Frontal lobe mechanisms that resolve proactive interference

Memory of a past experience can interfere with processing during a subsequent experience, a phenomenon termed proactive interference (PI). Neuroimaging and neuropsychological evidence implicate the left mid-ventrolateral prefrontal cortex (mid-VLPFC) in PI resolution during short-term item recognition, though the precise mechanisms await specification. The present functional magnetic resonance imaging (fMRI) experiment sought to further constrain theorizing regarding PI resolution. On each trial, subjects maintained a target set of words, and then decided if a subsequent probe was contained in the target set (positive) or not (negative). Importantly, for half of the negative and half of the positive trials, the probe had been contained in the previous target set (recent). Relative to non-recent trials, negative-recent trials produced an increase in response times and error rates, behavioral markers of PI. In fMRI measures, negative recency was associated with increased activation in the left mid-VLPFC, as well as in the bilateral fronto-polar cortex, providing evidence for multiple components in PI resolution. Furthermore, recency effects were evident during both negative and positive trials, with the magnitude of the recency effect in the mid-VLPFC being greater on negative trials. Collectively, these results serve to specify and constrain proposed models of PI resolution.     

Isolating rule- versus evidence-based prefrontal activity during episodic and lexical discrimination: a functional magnetic resonance imaging investigation of detection theory distinctions

Dorsolateral and frontopolar prefrontal cortices (PFCs) are often implicated in neuroimaging studies of memory retrieval, with this activity ascribed to controlled monitoring processes indicative of difficult or demanding retrieval. Difficulty, however, is multiply determined, with success rates governed both by the available evidence and by the nature of decision rules applied to that evidence. Using event-related functional magnetic resonance imaging, we isolated these factors by 1) contrasting different decision rules across matched evidence and 2) manipulating the level of evidence within a fixed decision rule. For identically constructed retrieval probes (1 old and 1 new item), same-different (are these different?) compared with forced-choice (which one is old?) decision rules yielded bilateral dorsolateral and right frontopolar PFC increases. However, these regions were unaffected when the available evidence was greatly lowered within forced-choice decisions. Thus, the regions were simultaneously sensitive to the type of decision rule and yet insensitive to the level of evidence supporting those decisions. Analogous lexical tasks yielded similar patterns, demonstrating that the PFC responses were not episodic memory specific. We discuss the mechanistic differences between same-different versus forced-choice decisions and the implications of these data for current theories of PFC activity during episodic remembering and executive control.     

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.     

Differential contributions of prefrontal, medial temporal, and sensory-perceptual regions to true and false memory formation

The neural correlates of true memory formation (TMF) and false memory formation (FMF) were investigated using functional magnetic resonance imaging (fMRI). Using a parametric subsequent memory paradigm, encoding activity was analyzed as a function of whether it predicted subsequent hits to targets (TMF activity) or subsequent false alarms to critical lures (FMF activity). The fMRI analyses yielded 3 main findings. First, the left prefrontal cortex (PFC) was involved in both TMF and FMF activities. This finding is consistent with the evidence that semantic elaboration, which has been associated with left PFC, tends to enhance both true and false remembering. Second, the left posterior medial temporal lobes (MTLs) contributed to TMF but not to FMF activity. This finding is consistent with the notion that MTL is involved in the storage of a consciously, but not unconsciously, processed event. Third, late visual regions were engaged in both TMF and FMF activities, whereas early visual areas were involved primarily in TMF activity. This dissociation indicates that elaborative perceptual processing, but not basic sensory processing, contributes to false remembering. Taken together, the results suggest that FMF is an unintended consequence, or by-product, of elaborative semantic and visual encoding processes.     

Role of prefrontal and parietal cortices in associative learning

Two studies were performed that compared a "Paired" condition in which participants studied paired associates with a "Generated" condition in which participants completed word fragments to produce paired associates. In both tasks, participants were responsible for memory of the material either studied or generated. The experiments revealed significant differences between the responses of a predefined prefrontal region and a predefined parietal region. The parietal region responded more in the Generated condition than the Paired condition, whereas there was no difference in the prefrontal region. On the other hand, the prefrontal region responded to the delay between study and test in both the Paired and Generated conditions, whereas the parietal region only responded to delay in the Generated condition. This pattern of results is consistent with the hypothesis that the parietal region is responsive to changes in problem representation and the prefrontal region to retrieval operations. An information-processing model embodying these assumptions was fit to the blood oxygen level-dependent responses in these regions.     

