Prefrontal activity associated with working memory and episodic long-term memory

Many recent neuroimaging studies have highlighted the role of prefrontal regions in the sustained maintenance and manipulation of information over short delays, or working memory (WM). In addition, neuroimaging findings have highlighted the role of prefrontal regions in the formation and retrieval of memories for events, or episodic long-term memory (LTM), but it remains unclear whether these regions are distinct from those that support WM. We used event-related functional magnetic resonance imaging (fMRI) to identify patterns of prefrontal activity associated with encoding and recognition during WM and LTM tasks performed by the same subjects. Results showed that the same bilateral ventrolateral prefrontal regions (at or near Brodmann's Areas [BA] 6, 44, 45, and 47) and dorsolateral prefrontal regions (BA 9/46) were engaged during encoding and recognition within the context of WM and LTM tasks. In addition, a region situated in the left anterior middle frontal gyrus (BA 10/46) was engaged during the recognition phases of the WM and LTM tasks. These results support the view that the same prefrontal regions implement reflective processes that support both WM and LTM.     

Episodic memory in patients with focal frontal lobe lesions

Episodic memory was evaluated in patients with unilateral, frontal lobe damage and matched controls using a list- method directed forgetting paradigm. Directed forgetting instructions (forget vs. remember the word), encoding instructions (learn vs. judge the word) and test format (recall vs. recognition) were manipulated in order to explore how variations in encoding and retrieval affect verbal memory. Controls demonstrated a normal directed forgetting effect in recall and less directed forgetting in recognition. Patients with left frontal (LF) damage did not show directed forgetting in either recall or recognition and patients with right frontal (RF) damage showed directed forgetting in recall, but not in recognition. Furthermore, the LF group recalled significantly more of the judge than learn words, suggesting that this group's performance improves by providing them with an encoding strategy. Conversely, the RF group's performance did not depend on encoding instructions and their recognition memory was impaired relative to the other two groups when they were instructed to judge the words. Our results suggest that (a) patients with LF damage show deficits in the rehearsal of to-be-remembered information, (b) whereas patients with RF damage show impairments in recognition memory. Furthermore, both patient groups show a lack of directed forgetting when familiarity-based processes guide performance.     

Disruption of inhibitory control of memory following lesions to the frontal and temporal lobes

A group of patients with lesions to the frontal lobes, a group with lesions to the temporal lobes, and groups of non-brain damaged controls took part in three experiments. The first experiment used directed forgetting (DF) by items, the second DF by lists, and the third retrieval induced forgetting (RIF). Frontal patients with right side lesions could not intentionally inhibit but all frontal patients showed normal RIF. Temporal patients with left side lesions had abnormal DF by lists and all the temporal patients had abnormal RIF. These findings are explained in terms of impairment to executive thought avoidance control processes in frontal patients and impaired knowledge access to long-term memory in temporal patients.     

Preliminary investigation of the influence of dopamine regulating genes on social working memory

Working memory (WM) refers to mental processes that enable temporary retention and manipulation of information, including information about other people (“social working memory”). Previous studies have demonstrated that nonsocial WM is supported by dopamine neurotransmission. Here, we investigated in 131 healthy adults whether dopamine is similarly involved in social WM by testing whether social and nonsocial WM are influenced by genetic variants in three genes coding for molecules regulating the availability of dopamine in the brain: catechol-O-methyltransferase (COMT), dopamine active transporter (DAT), and monoamine-oxidase A (MAOA). An advantage for the Met allele of COMT was observed in the two standard WM tasks and in the social WM task. However, the influence of COMT on social WM performance was not accounted for by its influence on either standard WM paradigms. There was no main effect of DAT1 or MAOA, but a significant COMT x DAT1 interaction on social WM performance. This study provides novel preliminary evidence of effects of genetic variants of the dopamine neurotransmitter system on social cognition. The results further suggest that the effects observed on standard WM do not explain the genetic effects on effortful social cognition.     

Prefrontal cortex dysfunction mediates deficits in working memory and prepotent responding in schizophrenia.

