Spatiotemporal characteristics of hemodynamic changes in the human lateral prefrontal cortex during working memory tasks

The prefrontal cortex (PFC) is widely believed to subserve mental manipulation and monitoring processes ascribed to the central executive (CE) of working memory (WM). We attempted to examine and localize the CE by functional imaging of the frontal cortex during tasks designed to require the CE. Using near-infrared spectroscopy, we studied the spatiotemporal dynamics of oxygenated hemoglobin (oxy-Hb), an indicator of changes in regional cerebral blood flow, in both sides of lateral PFC during WM intensive tasks. In most participants, increases in oxy-Hb were localized within one subdivison during performance of the n-back task, whereas oxy-Hb increased more diffusely during the random number generation (RNG) task. Activation of the ventrolateral PFC (VLPFC) was prominent in the n-back task; both sustained and transient dynamics were observed. Transient dynamics means that oxy-Hb first increases but then decreases to less than 50% of the peak value or below the baseline level before the end of the task. For the RNG task sustained activity was also observed in the dorsolateral PFC (DLPFC), especially in the right hemisphere. However, details of patterns of activation varied across participants: subdivisions commonly activated during performance of the two tasks were the bilateral VLPFCs, either side of the VLPFC, and either side of the DLPFC in 4, 2, and 4 of the 12 participants, respectively. The remaining 2 of the 12 participants had no regions commonly activated by these tasks. These results suggest that although the PFC is implicated in the CE, there is no stereotyped anatomical PFC substrate for the CE.     

Neural mechanisms of semantic interference and false recognition in short-term memory

Decades of research using the Deese-Roediger-McDermott (DRM) paradigm have demonstrated that episodic memory is vulnerable to semantic distortion, and neuroimaging investigations of this phenomenon have shown dissociations between the neural mechanisms subserving true and false retrieval from long-term memory. Recently, false short-term memories have also been demonstrated, with false recognition of items related in meaning to memoranda encoded less than 5s earlier. Semantic interference is also evident in short-term memory, such that correct rejection of related lures is slowed relative to correct rejection of unrelated lures. The present research constitutes the first fMRI investigation of false recognition and semantic interference in short-term memory using a short-term DRM paradigm in which participants retained 4 semantic associates over a short 4-s filled retention interval. Results showed increased activation in the left mid-ventrolateral prefrontal cortex (BA45) associated with semantic interference, and significant correlations between these increases and behavioral measures of interference across subjects. Furthermore, increases in dorsolateral PFC occurred when related lures were correctly rejected versus falsely remembered. Compared with false recognition, true recognition was associated with increases in left fusiform gyrus, a finding consistent with the notion that increased perceptual processing may distinguish true from false recognition over both short and long retention intervals. Findings are discussed in relation to current models of interference resolution in short-term memory, and suggest that false short-term recognition occurs as a consequence of the failure of frontally mediated cognitive control processes which adjudicate semantic familiarity in support of accurate mnemonic retrieval.     

Functional network in the prefrontal cortex during episodic memory retrieval

A recent consistent finding in neuroimaging studies of human memory is that the prefrontal cortex (PFC) is activated during episodic memory retrieval. To date, however, there has been no direct evidence to explain how activity in the right and left PFC and in the anterior and posterior PFC are functionally interconnected. The goal of the present study was to obtain such evidence by event-related functional magnetic resonance imaging (MRI) and the functional connectivity method. Subjects were first asked to try to remember a series of associate-word lists outside the MRI scanner in preparation for a later recognition test. In the MRI scanning phase, they were asked to make recognition judgments in regard to old words, semantically related lure words, and unrelated new words. The analysis of functional connectivity revealed that the posterior PFC in each hemisphere had strong functional interconnections with the contralateral posterior PFC, whereas the anterior PFC in each hemisphere had only weak functional interconnections with the contralateral anterior PFC. No strong functional interconnections were found between the anterior and posterior PFC in either hemisphere. These findings support the hypothesis of an associative contribution of the bilateral posterior PFC to episodic memory retrieval and a dissociative contribution of the bilateral anterior PFC.     

