Medial prefrontal cortex plays a critical and selective role in 'feeling of knowing' meta-memory judgments

The frontal lobes are thought to play a role in the monitoring of memory performance, or 'meta-memory', but the specific circuits involved have yet to be definitively established. Medial prefrontal cortex in general and the anterior cingulate cortex in particular, have been implicated in other forms of monitoring, such as error and conflict monitoring. Here, we tested the hypothesis that medial prefrontal cortex plays a critical role in memory monitoring, aiming to determine whether this region contributed to all, or only some classes of meta-memory judgments. We also investigated the relationship between these judgments and memory performance itself. Three types of meta-memory judgment were measured in 5 subjects with focal damage to medial prefrontal cortex, with maximal overlap in dorsal anterior cingulate cortex, compared to 19 healthy, demographically matched control subjects performing a face-name episodic memory task. Judgment-of-learning accuracy was not affected by such damage. In contrast, both recall confidence and feeling-of-knowing judgments were impaired. Memory performance was itself impaired in the patient group, so we performed a second experiment to examine the relationship between memory and meta-memory deficits. In an easier memory task, where patients performed as well as controls, recall confidence accuracy improved to within the control range despite medial prefrontal damage. In contrast, feeling-of-knowing judgments remained less accurate in the patient group. These results argue that medial prefrontal cortex plays a critical role in generating accurate recall confidence and feeling-of-knowing judgments, but is not necessary for judgment-of-learning. The role of this region in feeling-of-knowing seems to be, at least in part, independent of its role in memory itself.     

Metamemory for faces following frontal lobe damage.

Previous research has provided evidence of metamemory impairments in patients with frontal lobe damage on verbal episodic memory tasks. In the present study, we employed metamemory paradigms to investigate whether patients with frontal lesions show monitoring deficits on semantic memory tasks involving facial stimuli. Patients with frontal lobe damage and healthy control subjects made memory decisions to famous faces in a retrospective confidence judgment task and in a prospective feeling-of-knowing (FOK) task. Results indicated that frontal patients performed worse than controls on the retrospective confidence task, but there were no differences between the groups on the FOK task. These findings suggest that metamemory deficits in frontal patients are not confined to specific stimulus domains (words vs. faces) or memory systems (episodic vs. semantic). In addition, the dissociation between retrospective confidence judgments and FOK accuracy documented in this study and also in a recent report by Schnyer et al. suggesting that metamemory should not be considered a unitary function with a single neuroanatomic substrate.     

The role of VMPC in metamemorial judgments of content retrievability

Making judgments about the retrievability of information is a critical part of the metamemory processes engaged during remembering. A recent study of patients with frontal lesions suggests that ventral medial prefrontal cortex (VMPC) plays a critical role in such judgments [Schnyer, D. M., Verfaellie, M., Alexander, M. P., Lafleche, G., Nicholls, L., & Kaszniak, A. W. A role for right medial prefrontal cortex in accurate feeling of knowing judgments: Evidence from patients with lesions to frontal cortex. Neuropsychologia, 42, 957-966, 2004]. The observed impairment was thought to reflect an inability to determine the accessibility of memory contents. To further examine the neuroanatomical basis of content accessibility assessment, we used fMRI in an episodic feeling-of-knowing (FOK) paradigm. Participants were asked to make trial-by-trial predictions about the retrievability of the final word that completed studied sentences and then to select the correct completion from among alternatives. Results indicated that the VMPC is engaged during accurate FOK judgments and its activation is modulated by retrieval rating. Structural equations modeling supported the notion that VMPC, as part of a broader left hemisphere network involved in memory retrieval, monitors the output of the retrieval process. More generally, VMPC may participate in metacognitive processes that allow for the comparison of available data against an internal model.     

Autobiographical memory of the recent past following frontal cortex or temporal lobe excisions

Previous research has raised questions regarding the necessity of the frontal cortex in autobiographical memory and the role that it plays in actively retrieving contextual information associated with personally relevant events. Autobiographical memory was studied in patients with unilateral excisions restricted to the frontal cortex or temporal lobe involving the amygdalo-hippocampal region and in normal controls using an event-sampling method. We examined accuracy of free recall, use of strategies during retrieval and memory for specific aspects of the autobiographical events, including temporal order. Patients with temporal lobe excisions were impaired in autobiographical recall. By contrast, patients with frontal cortical excisions exhibited normal autobiographical recall but were less likely to use temporal order spontaneously to organize event retrieval. Instruction to organize retrieval by temporal order failed to improve recall in temporal lobe patients and increased the incidence of plausible intrusion errors in left temporal patients. In contrast, patients with frontal cortical excisions now surpassed control subjects in recall of autobiographical events. Furthermore, the retrieval accuracy for the temporal order of diary events was not impaired in these patients. In a subsequent cued recall test, temporal lobe patients were impaired in their memory for the details of the diary events and their context. In conclusion, a basic impairment in autobiographical memory (including memory for temporal context) results from damage to the temporal lobe and not the frontal cortex. Patients with frontal excisions fail to use organizational strategies spontaneously to aid retrieval but can use these effectively if instructed to do so.     