BACKGROUND: Schizophrenic patients show deficits in working memory (WM) and inhibition of prepotent responses. We examined brain activity while subjects performed tasks that placed demands on WM and overriding prepotent response tendencies, testing predictions that both processes engage overlapping prefrontal cortical (PFC) regions and that schizophrenic patients show reduced PFC activity and performance deficits reflecting both processes. METHODS: Functional magnetic resonance imaging data were acquired while 16 schizophrenic and 15 healthy subjects performed the N-Back task that varied WM load and a version of the AX-CPT that required overriding a prepotent response tendency. RESULTS: Both tasks engaged overlapping cortical networks (e.g., bilateral dorsolateral PFC, Broca's area, parietal cortex). Increased WM load monotonically increased activity; preparation to override a prepotent response produced greater and more enduring activity. Group differences on each task emerged in a right dorsolateral PFC region: schizophrenic subjects showed lesser magnitude increases under conditions of high WM and prepotent response override demands, with concomitant performance impairments. CONCLUSIONS: Schizophrenic patients exhibit PFC-mediated deficits in WM and preparation to override prepotent responses. Findings are consistent with the operation of a single underlying PFC-mediated cognitive control mechanism and with physiologic dysfunction of the dorsolateral PFC in schizophrenic patients reflecting impairments in this mechanism.     

Differential contributions of the parahippocampal place area and the anterior hippocampus to human memory for scenes

Past neuroimaging research has identified a parahippocampal place area (PPA) in the posterior medial temporal lobe (MTL), which responds preferentially to visual scenes and plays a role in episodic memory for this class of stimuli. In the present positron emission tomography study, we examined to what extent the functional characteristics of the PPA resemble those of other, more anterior MTL regions across various learning and recognition-memory tasks. We also determined whether the involvement of the PPA in recognition of previously studied scenes is specific to a particular type of scene information. We found that, like the PPA, anterior hippocampal regions showed a novelty response (higher activation for novel than repeated scenes) and a stimulus-related response (higher activation for scenes than objects) during learning, indicating that MTL structures other than the PPA contribute to the encoding of novel stimulus relationships in scenes. However, these anterior hippocampal regions showed no involvement during recognition of either spatial or nonspatial information contained in scenes. The PPA, by contrast, was consistently involved in recognition of all types of scene details, presumably through interactions with co-activated parietal and occipitotemporal cortices. We suggest that MTL contributions from the PPA are sufficient to support recognition of scenes when the task can be based on a perceptually based familiarity process.     

儿童和成年人项目记忆及源记忆的研究

目的探讨儿童和成年人项目记忆及源记忆的关系,检验额叶参与源记忆执行的假说及源记忆与项目记忆相互分离的假说。方法测试40名8~11岁正常儿童和40名正常成年人的项目记忆及源记忆,并进行双分离分析。结果项目记忆指标(Pr)成年组为0.73±0.14,儿童组为0.74±0.11,两组比较差异没有显著性(P>0.05);源记忆指标(I)成年组为0.73±0.13,儿童组为0.87±0.08,两组比较差异有极显著性(P<0.001)。将儿童组记忆指标分组后,项目记忆和源记忆指标存在双分离。结论推测额叶参与了源记忆的执行。项目记忆和源记忆双分离的结果支持其为情景记忆的双通道假说。     

Gamma oscillations during episodic memory processing provide evidence for functional specialization in the longitudinal axis of the human hippocampus

The question of whether the anterior and posterior hippocampus serve different or complementary functional roles during episodic memory processing has been motivated by noteworthy findings in rodent experiments and from noninvasive studies in humans. Researchers have synthesized these data to postulate several models of functional specialization, However, the issue has not been explored in detail using direct brain recordings. We recently published evidence that theta power increases during episodic memory encoding occur in the posterior hippocampus in humans. In our current investigation we analyzed an expanded data set of 32 epilepsy patients undergoing stereo EEG seizure mapping surgery with electrodes precisely targeted to the anterior and posterior hippocampus simultaneously who performed an episodic memory task. Using a repeated measures design, we looked for an interaction between encoding versus retrieval differences in gamma oscillatory power and anterior versus posterior hippocampal location. Our findings are consistent with a recently articulated model (the HERNET model) favoring posterior hippocampal activation during retrieval related processing. We also tested for encoding versus retrieval differences in the preferred gamma frequency band (high versus low gamma oscillations) motivated by published rodent data.     

