右侧背外侧前额叶在视觉工作记忆中的因果性作用

以往的影像学研究表明右侧背外侧前额叶皮层(DLPFC)在视觉工作记忆中发挥重要作用, 然而缺乏因果性的证据。本研究旨在考察右侧DLPFC的激活与视觉工作记忆容量的因果关系, 并探讨这一关系受到记忆负荷的调节及其神经机制。被试接受经颅直流电刺激之后完成视觉工作记忆变化检测任务, 根据被试在虚假刺激情况下从负荷4到负荷6任务记忆容量的增量将被试分为低记忆增长潜力组(简称低潜力组)和高记忆增长潜力组(简称高潜力组), 结果发现正性电刺激右侧DLPFC相对于虚假电刺激显著提升了高潜力组被试在低记忆负荷(负荷4)下的记忆容量及其对应的提取阶段的脑电指标SPCN成分。表明右侧DLPFC在视觉工作记忆的提取阶段发挥重要的因果性作用; 正性经颅直流电刺激右侧DLPFC可使工作记忆容量高潜力被试获得更多的脑活动增益, 并导致更好的行为提升效果。     

Persistent activity in the prefrontal cortex during working memory

The dorsolateral prefrontal cortex (DLPFC) plays a crucial role in working memory. Notably, persistent activity in the DLPFC is often observed during the retention interval of delayed response tasks. The code carried by the persistent activity remains unclear, however. We critically evaluate how well recent findings from functional magnetic resonance imaging studies are compatible with current models of the role of the DLFPC in working memory. These new findings suggest that the DLPFC aids in the maintenance of information by directing attention to internal representations of sensory stimuli and motor plans that are stored in more posterior regions.     

The role of episodic and semantic memory in episodic foresight

In this paper we describe a special form of future thinking, termed “episodic foresight” and its relation with episodic and semantic memory. We outline the methodologies that have largely been developed in the last five years to assess this capacity in young children and non-human animals. Drawing on Tulving's definition of episodic and semantic memory, we provide a critical analysis of the role that both types of memory might have on the episodic foresight tasks described in the literature. We conclude by highlighting some unanswered questions and suggesting future directions for research that could further our understanding of how memory is intimately connected to episodic foresight.     

Right prefrontal cortex responds to item familiarity during a memory encoding task

In a previous word-pair encoding study (Dolan & Fletcher, 1997), we examined the effect of introducing novelty, either in studied words or in their mutual associations. A left medial temporal lobe (MTL) sensitivity to novel words and left prefrontal cortex (PFC) to novel associations was observed. In this further report on the data, we explored the extent to which the right PFC, more generally implicated in retrieval operations (Fletcher, Frith, & Rugg, 1997), was sensitive to these manipulations. Specifically, we characterised changes associated with increasing familiarity of study material. We demonstrate that the response in right ventrolateral PFC is preferentially sensitive to a condition in which all material was familiar (that is, in which all material had been presented prior to scanning). A more dorsal region in right PFC was found to be relatively more active in association with a condition in which one item in the pair was familiar but was paired with a novel associate. Our results suggest that sensitivity to stimulus familiarity is expressed in right PFC, even within the context of an encoding task. The data also provide further evidence for functional heterogeneity within right PFC, with a more ventral region responding to familiarity of complete word pairs and a more dorsal region responding to familiar single words occurring in the context of new associative relationships.     

The role of prefrontal cortex in resolving distractor interference

We investigate the hypothesis that those subregions of the prefrontal cortex (PFC) found to support proactive interference resolution may also support delay-spanning distractor interference resolution. Ten subjects performed delayed-recognition tasks requiring working memory for faces or shoes during functional MRI scanning. During the 15-sec delay interval, task-irrelevant distractors were presented. These distractors were either all faces or all shoes and were thus either congruent or incongruent with the domain of items in the working memory task. Delayed-recognition performance was slower and less accurate during congruent than during incongruent trials. Our fMRI analyses revealed significant delay interval activity for face and shoe working memory tasks within both dorsal and ventral PFC. However, only ventral PFC activity was modulated by distractor category, with greater activity for congruent than for incongruent trials. Importantly, this congruency effect was only present for correct trials. In addition to PFC, activity within the fusiform face area was investigated. During face distraction, activity was greater for face relative to shoe working memory. As in ventrolateral PFC, this congruency effect was only present for correct trials. These results suggest that the ventrolateral PFC and fusiform face area may work together to support delay-spanning interference resolution.     

The TECO theory and lawful dependency in successive episodic memory tests.