Self-initiated movements in chronic prefrontal traumatic brain injury: an event-related functional MRI study

Electrophysiological studies found traumatic lesions of the prefrontal cortex (PFC) to affect the preparation of self-initiated movements. However, a precise localization of the observed effects has not been reported yet. Moreover, previous reports did not account for effects of lesion location. Therefore, the present study utilized functional MRI to investigate the influence of predominantly left or right hemispheric PFC lesions on movement preparation in chronic traumatic brain injury (TBI) patients. 18 TBI patients with MRI-defined contusions of the PFC as well as 18 healthy control subjects matched for age and gender were examined. Patients were divided into subgroups of predominantly left or right hemispheric lesions. During functional image acquisition, subjects performed self-initiated abductions of their right index finger. Neuropsychological tests of attention and working memory, which are supposed to modulate preparatory processes, were conducted. Patients with predominantly left contusions demonstrated enhanced activity of the dorsal lateral premotor cortex in comparison to healthy control subjects. In predominantly right lesioned patients, reduced activity within the right caudate head was observed. Compared to predominantly left lesioned patients, neuropsychological tests yielded reduced task performances in the right lesion subgroup. In line with previous electrophysiological research, imaging results of the present study are interpreted to represent altered preparatory networks in chronic prefrontal TBI patients. Since attentional and working memory functions are supposed to modulate preparatory processes, differences between the patient subgroups are suggested to result from the more pronounced cognitive impairments in the right-lesioned group.     

Neuroimaging a single thought: dorsolateral PFC activity associated with refreshing just-activated information.

Neuroimaging studies of human working memory (WM) show conflicting results regarding whether dorsolateral prefrontal cortex (PFC) contributes to maintaining information in consciousness or is recruited primarily when information must be manipulated. Using functional magnetic resonance imaging (fMRI), we looked at a minimal maintenance process--thinking back to a single, just-seen stimulus (refreshing). We found greater activity in left dorsolateral PFC (BA9) when participants refreshed a word compared to reading a word once or a second time. Furthermore, recognition memory was subsequently more accurate and faster for items that had been refreshed, demonstrating that a single thought that maintains activation can have consequences for long-term memory. Our fMRI results call into question any class of models of the functional organization of PFC and WM that associates simple and/or maintenance processes only with ventrolateral PFC or that associates dorsolateral PFC only with more complex processes such as manipulation.     

Dissociable correlates of two classes of retrieval processing in prefrontal cortex

Although substantial evidence suggests that the prefrontal cortex (PFC) implements processes that are critical for accurate episodic memory judgments, the specific roles of different PFC subregions remain unclear. Here, we used event-related functional magnetic resonance imaging to distinguish between prefrontal activity related to operations that (1) influence processing of retrieval cues based on current task demands, or (2) are involved in monitoring the outputs of retrieval. Fourteen participants studied auditory words spoken by a male or female speaker and completed memory tests in which the stimuli were unstudied foil words and studied words spoken by either the same speaker at study, or the alternate speaker. On "general" test trials, participants were to determine whether each word was studied, regardless of the voice of the speaker, whereas on "specific" test trials, participants were to additionally distinguish between studied words that were spoken in the same voice or a different voice at study. Thus, on specific test trials, participants were explicitly required to attend to voice information in order to evaluate each test item. Anterior (right BA 10), dorsolateral prefrontal (right BA 46), and inferior frontal (bilateral BA 47/12) regions were more active during specific than during general trials. Activation in anterior and dorsolateral PFC was enhanced during specific test trials even in response to unstudied items, suggesting that activation in these regions was related to the differential processing of retrieval cues in the two tasks. In contrast, differences between specific and general test trials in inferior frontal regions (bilateral BA 47/12) were seen only for studied items, suggesting a role for these regions in post-retrieval monitoring processes. Results from this study are consistent with the idea that different PFC subregions implement distinct, but complementary processes that collectively support accurate episodic memory judgments.     