Normal aging modulates prefrontoparietal networks underlying multiple memory processes

A functional decline of brain regions underlying memory processing represents a hallmark of cognitive aging. Although a rich literature documents age‐related differences in several memory domains, the effect of aging on networks that underlie multiple memory processes has been relatively unexplored. Here we used functional magnetic resonance imaging during working memory and incidental episodic encoding memory to investigate patterns of age‐related differences in activity and functional covariance patterns common across multiple memory domains. Relative to younger subjects, older subjects showed increased activation in left dorso‐lateral prefrontal cortex along with decreased deactivation in the posterior cingulate. Older subjects showed greater functional covariance during both memory tasks in a set of regions that included a positive prefronto‐parietal‐occipital network as well as a negative network that spanned the default mode regions. These findings suggest that the memory process‐invariant recruitment of brain regions within prefronto‐parietal‐occipital network increases with aging. Our results are in line with the dedifferentiation hypothesis of neurocognitive aging, thereby suggesting a decreased specialization of the brain networks supporting different memory networks.     

Prefrontal modulation of working memory performance in brain injury and disease

The inter-related cognitive constructs of working memory (WM) and processing speed are fundamental components to general intellectual functioning in humans. Importantly, both WM and processing speed are highly susceptible to disruption in cases of brain injury, neurologic illness, and even in normal aging. A goal of this article is to summarize and critique the functional imaging studies of speeded working memory in neurologically impaired populations. This review focuses specifically on the role of the lateral prefrontal cortex in mediating WM performance and integrates the relevant WM literature in healthy adults with the current findings in the clinical literature. One important finding emerging from a summary of this literature is the dissociable contributions made by ventrolateral and dorsolateral prefrontal cortex (VLPFC and DLPFC) in guiding performance on tasks of WM. Throughout this review, it is shown that when cerebral resources are challenged, it is DLPFC, and often right DLPFC specifically, that plays a critical role in modulating WM functioning. In addition, this article will examine the relationship between task performance and brain activation across studies to clarify the role of increased DLPFC activity in clinical samples. Finally, explanations are offered for the observed increased DLPFC activation and the potentially unique role of right DLPFC in mediating WM performance during periods of cerebral challenge.     

Long-term memory following transient global amnesia: an investigation of episodic and semantic memory

BACKGROUND: Several studies noted persistence of memory impairment following an episode of transient global amnesia (TGA) with standard tests. AIM: To specify long-term memory impairments in a group of patients selected with stringent criteria. METHODS: Both retrograde and anterograde memory were investigated in 32 patients 13-67 months after a TGA episode with original tasks encompassing retrograde semantic memory (academic, public and personal knowledge), retrograde episodic memory (autobiographical events) and anterograde episodic memory. RESULTS: Patients had preserved academic and public knowledge. Pathological scores were obtained in personal verbal fluency for the two most recent periods, and patients produced less autobiographical events than controls. However, when they were provided time to detail, memories were as episodic as in controls regardless of their remoteness. Anterograde episodic tasks revealed a mild but significant impairment of the capacity of re-living the condition of encoding, i.e. the moment at which words were presented. CONCLUSIONS: Patients who have suffered from an episode of TGA manifest deficits of memory focused on the retrieval of both recent semantic information and episodic memories and especially the capacity of re-living. These deficits may not result from a deterioration of memory per se but rather from difficulties in accessing memories.     

One month of human memory consolidation enhances retrieval-related hippocampal activity

We studied the role of the hippocampus in memory retrieval at 1 day and 1 month following associative learning of word pairs. Retrieval-related brain activity was recorded using functional magnetic resonance imaging in 20 healthy students, of which 12 were good learners and eight were poor learners. At the day lag, the poor learners exhibited enhanced neural recruitment in the hippocampus and neocortex to reach a retrieval performance comparable to that of the good learners. Over the 20 subjects, there was a positive correlation between retrieval-related hippocampal activity at the day lag and forgetting over the month retention interval (the greater the activity, the more forgetting). Although the poor learners' retrieval performance declined dramatically from the day to the month lag, the good learners maintained a high retrieval performance, which distinguishes them as good memory consolidators. Their retrieval-related hippocampal and neocortical activity increased from the day to the month lag. This increase was observed both when retrieval performance was matched between the day and the month lag and when the learning procedure for information retrieved at the day and the month lag was matched. This activity increase in the task-specialized neural network from the day lag to the month lag may reflect an increase in task demands or the proliferation of hippocampal-neocortical memory traces during memory consolidation as suggested by the multiple trace theory.     