Augmented prefrontal acetylcholine release during challenged attentional performance

Previous research has demonstrated that attentional performance depends on the integrity of the cortical cholinergic input system and that such performance is associated with increases in cortical acetylcholine (ACh) release. The present experiment tested the hypothesis that the attentional impairments produced by bilateral basal forebrain infusions of the NMDA receptor antagonist DL-2-amino-5-phosphonovaleric acid (APV) are associated with attenuation of performance-associated increases in ACh release. Rats were trained in a sustained attention task and equipped with three guide cannula for the bilateral infusion of the NMDA receptor antagonist APV (0, 3, 20 nmol) and for the insertion of a dialysis probe into the medial prefrontal cortex (mPFC). APV or vehicle was infused remotely following completion of the first of five blocks of trials. During the first block, attentional performance was associated with a 140% increase in ACh efflux. Infusions of APV decreased the animals' ability to detect signals and augmented the increases in ACh efflux observed prior to infusions. These data indicate a dissociation between levels of attentional performance and increases in mPFC ACh release. Augmentation of performance-associated increases in mPFC cholinergic transmission is hypothesized to mediate the increased demands on attentional 'effort' that are required to maintain performance under challenging conditions.     

Dynamics of prefrontal and cingulate activity during a reward-based logical deduction task

We used behavioral and functional magnetic resonance imaging (fMRI) methods to probe the cerebral organization of a simple logical deduction process. Subjects were engaged in a motor trial-and-error learning task, in which they had to infer the identity of an unknown 4-key code. The design of the task allowed subjects to base their inferences not only on the feedback they received but also on the internal deductions that it afforded (autoevaluation). fMRI analysis revealed a large bilateral parietal, prefrontal, cingulate, and striatal network that activated suddenly during search periods and collapsed during ensuing periods of sequence repetition. Fine-grained analyses of the temporal dynamics of this search network indicated that it operates according to near-optimal rules that include 1) computation of the difference between expected and obtained rewards and 2) anticipatory deductions that predate the actual reception of positive reward. In summary, the dynamics of effortful mental deduction can be tracked with fMRI and relate to a distributed network engaging prefrontal cortex and its interconnected cortical and subcortical regions.     

When remembering causes forgetting: electrophysiological correlates of retrieval-induced forgetting

People tend to forget information that is related to memories they are actively trying to retrieve. On the basis of results from behavioral studies, such retrieval-induced forgetting is held to result from inhibitory control processes that are recruited to attenuate interference caused by competing memory traces. Employing electrophysiological measures of brain activity, the present study examined the neural correlates of these inhibitory processes as they operate. The results demonstrate that sustained prefrontal event-related potentials were 1) related to whether or not selective memory retrieval was required during reprocessing of previously studied words and 2) predictive of individual differences in the amount of forgetting observed in an ensuing recall test. The present findings give support to an inhibitory control account of retrieval-induced forgetting and are in accord with the view that prefrontal regions play an important role in the selection and maintenance of relevant memory representations at the expense of those currently irrelevant.     

Cognition and dorsolateral prefrontal cortex volume in corticosteroid‐treated patients given lamotrigine