The neural basis of individual differences in working memory capacity: an fMRI study

Using fMRI, neural substrates of verbal working memory were investigated with respect to differences in working memory capacity. Listening-span test (LST), Listen, and Remember conditions were performed. Two subjects groups were selected: those who had large working memory capacities, labeled high-span subjects (HSS) according to the working memory span test, and those who had small working memory capacities, labeled low-span subjects (LSS). Significant activation was found mainly in three regions in comparison with resting control: left prefrontal cortex (PFC), anterior cingulate cortex (ACC) and temporal language area. For both groups, fMRI signal intensity increased in PFC during the LST condition compared to the Listen condition. A group difference was found in the ACC region; specifically, a significant increase in signal intensity was observed in ACC only for the HSS group and not for the LSS group. Behavioral data also showed that the performance was better in HSS than in LSS. These results indicate that the attention controlling system, supported by ACC, is more effective in HSS compared to that of LSS.     

Hippocampal gray matter reduction associates with memory deficits in adolescents with history of prematurity

Using optimized voxel-based morphometry (VBM), we compared the relationship between hippocampal and thalamic gray matter loss and memory impairment in 22 adolescents with history of prematurity (HP) and 22 normal controls. We observed significant differences between groups in verbal learning and verbal recognition, but not in visual memory. VBM analysis showed significant left hippocampal and bilateral thalamic reductions in HP subjects. Using stereological methods, we also observed a reduction in hippocampal volume, with left posterior predominance. We found correlations between left hippocampal gray matter reductions (assessed by VBM) and verbal memory (learning and percentage of memory loss) in the premature group. The stereological analysis showed a correlation between verbal learning and the left posterior hippocampus. Our results suggest that left hippocampal tissue loss may be responsible for memory impairment and is probably related to the learning disabilities that HP subjects present during schooling.     

A face to remember: emotional expression modulates prefrontal activity during memory formation

Emotion can exert a modulatory role on episodic memory. Several studies have shown that negative stimuli (e.g., words, pictures) are better remembered than neutral ones. Although facial expressions are powerful emotional stimuli and have been shown to influence perception and attention processes, little is known about their effect on memory. We used functional magnetic resonance imaging (fMRI) in humans to investigate the effects of expression (happy, neutral, and fearful) on prefrontal cortex (PFC) activity during the encoding of faces, using a subsequent memory effect paradigm. Our results show that activity in right PFC predicted memory for faces, regardless of expression, while a homotopic region in the left hemisphere was associated with successful encoding only for faces with an emotional expression. These findings are consistent with the proposed role of right dorsolateral PFC in successful encoding of nonverbal material, but also suggest that left DLPFC may be a site where integration of memory and emotional processes occurs. This study sheds new light on the current controversy regarding the hemispheric lateralization of PFC in memory encoding.     

Examining ERP correlates of recognition memory: evidence of accurate source recognition without recollection

Recollection is typically associated with high recognition confidence and accurate source memory. However, subjects sometimes make accurate source memory judgments even for items that are not confidently recognized, and it is not known whether these responses are based on recollection or some other memory process. In the current study, we measured event related potentials (ERPs) while subjects made item and source memory confidence judgments in order to determine whether recollection supported accurate source recognition responses for items that were not confidently recognized. In line with previous studies, we found that recognition memory was associated with two ERP effects: an early on-setting FN400 effect, and a later parietal old-new effect [late positive component (LPC)], which have been associated with familiarity and recollection, respectively. The FN400 increased gradually with item recognition confidence, whereas the LPC was only observed for highly confident recognition responses. The LPC was also related to source accuracy, but only for items that had received a high confidence item recognition response; accurate source judgments to items that were less confidently recognized did not exhibit the typical ERP correlate of recollection or familiarity, but rather showed a late, broadly distributed negative ERP difference. The results indicate that accurate source judgments of episodic context can occur even when recollection fails.     

