     

Differential anterior prefrontal activation during the recognition stage of a spatial working memory task

Neuroimaging studies commonly show widespread activations in the prefrontal cortex during various forms of working memory and long-term memory tasks. However, the anterior prefrontal cortex (aPFC, Brodmann area 10) has been mainly associated with retrieval in episodic memory, and its role in working memory is less clear. We conducted an event-related functional magnetic resonance imaging study to examine brain activations in relation to recognition in a spatial delayed-recognition task. Similar to the results from previous findings, several frontal areas were strongly activated during the recognition phase of the task, including the aPFC, the lateral PFC and the anterior cingulate cortex. Although the aPFC was more active during the recognition phase, it was also active during the delay phase of the spatial working memory task. In addition, the aPFC showed greater activity in response to negative probes (non-targets) than to positive probes (targets). While our analyses focused on examining signal changes in the aPFC, other prefrontal regions showed similar effects and none of the areas were more active in response to the positive probes than to the negative probes. Our findings support the conclusion that the aPFC is involved in working memory and particularly in processes that distinguish target and non-target stimuli during recognition.     

Prefrontal selection and medial temporal lobe reactivation in retrieval of short-term verbal information

Both the prefrontal cortex (PFC) and medial temporal lobe (MTL) are involved in memory retrieval. Here we distinguish between their roles by manipulating demand for interference resolution and reactivation of maintained information. Subjects were tested on a letter working memory task with distractors. When the memory delay was interrupted with letter distractors, there was higher activity in the middle frontal gyrus at retrieval compared to when the delay was interrupted by number distractors, suggesting the role of the PFC in interference resolution. By contrast, activity in the parahippocampal gyrus did not differ between the two conditions. The two structures were then compared using the dataset of our previous study on memory reactivation, where subjects performed a letter working memory task with arithmetic distractors or non-distractors. The activity in the parahippocampal gyrus at retrieval was higher when distractors interrupted rehearsal than when the intervening task was non-distracting and subjects continued to rehearse, suggesting the role of the MTL in reactivating the stored information. By contrast, the activity in the middle frontal gyrus did not differ between the two conditions. Taking these results together, we have shown the double dissociation between the PFC and MTL in memory retrieval.     

Functional interactions between the medial temporal lobes and posterior neocortex related to episodic memory retrieval

We applied structural equation modeling to positron emission tomography data in humans to examine functional interactions between the right medial temporal lobe (MTL) and selected right neocortical regions in relation to visual recognition memory. Using a priori knowledge about anatomical connections between these regions as a guiding constraint, we modeled the pattern of interactions [i.e. covariances in regional cerebral blood flow (rCBF)] associated with episodic memory retrieval of spatial location and compared it with the pattern for retrieval of object identity. We also compared these patterns with those associated with perceptual matching of spatial location and object identity. Although displaying no difference in average rCBF across tasks, the right MTL showed domain-specific qualitative differences in interactions with posterior dorsal (parieto-occipital sulcus, supramarginal gyrus) and ventral regions (fusiform gyrus, superior temporal sulcus) but not with a prefrontal region. MTL interactions involving dorsal regions were positive in the spatial retrieval task but negative for object retrieval. Interactions involving ventral regions showed the reverse pattern. No comparable changes were observed during perceptual matching. Using control models, we demonstrated the neuroanatomical specificity of these results. Our results provide support for the notion that the nature of interactions between the MTL and posterior neocortex depends on the domain of information to-be- recovered.      

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.     

Oscillatory EEG correlates of episodic trace decay

Recent studies suggest that human theta oscillations appear to be functionally associated with memory processes. It is less clear, however, to what type of memory sub-processes theta is related. Using a continuous word recognition task with different repetition lags, we investigate whether theta reflects the strength of an episodic memory trace or general processing demands, such as task difficulty. The results favor the episodic trace decay hypothesis and show that during the access of an episodic trace in a time window of approximately 200-400 ms, theta power decreases with increasing lag (between the first and second presentation of an item). LORETA source localization of this early theta lag effect indicates that parietal regions are involved in episodic trace processing, whereas right frontal regions may guide the process of retrieval. We conclude that episodic encoding can be characterized by two different stages: traces are first processed at parietal sites at approximately 300 ms, then further processing takes place in regions of the medial temporal lobe at approximately 500 ms. Only the first stage is related to theta, whereas the second is reflected by a slow wave with a frequency of approximately 2.5 Hz.     

Ketamine disrupts frontal and hippocampal contribution to encoding and retrieval of episodic memory: an fMRI study

The N-methyl-D-aspartate (NMDA) receptor antagonist ketamine produces episodic memory deficits. We used functional magnetic resonance imaging to characterize the effects of ketamine on frontal and hippocampal responses to memory encoding and retrieval in healthy volunteers using a double-blind, placebo-controlled, randomized, within-subjects comparison of two doses of intravenous ketamine. Dissociation of the effects of ketamine on encoding and retrieval processes was achieved using two study-test cycles: in the first, items were encoded prior to drug infusion and retrieval tested, during scanning, on drug; in the second, encoding was scanned on drug, and retrieval tested once ketamine plasma levels had declined. We additionally determined the interaction of ketamine with the depth of processing that occurred at encoding. A number of effects upon task-dependent activations were seen. Overall, our results suggest that left frontal activation is augmented by ketamine when elaborative semantic processing is required at encoding. In addition, successful encoding on ketamine is supplemented by additional non-verbal processing that is incidental to task demands. The effects of ketamine at retrieval are consistent with impaired access to accompanying contextual features of studied items. Our findings show that, even when overt behaviour is unimpaired, ketamine has an impact upon the recruitment of key regions in episodic memory task performance.     