Frontal and posterior cingulate metabolic impairment in the behavioral variant of frontotemporal dementia with impaired autonoetic consciousness

Although memory dysfunction is not a prominent feature of the behavioral variant of frontotemporal dementia (bv-FTD), there is evidence of specific deficits of episodic memory in these patients. They also have problems monitoring their memory performance. The objective of the present study was to explore the ability to consciously retrieve own encoding of the context of events (autonoetic consciousness) and the ability to monitor memory performance using feeling-of-knowing (FOK) in bv-FTD. Analyses of the patients' cerebral metabolism (FDG-PET) allowed an examination of whether impaired episodic memory in bv-FTD is associated with the frontal dysfunction characteristic of the pathology or a dysfunction of memory-specific regions pertaining to Papez's circuit. Data were obtained from eight bv-FTD patients and 26 healthy controls. Autonoetic consciousness was evaluated by Remember responses during the recognition memory phase of the FOK experiment. As a group, bv-FTD patients demonstrated a decline in autonoetic consciousness and FOK accuracy at the chance level. While memory monitoring was impaired in most (seven) patients, four bv-FTD participants had individual impairment of autonoetic consciousness. They specifically showed reduced metabolism in the anterior medial prefrontal cortex, the left dorsolateral prefrontal cortex (near the superior frontal sulcus), parietal regions, and the posterior cingulate cortex. These findings were tentatively interpreted by considering the role of the metabolically impaired brain regions in self-referential processes, suggesting that the bv-FTD patients' problem consciously retrieving episodic memories may stem at least partly from deficient access to and maintenance/use of information about the self. Frontal and posterior cingulate metabolic impairment in the behavioral variant of frontotemporal dementia with impaired autonoetic consciousness     

Damage to the lateral prefrontal cortex impairs familiarity but not recollection

Frontal lobe lesions impair recognition memory but it is unclear whether the deficits arise from impaired recollection, impaired familiarity, or both. In the current study, recognition memory for verbal materials was examined in patients with damage to the left or right lateral prefrontal cortex. Words were incidentally encoded under semantic or phonological orienting conditions, and recognition memory was tested using a 6-point confidence procedure. Receiver operating characteristics (ROCs) were examined in order to measure the contributions of recollection and familiarity to recognition memory. In both encoding conditions, lateral prefrontal cortex damage led to a deficit in familiarity but not recollection. Similar deficits were observed in left and right hemisphere patients. The results indicate that the lateral prefrontal cortex plays a critical role in the monitoring or decision processes required for accurate familiarity-based recognition responses.     

Impairment of social perception associated with lesions of the prefrontal cortex

OBJECTIVE: Behavioral and social impairments have been frequently reported after damage to the prefrontal cortex in humans. This study evaluated social perception in patients with prefrontal cortex lesions and compared their performance on a social perception task with that of healthy volunteers. METHOD: Thirty-three patients with prefrontal cortex lesions and 31 healthy volunteers were tested with the Interpersonal Perception Task. In this task, subjects viewed videotaped social interactions and relied primarily on nonverbal cues to make interpersonal judgments, such as determining the degree of intimacy between two persons depicted in the videotaped scene. Patients with prefrontal cortex lesions were classified according to lesion involvement of specific regions, including the orbitofrontal cortex, dorsolateral prefrontal cortex, and anterior cingulate cortex. RESULTS: Relative to the comparison subjects, patients whose lesions involved the orbitofrontal cortex demonstrated impaired social perception. Contrary to predictions, patients with lesions in the dorsolateral prefrontal cortex also showed deficits in using social cues to make interpersonal judgments. All patients, particularly those with lesions in the dorsolateral prefrontal cortex, showed poorer insight into their deficits, relative to healthy volunteers. CONCLUSIONS: These findings of deficits in social perception after damage to the orbitofrontal cortex extend previous clinical and experimental evidence of damage-related impairment in other aspects of social cognition, such as the ability to accurately evaluate emotional facial expressions. In addition, the results suggest that the dorsolateral prefrontal cortex is recruited when inferences about social interactions are made on the basis of nonverbal information.     