"Sculpting the response space"--an account of left prefrontal activation at encoding

Left lateral prefrontal cortex (PFC) is consistently activated in neuroimaging studies of memory encoding. Its role, however, remains unclear. We describe two functional magnetic resonance imaging (fMRI) studies addressing this question. In the first we used a blocked experimental design to explore the effect of repeated encoding of word paired associates. Initial presentation of word pairs was associated with left ventrolateral PFC activation that attenuated with subsequent presentations of the same lists. When well-learned lists were presented with word pairs rearranged, a left PFC activation, greater than that associated with the initial presentation, was observed. In a second experiment, the formation of these associative relationships was explored using an event-related design. Two types of word pairs were presented: closely related (e.g., King...Queen) and distantly related (e.g., Net...Ship). The same region of left PFC was differentially sensitive to these two event-types, showing a greater response for distantly related pairs. We suggest that left PFC activity, at memory encoding, reflects operations necessary to the formation of meaningful associations in the service of optimal learning. A crucial feature of such associative processing lies in selecting appropriate, and inhibiting inappropriate, semantic attributes of the study material.     

Prefrontal Contributions to Executive Control: fMRI Evidence for Functional Distinctions within Lateral Prefrontal Cortex

The prefrontal cortex (PFC) plays a fundamental role in internally guided behavior. Although it is generally accepted that PFC subserves working memory and executive control operations, it remains unclear whether the subregions within lateral PFC support distinct executive control processes. An event-related fMRI study was implemented to test the hypothesis that ventrolateral and dorsolateral PFC are functionally distinct, as well as to assess whether functional specialization exists within ventrolateral PFC. Participants performed two executive control tasks that differed in the types of control processes required. During rote rehearsal, participants covertly rehearsed three words in the order presented, thus requiring phonological access and maintenance. During elaborative rehearsal, participants made semantic comparisons between three words held in working memory, reordering them from least to most desirable. Thus, in addition to maintenance, elaborative rehearsal required goal-relevant coding of items in working memory ("monitoring") and selection from among the items to implement their reordering. Results revealed that left posterior ventrolateral PFC was active during performance of both tasks, whereas right dorsolateral PFC was differentially engaged during elaborative rehearsal. The temporal characteristics of the hemodynamic responses further suggested that dorsolateral activation lagged ventrolateral activation. Finally, differential activation patterns were observed within left ventrolateral PFC, distinguishing between posterior and anterior regions. These data suggest that anatomically separable subregions within lateral PFC may be functionally distinct and are consistent with models that posit a hierarchical relationship between dorsolateral and ventrolateral regions such that the former monitors and selects goal-relevant representations being maintained by the latter.     

The role of precuneus and left inferior frontal cortex during source memory episodic retrieval

The posterior medial parietal cortex and left prefrontal cortex (PFC) have both been implicated in the recollection of past episodes. In a previous study, we found the posterior precuneus and left lateral inferior frontal cortex to be activated during episodic source memory retrieval. This study further examines the role of posterior precuneal and left prefrontal activation during episodic source memory retrieval using a similar source memory paradigm but with longer latency between encoding and retrieval. Our results suggest that both the precuneus and the left inferior PFC are important for regeneration of rich episodic contextual associations and that the precuneus activates in tandem with the left inferior PFC during correct source retrieval. Further, results suggest that the left ventro-lateral frontal region/frontal operculum is involved in searching for task-relevant information (BA 47) and subsequent monitoring or scrutiny (BA 44/45) while regions in the dorsal inferior frontal cortex are important for information selection (BA 45/46).     

Parahippocampal Activation during Successful Recognition of Words: A Self-Paced Event-Related fMRI Study

In this study, we investigated retrieval from verbal episodic memory using a self-paced event-related fMRI paradigm, similar to the designs typically used in behavioral studies of memory function. We tested the hypothesis that the medial temporal lobe (MTL) is involved in the actual recovery of verbal information (retrieval success) rather than in the attempt to retrieve information (retrieval attempt). To this end, we used a verbal recognition task, distinguishing correctly recognized words, correctly rejected words, and a low-level baseline condition. Directly contrasting correct recognition with correct rejection of words, we found activation in the left fusiform/parahippocampal gyrus, indicating that this region has a distinct role in the successful retrieval of verbal information. Furthermore, our results were in agreement with those of previous imaging studies that compared a fixed-paced verbal recognition task to a baseline condition, showing activation in bilateral inferior frontal cortex, left dorsolateral prefrontal cortex, left anterior insular cortex, and anterior cingulate. This demonstrates the applicability of a self-paced event-related design within imaging studies of memory function.     