A large number of experiments in successive tests of episodic memory have focused on an experimental paradigm called recognition failure of recallable words. In this paradigm, a cued recall test follows a recognition test. Large amounts of data have revealed a lawful moderate dependence between recognition and cued recall. TECO (Sikstr?m, 1996b), a general connectionist theory of memory, has been applied for the phenomenon of recognition failure. This paper makes a strong claim that all possible pairwise combinations of successive tests between recognition, cued recognition, cued recall, and free recall follow a lawful relationship. The quantitative degree of the dependency predicted between these tests can be summarized in one function. Four experiments were conducted to test this claim. In line with the predictions, the results show that all pairwise combinations of these tests fit reasonably well with the proposed function. The TECO theory suggests theoretical insights into how recognition and recall may be divided into a recollection component, a familiarity component, and a cue-target integration component.     

The medial prefrontal cortex and memory of cue location in the rat

We developed a single-trial cue-location memory task in which rats experienced an auditory cue while exploring an environment. They then recalled and avoided the sound origination point after the cue was paired with shock in a separate context. Subjects with medial prefrontal cortical (mPFC) lesions made no such avoidance response, but both lesioned and control subjects avoided the cue itself when presented at test. A follow up assessment revealed no spatial learning impairment in either group. These findings suggest that the rodent mPFC is required for incidental learning or recollection of the location at which a discrete cue occurred, but is not required for cue recognition or for allocentric spatial memory.     

The role of familiarity in episodic memory and metamemory for music

Participants heard music snippets of varying melodic and instrumental familiarity paired with animal-name titles. They then recalled the target when given either the melody or the title as a cue, or they gave name feeling-of-knowing (FOK) ratings. In general, recall for titles was better than it was for melodies, and recall was enhanced with increasing melodic familiarity of both the cues and the targets. Accuracy of FOK ratings, but not magnitude, also increased with increasing familiarity. Although similar ratings were given after melody and title cues, accuracy was better with title cues. Finally, knowledge of the real titles of the familiar music enhanced recall but had, by and large, no effect on the FOK ratings.     

Egocentric-updating during navigation facilitates episodic memory retrieval

Influential models suggest that spatial processing is essential for episodic memory [O’Keefe, J., & Nadel, L. (1978). The hippocampus as a cognitive map. London: Oxford University Press]. However, although several types of spatial relations exist, such as allocentric (i.e. object-to-object relations), egocentric (i.e. static object-to-self relations) or egocentric updated on navigation information (i.e. self-to-environment relations in a dynamic way), usually only allocentric representations are described as potentially subserving episodic memory [Nadel, L., & Moscovitch, M. (1998). Hippocampal contributions to cortical plasticity. Neuropharmacology, 37(4-5), 431-439]. This study proposes to confront the allocentric representation hypothesis with an egocentric updated with self-motion representation hypothesis. In the present study, we explored retrieval performance in relation to these two types of spatial processing levels during learning. Episodic remembering has been assessed through Remember responses in a recall and in a recognition task, combined with a “Remember-Know-Guess” paradigm [Gardiner, J. M. (2001). Episodic memory and autonoetic consciousness: A first-person approach. Philosophical Transactions of the Royal Society B: Biological Sciences, 356(1413), 1351-1361] to assess the autonoetic level of responses. Our results show that retrieval performance was significantly higher when encoding was performed in the egocentric-updated condition. Although egocentric updated with self-motion and allocentric representations are not mutually exclusive, these results suggest that egocentric updating processing facilitates remember responses more than allocentric processing. The results are discussed according to Burgess and colleagues’ model of episodic memory [Burgess, N., Becker, S., King, J. A., & O’Keefe, J. (2001). Memory for events and their spatial context: models and experiments. Philosophical Transactions of the Royal Society of London. Series B: Biological Sciences, 356(1413), 1493-1503].     

The role of the episodic buffer in working memory for language processing

A body of work has accumulated to show that the cognitive process of binding information from different mnemonic and sensory sources as well as in different linguistic modalities can be fractionated from general executive functions in working memory both functionally and neurally. This process has been defined in terms of the episodic buffer (Baddeley in Trends Cogn Sci 4(11):417–423, 2000). This paper considers behavioural, neuropsychological and neuroimaging data that elucidate the role of the episodic buffer in language processing. We argue that the episodic buffer seems to be truly multimodal in function and that while formation of unitary multidimensional representations in the episodic buffer seems to engage posterior neural networks, maintenance of such representations is supported by frontal networks. Although, the episodic buffer is not necessarily supported by executive processes and seems to be supported by different neural networks, it may operate in tandem with the central executive during effortful language processing. There is also evidence to suggest engagement of the phonological loop during buffer processing. The hippocampus seems to play a role in formation but not maintenance of representations in the episodic buffer of working memory.     