Frontal lobe involvement in spatial span: converging studies of normal and impaired function

Although monkey lesion studies involving the prefrontal cortex commonly report working memory deficits, and neuroimaging studies consistently show prefrontal involvement in such tasks, patients with damage to this region commonly fail to show any working memory impairment. Such a discrepancy may be due to insensitive testing measures for patients, as well as small, yet critical differences between working memory tasks in imaging and patient studies. The current study utilised a more sensitive measure of spatial working memory spans, based either on structured or unstructured spatial arrays. A PET study in normal subjects confirmed that both variants did indeed activate prefrontal cortex. The same tasks were given to frontal lobe patients and closely matched controls. Patients with large frontal lesions were significantly impaired on this task, with those patients with damage to the right dorsolateral prefrontal cortex appearing particularly impaired. This result demonstrates that prefrontal cortex is necessary for normal working memory, even in simple tasks, such as spatial span. It is suggested, however, that the patient deficit reflects strategic or goal-based dysfunction, rather than storage limitations.     

Deficits in prospective memory following damage to the prefrontal cortex

Neuropsychological investigations of prospective memory (PM), representing memory of future intentions or plans, have evolved over the past two decades. The broadly accepted divisions involved in PM consist of a prospective memory component (PMC), a process for remembering to remember, and a retrospective memory component, a process for remembering the content of the intended action. Previous functional neuroimaing studies have provided some evidence that the rostral prefrontal cortex (BA10) is one of areas that is critical for prospective remembering. However, the question of whether damage to part of the prefrontal cortex affects attenuated performance for PMC remains unresolved. In this study, 74 participants with traumatic brain injury (TBI) including focal damage to frontal or temporal lobe areas were administered thirteen standard neuropsychological tests and the PM task. To identify influential areas contributing to PM performance, discriminant function analysis was conducted. The results indicated that the following three areas are highly contributory to PM performance: the right dorsolateral prefrontal cortex; the right ventromedial prefrontal cortex; and the left dorsomedial prefrontal cortex. Comparing differences in neuropsychological test scores showed that orientation scores were significantly higher in the greater PM performance group, suggesting that PMC represents an integrated memory function associated with awareness of current status. These data contribute to our understanding of the neural substrates and functional characteristics of the PMC.     

Alzheimer's disease and feeling-of-knowing in episodic memory

Episodic memory feeling-of-knowing (FOK) was examined in 16 patients with Alzheimer’s disease (AD), 16 elderly participants, and 16 younger adults. Participants were given cued recall and recognition tests of 20 critical cue-target words. Subsequently, they judged their FOK for non-recalled words in terms of how likely they thought they would be to recognize the keywords on a subsequent recognition test. The results indicated dementia-related deficits on both the recall and recognition tests. Compared to older adults, AD patients exhibited impaired FOK accuracy. This pattern of outcome indicates that early AD is associated with a deficit in episodic memory and a deficit in memory monitoring for newly learned information. Furthermore, our observation revealed that in AD, episodic memory may be a more important factor than executive function in explaining the FOK inaccuracy.     

Metamemory monitoring and Parkinson's disease

Feeling-of-knowing (FOK) and global prediction in episodic memory were examined in 16 patients with Parkinson's disease (PD) and 16 elderly control subjects. Subjects were given cued recall and recognition tests of 20 critical cue-target words. Prior to the study phase, participants were asked to predict the number of words they could recall. During the recall phase, they judged their FOK for non-recalled words in terms of how likely they thought they would be able to recognize the key words on a subsequent recognition test. No difference was found in the two groups for global prediction accuracy. However in comparison to the older adults, PD patients exhibit impaired FOK accuracy, suggesting that in some circumstances metamemory may be altered in Parkinson's disease.     