The role of frontopolar cortex in subgoal processing during working memory

Neuroimaging studies have implicated the anterior-most or frontopolar regions of prefrontal cortex (FP-PFC, e.g., Brodmann's Area 10) as playing a central role in higher cognitive functions such as planning, problem solving, reasoning, and episodic memory retrieval. The current functional magnetic resonance imaging (fMRI) study tested the hypothesis that FP-PFC subserves processes related to the monitoring and management of subgoals, while maintaining information in working memory (WM). Subjects were scanned while performing two variants of a simple delayed response WM task. In the control WM condition, subjects monitored for the presence of a specific concrete probe word (LIME) occurring following a specific abstract cue word (FATE). In the subgoal WM condition, subjects monitored for the presence of any concrete probe word immediately following any abstract cue word. Thus, the task required semantic classification of the probe word (the subgoal task), while the cue was simultaneously maintained in WM, so that both pieces of information could be integrated into a target determination. In a second control condition, subjects performed abstract/concrete semantic classification without WM demands. A region within right FP-PFC was identified which showed significant activation during the subgoal WM condition, but no activity in either of the two control conditions. However, this FP-PFC region was not modulated by direct manipulation of active maintenance demands. In contrast, left dorsolateral PFC was affected by active maintenance demands, but the effect did not interact with the presence of a subgoal task. Finally, left ventral PFC regions showed activation in response to semantic classification, but were not affected by WM demands. These results suggest a triple dissociation of function within PFC regions, and further indicate that FP-PFC is selectively engaged by the requirement to monitor and integrate subgoals during WM tasks.     

The Role of Prefrontal Cortex in Sensory Memory and Motor Preparation: An Event-Related fMRI Study

Delayed-response tasks are behavioral paradigms in which subjects must remember stimulus attributes across a delay to subsequently perform the appropriate motor response. Quintana and Fuster (1992), reported that there exist subpopulations of neurons in monkey lateral prefrontal cortex (PFC) whose firing rates during the delay are tuned to either sensorial attributes of the stimulus (i.e., involved in sensory memory) or the direction of a postdelay motor response associated with the stimulus (i.e., involved in motor preparation). We studied human subjects with an event-related fMRI method that would allow us to test the hypothesis that there are regions within the PFC that are recruited during both motor preparation and sensory memory. Subjects performed a delayed-response task with two types of trials that either (1) allowed subjects to prepare during a delay period for a specific motor response or (2) required that subjects maintain a sensory attribute (specifically, color) during a delay period for correct performance postdelay. It was assumed that during the delay periods, the delayed-response trials would engage motor preparation while delayed-match trials would engage sensory memory. Behavioral data supported this assumption. Imaging results support the hypothesis that the PFC is involved in both motor preparation and sensory memory. Furthermore, no selectivity (in terms of intensity of neural representation on the spatial scale of the voxel size <5 mm³) for motor preparation over sensory memory (or vice-versa) was detected within the PFC. This latter result fails to support a gross anatomical segregation within the PFC with respect to involvement in these two cognitive processes.     

Enhancement of False Memory for Negative Material in Dysphoria: Mood Congruency or Response Bias?