The prefrontal cortex in sleep

Experimental data indicate a role for the prefrontal cortex in mediating normal sleep physiology, dreaming and sleep-deprivation phenomena. During nonrandom-eye-movement (NREM) sleep, frontal cortical activity is characterized by the highest voltage and the slowest brain waves compared to other cortical regions. The differences between the self-awareness experienced in waking and its diminution in dreaming can be explained by deactivation of the dorsolateral prefrontal cortex during REM sleep. Here, we propose that this deactivation results from a direct inhibition of the dorsolateral prefrontal cortical neurons by acetylcholine, the release of which is enhanced during REM sleep. Sleep deprivation influences frontal executive functions in particular, which further emphasizes the sensitivity of the prefrontal cortex to sleep.     

Emotional arousal impairs association memory: roles of prefrontal cortex regions

The brain processes underlying impairing effects of emotional arousal on associative memory were previously attributed to two dissociable routes using high-resolution fMRI of the MTL (Madan et al. 2017). Extrahippocampal MTL regions supporting associative encoding of neutral pairs suggested unitization; conversely, associative encoding of negative pairs involved compensatory hippocampal activity. Here, whole-brain fMRI revealed prefrontal contributions: dmPFC was more involved in hippocampal-dependent negative pair learning and vmPFC in extrahippocampal neutral pair learning. Successful encoding of emotional memory associations may require emotion regulation/conflict resolution (dmPFC), while neutral memory associations may be accomplished by anchoring new information to prior knowledge (vmPFC).