Dissociable roles of prefrontal subregions in self-ordered working memory performance

The anatomical segregation of executive control processes within the prefrontal cortex remains poorly defined. The present study focused on strategy implementation on two working memory tasks: the CANTAB spatial working memory task and a visuospatial sequence generation task. These measures were administered to a group of frontal lesion patients and a comparison group of healthy subjects. Frontal patients with damage to the right inferior frontal gyrus were impaired on the CANTAB spatial working memory task, compared with healthy controls and patients without damage to this region. This deficit was most strongly related to the pars opercularis subregion (BA44) and was accompanied by poor strategy usage. On the sequence generation task, frontal lesion patients were impaired on a strategy-training phase when the working memory demands of the task were reduced, but had relatively intact performance on other phases of the task. Performance on the training phase was correlated with the amount of damage to the dorsolateral prefrontal cortex (DLPFC: BA46/9). These results support theoretical notions of prefrontal cortical function that emphasise its contribution to executive processes such as mnemonic strategies and monitoring over its role as a short-term memory store. Moreover, we provide evidence for the first time that such functions are dependent on dissociable brain regions within the prefrontal cortex.     

The posterior parietal cortex in recognition memory: a neuropsychological study

Several recent functional neuroimaging studies have reported robust bilateral activation (L>R) in lateral posterior parietal cortex and precuneus during recognition memory retrieval tasks. It has not yet been determined what cognitive processes are represented by those activations. In order to examine whether parietal lobe-based processes are necessary for basic episodic recognition abilities, we tested a group of 17 first-incident CVA patients whose cortical damage included (but was not limited to) extensive unilateral posterior parietal lesions. These patients performed a series of tasks that yielded parietal activations in previous fMRI studies: yes/no recognition judgments on visual words and on colored object pictures and identifiable environmental sounds. We found that patients with left hemisphere lesions were not impaired compared to controls in any of the tasks. Patients with right hemisphere lesions were not significantly impaired in memory for visual words, but were impaired in recognition of object pictures and sounds. Two lesion--behavior analyses--area-based correlations and voxel-based lesion symptom mapping (VLSM)---indicate that these impairments resulted from extra-parietal damage, specifically to frontal and lateral temporal areas. These findings suggest that extensive parietal damage does not impair recognition performance. We suggest that parietal activations recorded during recognition memory tasks might reflect peri-retrieval processes, such as the storage of retrieved memoranda in a working memory buffer for further cognitive processing.     

Memory performance on the California Verbal Learning Test-II: findings from patients with focal frontal lesions.

Numerous studies have suggested that frontal cortex plays a strategic, rather than an absolute, role in memory performance. Typically, frontal patients are reported to have impaired recall but normal recognition memory. A recent meta-analysis, however, has questioned this conclusion. To further investigate the role of frontal cortex in long-term memory, patients with focal frontal lesions and age- and education-matched controls were tested on a new version of the California Verbal Learning Test (CVLT-II). Frontal patients exhibited a number of deficits on this test, including overall poorer recall, an increased tendency to make intrusions, reduced semantic clustering, and impaired yes/no recognition performance. Further analysis of the error rates in the yes/no recognition task revealed that frontal patients were most likely to mistakenly endorse 2 types of distractors: semantically related words and words from an interference list. These findings are discussed with respect to the role of frontal dysfunction in false recollections and poor source memory, as well as the distinction between the roles of frontal and temporal cortex in long-term memory.     

Directed forgetting in frontal patients' episodic recall

The aim of this study was to examine the performance of a group of patients with lesions of the prefrontal cortex in directed forgetting in episodic memory, i.e. the capacity to actively forget irrelevant information. Four lists of 24 intermixed to-be-remembered (TBR) and to-be-forgotten (TBF) words were presented for retention. Restricted (TBR only) and unrestricted (TBR and TBF) recall were tested. The results showed that prefrontal patients presented with a general reduction in episodic memory but a normal ability to selectively recall the TBR items during restricted and unrestricted recall. These results are consistent with previous reports of intact directed forgetting in frontal patients and are discussed in terms of their implications for the current debate on the neural substrate of executive functions.     

Story processing in patients with damage to the prefrontal cortex

The prefrontal cortex is known to be involved in performing complex cognitive tasks requiring reasoning, planning and decision-making. Neuropsychological evidence also supports the idea that the prefrontal cortex is generally involved in encoding and retrieving complex events, such as action and narrative knowledge. Patients with frontal lobe damage are reported to have difficulty in processing different aspects of narrative representations, such as the figurative moral meaning, syntactic features, and inference generation. In the present study, we examined story processing in 17 patients with frontal lobe lesions and compared their performance to 7 amnesic patients and 17 normal controls. Two stories were presented by using two slightly different processing demands in order to assess the subject's ability to draw inferences on-line during the course of comprehension or later retrieval. Although all patients had impaired story memory, patients with frontal lobe lesions showed a pattern of deficit at an early stage of story comprehension that specifically involved the ability to reconstruct the sequential links among events and to extract inferential knowledge from the text during encoding. Amnesic patients were severely impaired in recalling story semantic units, including single events and larger narrative constituents, as well as in the event recognition task. Consequently, they were unable to establish inferential relations among the events and, thus, the global sequential structure of the stories during retrieval. In contrast, they had no difficulty in extracting inferential knowledge during story comprehension on the basis of readily available information. This study shows that damage to different cortical regions may induce impairments at various levels of story processing.     