Although there is an extensive literature on the effects of depression and dysphoria on memory accuracy, few studies have examined the effects of depression or dysphoria on false memory. This study used the Deese-Roediger-McDermott paradigm (Roediger and McDermott in J Exp Psychol Learn Mem Cogn 21:803–814, 1995) to look for evidence of a mood congruent false memory effect in dysphoric individuals. Participants studied lists of semantically associated negative and neutral words for a recognition memory test. The memory test included critical lures (words not presented in the study lists, but strongly related to words on the lists) to assess false memory and non-presented negative and neutral unrelated words to assess participants’ response bias. Although dysphoric participants falsely recognized significantly more critical lures related to the negative word lists, additional analyses revealed that this difference could be explained by a response bias that inflated their recognition responses to negatively valenced words. Directions for future research are discussed.     

Sleep Loss Produces False Memories

People sometimes claim with high confidence to remember events that in fact never happened, typically due to strong semantic associations with actually encoded events. Sleep is known to provide optimal neurobiological conditions for consolidation of memories for long-term storage, whereas sleep deprivation acutely impairs retrieval of stored memories. Here, focusing on the role of sleep-related memory processes, we tested whether false memories can be created (a) as enduring memory representations due to a consolidation-associated reorganization of new memory representations during post-learning sleep and/or (b) as an acute retrieval-related phenomenon induced by sleep deprivation at memory testing. According to the Deese, Roediger, McDermott (DRM) false memory paradigm, subjects learned lists of semantically associated words (e.g., “night”, “dark”, “coal”,…), lacking the strongest common associate or theme word (here: “black”). Subjects either slept or stayed awake immediately after learning, and they were either sleep deprived or not at recognition testing 9, 33, or 44 hours after learning. Sleep deprivation at retrieval, but not sleep following learning, critically enhanced false memories of theme words. This effect was abolished by caffeine administration prior to retrieval, indicating that adenosinergic mechanisms can contribute to the generation of false memories associated with sleep loss.     

Magnetoencephalographic correlates of different levels in subjective recognition memory

In our current study we employed whole-head magnetoencephalography (MEG) to identify neurophysiological correlates (event-related fields, ERFs) of different phenomenologies in human recognition memory. Words which had previously been semantically processed were presented along with previously unstudied words. Via button presses, participants provided subjective indices of three forms of memory: confident recognition, familiarity-based recognition, and misclassification of previously presented items as new (no recognition, misses). Behavioral results revealed a clear distinction between confident recognition (shortest reaction times) and familiarity-based recognition and misses, respectively, and physiological data pointed to bilateral anterior and left anterior/central regions in which magnetic field patterns were directly related to word recognition from approximately 300 ms to 500 ms after word onset. In the context of the prevalent dual process controversy on the roles of familiarity and recollection in recognition memory, we first highlight that two operationalizations of recollection need to be differentiated: We argue that a strategic search for a particular contextual feature stands in clear contrast to the fast and incidental availability of some contextual feature and derive experimental and behavioral indicators for either form of recollection. These indicators are used to select from manifold cognitive neuroscientific work on recognition memory in order to further discuss the neurocognitive characteristics of incidental recollection in contrast to other forms of episodic memory.     

Neural correlates of memory confidence

The present study aimed to shed light on the neural underpinnings of high vs. low memory confidence. To dissociate memory confidence from accuracy, the Deese-Roediger McDermott (DRM) paradigm was employed, which - compared to other memory paradigms - elicits a rather evenly distributed number of high-confident responses across all possible combinations of memory response types (i.e., hits, false alarms, correct rejections, and misses). In the standard DRM procedure, subjects are first presented with thematically interrelated word lists at encoding, which at recognition are intermixed with related and unrelated distractor items. The signature of a false memory or DRM effect is an increased number of high-confident false memories, particularly for strongly related lure items. For the present study, 17 female subjects were administered a verbal DRM task, whereas neural activation was indexed by fMRI. The behavioral analyses confirmed the expected false memory effect: subjects made more high-confident old responses (both hits and false alarms) the closer the items were related to the central list theme. Across all four memory response types, an increase in confidence at recognition was associated with bilateral activation in the anterior and posterior cingulate cortex along with medial temporal regions. In contrast, increments in doubt were solely related to activation in the superior posterior parietal cortex. To conclude, the study provides some evidence for dissociable systems for confidence and doubt.