Epistatic interaction of genetic depression risk variants in the human subgenual cingulate cortex during memory encoding

Recent genome-wide association studies have pointed to single-nucleotide polymorphisms (SNPs) in genes encoding the neuronal calcium channel Ca_V1.2 (CACNA1C; rs1006737) and the presynaptic active zone protein Piccolo (PCLO; rs2522833) as risk factors for affective disorders, particularly major depression. Previous neuroimaging studies of depression-related endophenotypes have highlighted the role of the subgenual cingulate cortex (CG25) in negative mood and depressive psychopathology. Here, we aimed to assess how recently associated PCLO and CACNA1C depression risk alleles jointly affect memory-related CG25 activity as an intermediate phenotype in clinically healthy humans. To investigate the combined effects of rs1006737 and rs2522833 on the CG25 response, we conducted three functional magnetic resonance imaging studies of episodic memory formation in three independent cohorts (N=79, 300, 113). An epistatic interaction of PCLO and CACNA1C risk alleles in CG25 during memory encoding was observed in all groups, with carriers of no risk allele and of both risk alleles showing higher CG25 activation during encoding when compared with carriers of only one risk allele. Moreover, PCLO risk allele carriers showed lower memory performance and reduced encoding-related hippocampal activation. In summary, our results point to region-specific epistatic effects of PCLO and CACNA1C risk variants in CG25, potentially related to episodic memory. Our data further suggest that genetic risk factors on the SNP level do not necessarily have additive effects but may show complex interactions. Such epistatic interactions might contribute to the ‘missing heritability'' of complex phenotypes.     

Effects of memory consolidation on human hippocampal activity during retrieval

Day-to-day memories undergo transformation from short-term to long-term storage, a process called memory consolidation. Animal studies showed that memory consolidation requires protein synthesis and the growth of new hippocampal synapses within 24 h. To test for effects of memory consolidation in the human, we examined brain activation during the retrieval of information at 10 min and at 24 h following learning using functional magnetic resonance imaging (fMRI), an indirect measure of synaptic activity. Learning instructions were adjusted to yield a comparable retrieval quantity and retrieval quality at 10 min and 24 h after learning. The left hippocampal formation exhibited enhanced activity during the retrieval at the 24 h lag compared to the retrieval at the 10 min lag. Moreover, the activity in the left anterior hippocampal formation showed stronger correlations with retrieval quantity and retrieval quality at the 24 h lag than at the 10 min lag. This suggests that the relation between left anterior hippocampal activity and retrieval success became closer as consolidation progressed. These fMRI results in the human hippocampal formation may correspond to the neurobiological results in the animal hippocampal formation of a strengthening and growth of synaptic connections within 24 h.     

Time,memory, and the legacy of Howard Eichenbaum

Over the past 15 years, there has been an explosion of new research on the role of the hippocampus in the representation of information about time in memory. Much of this work was inspired by the ideas and research of Howard Eichenbaum, who made major contributions to our understanding of the neurobiology of episodic memory and the neural representation of time. In this article, I will review evidence regarding the role of time in understanding hippocampal function. This review will cover a broad range of evidence from studies of humans and nonhuman animals with a narrative arc that follows Howard's major discoveries. These studies demonstrate that the hippocampus encodes information in relation to an episodic context, and that time, as well as space, serves to define these contexts. Moreover, the research has shown that the hippocampus can encode temporal, spatial, and situational information in parallel. Building on this work, I present a new framework for understanding temporal structure in human episodic memory. I conclude by outlining current controversies and new questions that must be addressed by the field in the years to come.     