The role of prefrontal cortex in object-in-place learning in monkeys

Previous ablation studies in monkeys suggest that prefrontal cortex is involved in a wide range of learning and memory tasks. However, monkeys with crossed unilateral lesions of frontal and temporal cortex are unimpaired at concurrent object-reward association learning but are impaired at conditional learning and the implementation of memory-based performance rules. We trained seven monkeys preoperatively on an associative learning task that required them to associate objects embedded in unique complex scenes with reward. Three monkeys then had crossed unilateral lesions of frontal and inferior temporal cortex and the remaining monkeys had bilateral prefrontal cortex ablation. Both groups were severely impaired postoperatively. These results show that both bilateral prefrontal cortex ablation and frontal-temporal disconnection impair associative learning for objects embedded in scenes. The results provide evidence that the function of frontal-temporal interactions in memory is not limited to conditional learning tasks and memory-dependent performance rules. We propose that rapid object-in-place learning requires the interaction of frontal cortex with inferotemporal cortex because visual object and contextual information which is captured over multiple saccades must be processed as a unique complex event that is extended in time. The present results suggest a role for frontal-temporal interaction in the integration of visual information over time.     

A verbal long term memory deficit in frontal lobe damaged patients

The retention performance for learned words was compared in two groups of cortically damaged patients: A group of 14 patients with uni- or bilateral damage to the frontal lobes (group F), and a group of 14 patients with postrolandic damage. The patients learned three lists of words each of which had to be reproduced after 15 min. and after 1 day: one list under free recall, one under cued recall, and one under a recognition condition. While the performance of the two groups of patients was similar under all three conditions when tested after 15 min., group F was significantly inferior in the one day free recall retention test. We interpret this deficit as related in part to the classic "frontal" symptomatology (reduced attention and lack of initiative, drive, and concentration), and in part to a distinct disturbance of long term memory. We base this conclusion on the similar performance levels of frontal and non-frontal patients under all other conditions of testing, in particular under the free recall condition after the 15 min. delay. Reasons are given why attentive and drive related components might be mediated by prefrontal cortical neurons themselves, while mnemonic components might be mediated by mediodorsal thalamic neurons projecting to the prefrontal cortex. No or only minor differences could be established between the side of damage or between uni- versus bilateral frontal damage.     

Deficits in social knowledge following damage to ventromedial prefrontal cortex

Patients with damage to the frontal lobes frequently exhibit impaired social behavior, but it is not clear which specific processes are disrupted. The authors investigated the ability to interpret nonverbal emotional expression in patients with lesions involving ventromedial (N=20) or dorsolateral prefrontal cortex (N=9) and in healthy volunteers (N=23). As hypothesized, only patients with ventromedial prefrontal lesions showed impaired task performance relative to normal comparison subjects. These results suggest that deficits in social knowledge, namely difficulty interpreting nonverbal emotional expression, contribute to the aberrant social behavior observed following ventromedial prefrontal cortex lesions.     

The frontal cortex and exogenous attentional orienting

Normal functioning of the attentional orienting system is critical for effective behavior and is predicated on a balanced interaction between goal-directed (endogenous) processes and stimulus-driven (exogenous) processes. Although both systems have been subject to much investigation, little is known about the neural underpinnings of exogenous orienting. In the present study, we examined the early facilitatory effects and later inhibition of return effects of exogenous cues in patients with frontal and parietal lesions. Three novel findings emerged from this study. First, unilateral frontoparietal damage appears not to affect the early facilitation effects of exogenous cues. Second, dorsolateral prefrontal damage, especially lesions involving the inferior frontal gyrus, produces an exogenous disengage deficit (i.e., the sluggish withdrawal of attention from the ipsilesional to the contralesional field). Third, a subset of patients with dorsolateral prefrontal damage, with lesions involving the middle frontal gyrus, have a reorienting deficit that extends in duration well beyond established boundaries of the normal reflexive orienting system. These results suggest that the dorsolateral prefrontal cortex plays an important role in exogenous orienting and that component processes of this system may be differentially impaired by damage to different parts of the dorsolateral prefrontal cortex.