Dynamics of oscillatory activity during auditory decision making

Perceptual decision making requires the comparison and integration of sensory evidence to generate a behavioral response. We used magnetoencephalography to investigate the temporal dynamics of decision making during an auditory task that required forced-choice decisions about whether a pair of syllables S1 and S2 differed either in their acoustic patterns or in the perceived position of their sound sources. Conditions with easy and difficult decisions were created by varying the similarity of S1 and S2. Statistical probability mapping showed enhanced gamma-band activity (GBA) over posterior parietal cortex for spatial and over left inferior frontal cortex for pattern changes (at approximately 120 to 220 ms after S2 onset). Activations were stronger for easy than difficult decisions. GBA over dorsolateral prefrontal cortex was more pronounced at approximately 280 to 430 ms for easy than difficult decisions regardless of type of change, possibly reflecting decision-relevant networks that integrate information from higher sensory areas representing the perceptual alternatives. Sensorimotor beta desynchronization as a measure of motor preparation peaked at approximately 460 ms for easy and at approximately 520 ms for difficult decisions, thus reflecting the reaction time difference between both conditions. In summary, the analysis of oscillatory activity in magnetoencephalogram served to elucidate the temporal dynamics of perceptual decision making in humans.     

V1 activation in congenitally blind humans is associated with episodic retrieval

Recently we showed that the occipital cortex of congenitally blind humans is activated during verbal-memory tasks. Activation was found in regions corresponding to the retinotopic visual areas of sighted humans, including the calcarine sulcus (V1). No such occipital activation was found in sighted humans. One year later, the same blind subjects participated in a second fMRI scan, to study the contribution of semantic elements and episodic memory to the occipital activation. The subjects performed an episodic-memory task, requiring recognition of words that were originally presented in the first scan. We demonstrate here that the magnitude of V1 activation during the recognition task is correlated with memory performance, assessed during the scan. Across the blind, the better-remembered set of words elicited greater V1 activation than words from the poorly-remembered set, although the semantic components and the behavioral task were similar in the two sets. This indicates that on top of semantic processing (suggested previously), V1 activation in the blind is probably associated with long-term episodic memory. Indeed, within the blind, those who showed better recognition-memory performance had greater V1 activation compared with the poorer performers. We conclude that the posterior occipital cortex (including V1) of the congenitally blind is likely to be involved in episodic retrieval.     

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.     

Age effects on the neural correlates of episodic retrieval: increased cortical recruitment with matched performance

Functional neuroimaging investigations have revealed a range of age-related differences in the neural correlates of episodic memory retrieval. Typically, whereas activity is reduced in older compared with younger adults in some regions, other regions are engaged exclusively, or to a greater extent, in older adults. It is unclear whether such differences merely represent the neural correlates of the lower levels of memory performance and impaired recollection typical of older adults. This issue was addressed in the present event-related functional magnetic resonance imaging study. The level of recollection was matched between groups of healthy younger and older adults for a subset of picture items in a source memory task by manipulating the number of study presentations. Contrasts of the activity elicited by old items attracting correct source judgments and correctly identified new items revealed that the 2 groups recruited many of the same brain regions. However, a striking pattern of age-related differences was also observed. In older adults, retrieval-related increases in activity were more widespread and of greater magnitude than in the young. Moreover, regions demonstrating retrieval-related decreases in activity were almost absent in the older participants. These findings suggest an age-related decline in the efficiency with which neural populations support cognitive function.     

Contextual processing in episodic future thought

Remembering events from one's past (i.e., episodic memory) and envisioning specific events that could occur in one's future (i.e., episodic future thought) invoke highly overlapping sets of brain regions. The present study employed functional magnetic resonance imaging to test the hypothesis that one source of this shared architecture is that episodic future thought--much like episodic memory--tends to invoke memory for known visual-spatial contexts. That is, regions of posterior cortex (within posterior cingulate cortex [PCC], parahippocampal cortex [PHC], and superior occipital gyrus [SOG]) elicit indistinguishable activity during remembering and episodic future thought, and similar regions have been identified as important for establishing visual-spatial contextual associations. In the present study, these regions were similarly engaged when participants thought about personal events in familiar contexts, irrespective of temporal direction (past or future). The same regions, however, exhibited very little activity when participants envisioned personal future events in unfamiliar contextual settings. These findings suggest that regions within PCC, PHC, and SOG support the activation of well-known contextual settings that people tend to imagine when thinking about personal events, whether in the past or future. Hence, this study pinpoints an important similarity between episodic future thought and episodic memory.