Prefrontal cortex hemispheric specialization for categorical and coordinate visual spatial memory

During visual spatial perception of multiple items, the left hemisphere has been shown to preferentially process categorical spatial relationships while the right hemisphere has been shown to preferentially process coordinate spatial relationships. We hypothesized that this hemispheric processing distinction would be reflected in the prefrontal cortex during categorical and coordinate visual spatial memory, and tested this hypothesis using functional magnetic resonance imaging (fMRI). During encoding, abstract shapes were presented in the left or right hemifield in addition to a dot at a variable distance from the shape (with some dots on the shape); participants were instructed to remember the position of each dot relative to the shape. During categorical memory retrieval, each shape was presented centrally and participants responded whether the previously corresponding dot was 'on' or 'off' of the shape. During coordinate memory retrieval, each shape was presented centrally and participants responded whether the previously corresponding dot was 'near' or 'far' from the shape (relative to a reference distance). Consistent with our hypothesis, a region in the left prefrontal cortex (BA10) was preferentially associated with categorical visual spatial memory and a region in the right prefrontal cortex (BA9/10) was preferentially associated with coordinate visual spatial memory. These results have direct implications for interpreting previous findings that the left prefrontal cortex is associated with source memory, as this cognitive process is categorical in nature, and the right prefrontal cortex is associated with item memory, as this process depends on the precise spatial relations among item features or components.     

The hippocampal indexing theory and episodic memory: updating the index

A little over 20 years ago, (Teyler and DiScenna,1986; Behav Neurosci 100:147-152) proposed the hippocampal memory index theory. It offered an account of episodic memory based on the intrinsic organization of the hippocampus, its synaptic physiology and its anatomical relationship to other regions of the brain. The essence of their idea was that the hippocampus was functionally designed and anatomically situated to capture information about neocortical activity generated by the individual features of behavioral episode. Moreover, because the hippocampus projects back to these neocortical regions the information it stored could serve as an index to the pattern of neocortical activity produced by the episode. Consequently, a partial cue that activated the index could activate the neocortical patterns and thus retrieve the memory of the episode. In this article we revisit and update indexing theory. Our conclusion is that it has aged very well. Its core ideas can be seen in many contemporary theories and there is a wealth of data that support this conceptual framework.     

The Naïve and the Distrustful: State dependency of hippocampal computations in manipulative memory distortion

Flexible mnemonic mechanisms that adjust to different internal mental states can provide a major adaptive advantage. However, little is known regarding how this flexibility is achieved in the human brain. We examined brain activity during retrieval of false memories of a movie, generated by exposing participants to misleading information. Half of the participants suspected the memory manipulation (Distrustful), whereas the other half did not (Naïve). Distrustful displayed more accurate memory performance and a brain signature different than that of Naïve. In Distrustful, the ability to differentiate true from false information was driven by a qualitatively distinct hippocampal activity for endorsed items, consistent with the view that hippocampal encoding allows recollection of a specific source. Conversely, in Naïve, BOLD differences between true and false memories were linearly correlated with accuracy across participants, suggesting that Naïve subjects needed to reinstate and evaluate stored information to discern true from false. We propose that our results lend support to models suggesting that hippocampal activity can exhibit different computational schemes, depending on memorandum attributes. Furthermore, we show that trust, considered as a subjective state of mind, may alter basic hippocampal strategies, influencing the ability to separate real from false memory. © 2014 Wiley Periodicals, Inc.     

Associations between sleep and episodic memory updating

Prior research shows that contextual reminders can reactivate hippocampal links to previously consolidated memories, rendering them susceptible to being updated with new information which then is reconsolidated. Studies implicate sleep in the reconsolidation of reactivated memories, but it is unknown what role sleep plays in updating of a previously consolidated trace with new information. We tracked participants' sleep during an episodic reconsolidation paradigm, first with actigraphy (Experiment 1) then with polysomnography (Experiment 2). Our paradigm involved two learning sessions and a retrieval session, each separated by 48 hr. We reminded participants of the first learning experience immediately prior to the second, which led them to update the earlier memory with elements of the later experience. In Experiment 1, less sleep after Session 1 and more sleep after Session 2 are associated with increased updating. In Experiment 2, N2 sleep spindles (SSs) after the reminder and new learning are associated with more updating, but primarily when spindle activity after Session 1 is low. Thus, total sleep time and N2 SSs contribute to sleep‐dependent updating of episodic memory. This outcome is consistent with other work connecting SS activity to the integration of novel information into existing knowledge structures, extended here with the study of how variations in sleep over successive nights contribute to this process. We discuss some possible roles of spindles in the decontextualization of hippocampal memory over time. Although much work addresses the role of sleep in the consolidation of new memories, this work uniquely addresses the contribution of sleep to the updating of a previously consolidated trace with new information.