In addition to changes in declarative memory and the hippocampus, corticosteroid excess is associated with prefrontal cortex changes. We previously reported that patients receiving exogenous corticosteroid therapy had impaired performance on prefrontal cortex‐related tasks, including working memory and executive functioning tasks. Glutamate release inhibitors attenuate corticosteroid‐effects on the hippocampus in both animal and human models. Twenty‐eight outpatients receiving chronic prednisone therapy for transplant rejection or other medical conditions were randomized to lamotrigine (a glutamate release inhibitor) or placebo for 24 weeks. Dorsolateral prefrontal cortex (DLPFC) volume was manually traced from MRI scans by trained staff members. Cognition was examined using the Stroop Color Word Test (SCWT), Delis‐Kaplan Executive Function System (D‐KEFS) and the Trail Making Test. Groups were compared using analysis of covariance. Consistent with prior findings in corticosteroid‐treated patients, baseline cognitive function was in the low normal range. At baseline, prednisone duration showed a trend towards negative correlation with SCWT and D‐KEFS inhibition switching time error scores, and DLPFC volume showed a trend towards a positive correlation with SCWT scores. No significant between‐group differences in outcomes were observed following lamotrigine therapy. Thus, this study found lamotrigine to not be associated with either positive or negative effects on cognition or DLPFC volume. Copyright © 2010 John Wiley & Sons, Ltd.     

The prefrontal cortex shows context-specific changes in effective connectivity to motor or visual cortex during the selection of action or colour

The role of the prefrontal cortex remains controversial. Neuroimaging studies support modality-specific and process-specific functions related to working memory and attention. Its role may also be defined by changes in its influence over other brain regions including sensory and motor cortex. We used functional magnetic imaging (fMRI) to study the free selection of actions and colours. Control conditions used externally specified actions and colours. The prefrontal cortex was activated during free selection, regardless of modality, in contrast to modality-specific activations outside prefrontal cortex. Structural equation modelling (SEM) of fMRI data was used to test the hypothesis that although the same regions of prefrontal cortex may be active in tasks within different domains, there is task-dependent effective connectivity between prefrontal cortex and non-prefrontal cortex. The SEM included high-order interactions between modality, selection and regional activity. There was greater coupling between prefrontal cortex and motor cortex during free selection and action tasks, and between prefrontal cortex and visual cortex during free selection of colours. The results suggest that the functions of the prefrontal cortex may be defined not only by selection-specific rather than modality-specific processes, but also by changing patterns of effective connectivity from prefrontal cortex to motor and sensory cortices.     

Ventromedial prefrontal cortex is obligatory for consolidation and reconsolidation of object recognition memory

Once consolidated, a long-term memory item could regain susceptibility to consolidation blockers, that is, reconsolidate, upon its reactivation. Both consolidation and reconsolidation require protein synthesis, but it is not yet known how similar these processes are in terms of molecular, cellular, and neural circuit mechanisms. Whereas most previous studies focused on aversive conditioning in the amygdala and the hippocampus, here we examine the role of the ventromedial prefrontal cortex (vmPFC) in consolidation and reconsolidation of object recognition memory. Object recognition memory is the ability to discriminate the familiarity of previously encountered objects. We found that microinfusion of the protein synthesis inhibitor anisomycin or the N-methyl-D-aspartate (NMDA) receptor antagonist D,L-2-amino-5-phosphonovaleric acid (APV) into the vmPFC, immediately after training, resulted in impairment of long-term (24 h) but not short-term (3 h) recognition memory. Similarly, microinfusion of anisomycin or APV into the vmPFC immediately after reactivation of the long-term memory impaired recognition memory 24 h, but not 3 h, post-reactivation. These results indicate that both protein synthesis and NMDA receptors are required for consolidation and reconsolidation of recognition memory in the vmPFC.     

Neural processing of fearful faces: effects of anxiety are gated by perceptual capacity limitations

Debate continues as to the automaticity of the amygdala's response to threat. Accounts taking a strong automaticity line suggest that the amygdala's response to threat is both involuntary and independent of attentional resources. Building on these accounts, prominent models have suggested that anxiety modulates the output of an amygdala-based preattentive threat evaluation system. Here, we argue for a modification of these models. Functional magnetic resonance imaging data were collected while volunteers performed a letter search task of high or low perceptual load superimposed on fearful or neutral face distractors. Neither high- nor low-anxious volunteers showed an increased amygdala response to threat distractors under high perceptual load, contrary to a strong automaticity account of amygdala function. Under low perceptual load, elevated state anxiety was associated with a heightened response to threat distractors in the amygdala and superior temporal sulcus, whereas individuals high in trait anxiety showed a reduced prefrontal response to these stimuli, consistent with weakened recruitment of control mechanisms used to prevent the further processing of salient distractors. These findings suggest that anxiety modulates processing subsequent to competition for perceptual processing resources, with state and trait anxiety having distinguishable influences upon the neural mechanisms underlying threat evaluation and "top-down" control.     

Dorsal anterior cingulate cortex resolves conflict from distracting stimuli by boosting attention toward relevant events

In everyday life, we often focus greater attention on behaviorally relevant stimuli to limit the processing of distracting events. For example, when distracting voices intrude upon a conversation at a noisy social gathering, we concentrate more attention on the speaker of interest to better comprehend his or her speech. In the present study, we investigated whether dorsal/caudal regions of the anterior cingulate cortex (dACC), thought to make a major contribution to cognitive control, boost attentional resources toward behaviorally relevant stimuli as a means for limiting the processing of distracting events. Sixteen healthy participants performed a cued global/local selective attention task while brain activity was recorded with event-related functional magnetic resonance imaging. Consistent with our hypotheses, greater dACC activity during distracting events predicted reduced behavioral measures of interference from those same events. dACC activity also differed for cues to attend to global versus local features of upcoming visual objects, further indicating a role in directing attention toward task-relevant stimuli. Our findings indicate a role for dACC in focusing attention on behaviorally relevant stimuli, especially when the achievement of our behavioral goals is threatened by distracting events.     

Contrasting effects of reward expectation on sensory and motor memories in primate prefrontal neurons

The value of reward obtained with successful behavior is important for guiding purposeful behavior. The lateral prefrontal cortex (LPFC) has been implicated in working memory that guides goal-directed behavior. However, mechanism that integrates the reward value into the working memory for goal-directed behavior is not understood. To help clarify this issue, we examined the effect of reward expectation on the neuronal process in the LPFC associated with memory-based sensorimotor processing. By temporally dissociating visuospatial sensory and saccade-directional motor memories in the LPFC, we here show that reward expectation significantly enhanced the directional selectivity of sensory working memory but did not affect the directional selectivity of motor memory. The enhancement of sensory working memory in the neuronal population was sustained during the delay but extinguished soon after the motor memory appeared. These results suggest that the expectation of high reward value primarily affects the sensory working memory that may be used for behavioral guidance rather than preparation for forthcoming saccades. It thus appears that the LPFC is a neuronal substrate for working memory used to guide a reward-oriented behavior, rather than reflecting an efficient control of motor action in motivated states.     

Increased neural efficiency with repeated performance of a working memory task is information-type dependent

Unlike tasks in which practice leads to an automatic stimulus-response association, it is thought working memory (WM) tasks continue to require cognitive control processes after repeated performance. Previous studies investigating WM task repetition are in accord with this. However, it is unclear whether changes in neural activity after repetition imply alterations in general control processes common to all WM tasks or are specific to the selection, encoding and maintenance of the relevant information. In the present study, functional magnetic resonance imaging (fMRI) was used to examine changes during sample, delay and test periods during repetition of both object and spatial delayed recognition tasks. We found decreases in fMRI activation in both spatial and object-selective areas after spatial WM task repetition, independent of behavioral performance. Few areas showed changed activity after object WM task repetition. These results indicate that spatial task repetition leads to increased efficiency of maintaining task-relevant information and improved ability to filter out task-irrelevant information. The specificity of this repetition effect to the spatial task suggests a difference exists in the nature of the representation of object and spatial information and that their maintenance in WM is likely subserved by different neural systems.     

The neural correlates of human working memory for haptically explored object orientations

Skillful object manipulation requires that haptically explored spatial object characteristics like orientation be adequately represented in working memory. In the current functional magnetic resonance imaging study, healthy right-handed participants explored a bar-shaped reference object with the left hand, memorizing its orientation. After a variable delay (0.5, 5, or 10 s), participants used their right hand to match the orientation by rotating a second, identical object. In the first seconds of the delay, right sensorimotor cortex was active, whereas clusters in left anterior prefrontal cortex (aPFC) (Brodmann area 10) became dominant 2 s after the end of exploration, showing sustained activity for several seconds. In contrast, left parieto-occipital cortex was involved toward the end of the delay interval. Our results indicate that a dynamic network of brain areas subserves hapticospatial information processing in the delay between haptic stimulus exploration and orientation matching. We propose that haptic sensory traces, maintained in contralateral sensorimotor cortex, are transformed into more abstract hapticospatial representations in the early delay stages. Maintenance of these representations engages aPFC and parieto-occipital cortex. Whereas aPFC possibly integrates spatial and motor components of hapticospatial working memory, parieto-occipital cortex might be involved in orientation imagery, supporting working memory, and the preparation of haptic matching.     

Dopamine and noradrenaline efflux in the medial prefrontal cortex during serial reversals and extinction of instrumental goal-directed behavior

The prefrontal cortex (PFC) of the rat supports cognitive flexibility, the ability to spontaneously adapt goal-directed behavior in response to radically changing situational demands. We have shown previously that transient inactivation of the rat medial PFC (mPFC) impairs initial reversal learning in a spatial 2-lever discrimination task. Given the importance of dopamine (DA) for PFC function, we studied DA (and noradrenaline [NA]) efflux in the mPFC during reversal learning. We observed a higher and more extended increase in DA efflux in rats performing the first reversal compared with controls performing the previously acquired discrimination. The results of an additional experiment suggest that such a difference between the reversal- and control-induced DA increases was absent during a third reversal. During the extinction session, DA efflux did not increase from basal levels. Increases in NA efflux were less than in DA and did not differ between control and any condition. We conclude that prefrontal DA activity is increased during execution of instrumental discrimination tasks and that this increase is amplified during the acquisition of a first, but not of later reversals. These data corroborate our previous findings and indicate that DA is critically involved in this form of cognitive flexibility.     

The role of prefrontal cortex CB1 receptors in the modulation of fear memory

Understanding the mechanism of how fear memory can be extinguishedcould provide potential therapeutic strategies for the treatmentof posttraumatic stress disorders. Here we show that infusionof CB1 receptor antagonist into the infralimbic (IL) subregionof the medial prefrontal cortex (mPFC) retarded cue-alone–inducedreduction of fear-potentiated startle. Conversely, cannabinoidagonist WIN55212-2 (WIN) facilitated the extinction. Unexpectedly,administration of WIN without cue-alone trials reduced startlepotentiation in a dose-dependent manner. The effect of cannabinoidagonists was mimicked by endocannabinoid uptake or fatty acidamide hydrolase inhibitors. Rats were trained with 10 conditionedstimulus (CS⁺) (yellow light)–shock pairings. Extinctiontraining with CS⁺ (yellow light)-alone but not CS^– (bluelight)-alone trials decreased fear-potentiated startle. Intra-ILinfusion of WIN before CS^–-alone trials decreased startlepotentiation, suggesting that the cannabinoid agonist decreasedconditioned fear irrespective of whether the rats underwentCS⁺- or CS^–-alone trials. Cannabinoid agonists activatedextracellular signal-regulated kinases (ERKs) in mPFC slices,and ERK inhibitor blocked the effect of cannabinoid agonistson fear-potentiated startle. These results suggest that CB1receptors acting through the phosphorylation of ERK are involvednot only in the extinction of conditioned fear but also in theadaptation to aversive situations in general.     

Control of object-based attention in human cortex

Visual attention is a mechanism by which observers select relevant or important information from the current visual array. Previous investigations have focused primarily on the ability to select a region of space for further visual analysis. These studies have revealed a distributed frontoparietal circuit that is responsible for the control of spatial attention. However, vision must ultimately represent objects and in real scenes objects often overlap spatially; thus attention must be capable of selecting objects and their properties nonspatially. Little is known about the neural basis of object-based attentional control. In two experiments, human observers shifted attention between spatially superimposed faces and houses. Event-related functional magnetic resonance imaging (fMRI) revealed attentional modulation of activity in face- and house-selective cortical regions. Posterior parietal and frontal regions were transiently active when attention was shifted between spatially superimposed perceptual objects. The timecourse of activity provides insight into the functional role that these brain regions play in attentional control processes.     

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.