Emotional arousal is well known to enhance memory for individual items (Schümann and Sommer 2018), but can have impairing effects on associative memory, particularly when items cannot be easily unitized and interitem associations have to be formed (Madan et al. 2012; Murray and Kensinger 2013; Bisby and Burgess 2017). The neural substrates of the impairing effect of emotional arousal on associative memory have only begun to be explored (Bisby et al. 2016; Madan et al. 2017). Emotional arousal may disrupt hippocampal functions that are critical to promote binding and thereby lead to reduced associative memory for emotionally arousing items (“disruption hypothesis”) (Bisby et al. 2016). Conversely, encoding of neutral items may engage extrahippocampal medial temporal lobe (MTL) regions, areas we interpreted to promote better incidental unitization of neutral than negative items, leading to a net-decrease in associative memory for negative items (“bypassing hypothesis”) (Madan et al. 2017).Specifically, in our previous high-resolution fMRI study focussing on MTL regions (Madan et al. 2017), extrahippocampal MTL cortex was more active during encoding of neutral than negative picture pairs, showed a subsequent memory effect (SME) for neutral picture pairs, and neutral pair encoding was accompanied by more between-picture saccadic eye movements compared with negative pairs. In line with previous findings of extrahippocampal MTL areas involved in association memory formation of merged or unitized items (Giovanello et al. 2006; Quamme et al. 2007; Diana et al. 2008; Delhaye et al. 2019), we interpreted our fMRI and eye movement findings to suggest better incidental unitization of neutral picture pairs than negative pictures pairs. A behavioral follow-up study confirmed that unitization, that is, imagining the two pictures as one (“interactive imagery”), was indeed rated as higher for neutral than negative pairs, and this advantage in interactive imagery was linked to better associative memory for neutral pairs, lending further support to the bypassing hypothesis (Caplan et al. 2019).What would prevent emotional pairs from being as easily merged as neutral pairs? We observed that during negative pair encoding, each individual picture was fixated longer compared with neutral pictures. These longer fixation durations for negative pictures were related to greater activity during negative than neutral pair encoding in the dorsal amygdala (likely the centromedial group) (Hrybouski et al. 2016), an activation which was functionally coupled to the more ventral amygdala (likely the lateral nucleus) (Hrybouski et al. 2016). This ventral amygdala activation exhibited a subsequent forgetting effect specifically for negative pairs. Given that emotional items attract more attention to themselves and are more likely processed as individual items (Markovic et al. 2014; Mather et al. 2016), we conjectured that this may make pairs of emotional items harder to unitize and to benefit from extrahippocampal unitization-related processes such as interactive imagery. Interestingly, the hippocampus revealed a subsequent memory effect specifically for negative pairs in Madan et al. (2017). We concluded that when sufficiently arousing information precludes extrahippocampal unitization-based encoding, an alternative, compensatory, and effortful relational hippocampus-dependent encoding strategy may be used.Both findings, extrahippocampal MTL encoding for neutral pairs and compensatory hippocampal encoding for negative pairs, raise the question of which cortical areas could be involved in these two dissociable associative encoding processes. Conceivably, successful associative encoding of negative information may require participants to evaluate the emotional content, and regulate emotional arousal/conflict, functions primarily associated with dorso-medial PFC regions (dmPFC; Dixon et al. 2017), the anterior cingulate cortex (ACC) (Botvinick 2007), and posterior areas of the ventro-medial PFC (vmPFC) (Yang et al. 2020). To unitize two pictures through interactive imagery, retrieval of semantic memories and prior knowledge regarding the contents of the two pictures is likely helpful. Semantic memory processes have been attributed to the left inferior frontal gyrus (left IFG) (Binder and Desai 2011). The vmPFC (more anterior portions) could also be involved, owing to its role in relating new information during encoding to prior knowledge, that is, a “unitization-like” process (Gilboa and Marlatte 2017; Sommer 2017). Motivated by our previous discovery and interpretation of the two distinct encoding processes in the MTL (Madan et al. 2017), the potential contribution of these cortical areas in neutral and negative association memory was explored here by using a whole-brain scan and overcoming the limitations of our previous high-resolution fMRI sequence focused only on the MTL in Madan et al. (2017).In the current study, we therefore acquired standard-resolution whole-brain fMRI (3 Tesla Siemens Trio scanner, 3-mm thickness, TR 2.21 sec, TE 30 msec) of 22 male participants during exactly the same task as in Madan et al. (2017). Only male participants were recruited because of known sex-dependent lateralization of amygdala activity (Cahill et al. 2004; Mackiewicz et al. 2006), limiting the conclusions of the current study to males. Eye movements were assessed as a proxy for overt attention (EyeLink 1000, SR Research, 17 participants with usable eye-tracking data). In each of three encoding-retrieval cycles, 25 neutral and 25 negative picture pairs were intentionally encoded. Pictures (e.g., objects, scenes, humans, and animals) were selected from the International Affective Picture System (Lang et al. 2008) and the internet, and confirmed to have different valence and arousal through independent raters (details in Madan et al. 2017). Each encoding round was followed by a two-step memory test for each pair: In a judgement of memory (JoM) task one picture served as retrieval cue and volunteers indicated their memory (yes/no) for the other picture of the original pair. Then the same picture was centrally presented again, surrounded by five same-valence pictures (one correct target, four lures) in a five-alternative forced-choice associative recognition test. Participants chose the target picture from the array with an MR-compatible joystick.As in our previous studies, associative recognition was less accurate for negative (NN) (M = 0.47) than neutral (nn) pairs (M = 0.51; t(22) = 2.49, P = 0.02). Subjective memory confidence (JoM) for neutral pairs (M = 0.41) was not significantly different from confidence for negative pairs (M = 0.43; t(22) = 1.19, P = 0.25) (Fig. 1A; Madan et al. 2017; Caplan et al. 2019).Open in a separate windowFigure 1.Behavioral and eye tracking results. (A) Accuracy in the associative recognition task (5-AFC) for all negative (NN) and neutral (nn) pairs. Chance level in the 5-AFC associative recognition task was 1/5 = 0.20. (B) Mean number of saccades between the two pictures of a pair for remembered (Hit) and forgotten (Miss) negative (NN) and neutral (nn) pairs. (C) Mean number of saccades within pictures. Error bars are 95% confidence intervals around the mean, corrected for interindividual differences (Loftus and Mason 1994).Average fixation duration (a proxy for the depth of processing of individual pictures) was longer for negative than neutral pictures (F_(1,16) = 9.59, P = 0.007), with no main effect of memory (F_(1,16) = 0.11, P = 0.75), nor emotion–memory interaction (F_(1,16) = 1.27, P = 0.28). The number of fixations was also higher for negative than neutral pictures (F_(1,16) = 5.56, P = 0.03), again with no main effect of memory (F₍₁₎ = 1.56, P = 0.23) or interaction (F_(1,16) = 0.26, P = 0.61). The number of saccades within each picture (i.e., visual exploration within but not across items, reflecting intraitem processing) was higher for negative than neutral pairs (Fig. 1B; F_(1,16) = 33.38, P < 0.001), with no main effect of memory (F_(1,16) = 0.02, P = 0.89) nor interaction (F_(1,16) = 0.15, P = 0.71). However, the number of saccades between the two pictures of a pair, which may support associative processing, was substantially lower for negative than neutral pairs (Fig. 1C; F_(1,16) = 7.67, P = 0.01). Importantly, there were more between-picture saccades for pairs that were later remembered than forgotten, that is, a subsequent memory effect based on between-picture saccades (F_(1,16) = 8.43, P = 0.01). This effect did not further interact with emotion (F_(1,16) = 2.64, P = 0.12). Thus, association memory success was driven by interitem saccades, and these were reduced in negative trials. Participants spent more attention to individual negative than neutral pictures (fixation duration and number of within-picture saccades), but this was unrelated to association memory success.The fMRI data were preprocessed (slice timing corrected, realigned and unwarped, normalized using DARTEL and smoothed, FWHM = 8 mm) and analyzed using SPM12. First-level models were created with four regressors that modeled the onsets of the 2 (negative and neutral) × 2 (subsequent hits and misses) conditions of interest. Results of all fMRI analyses were considered significant at P < 0.05, family-wise error (FWE) corrected for multiple comparisons across the entire scan volume or within the a priori anatomical regions of interest (ROIs). ROIs for the hippocampus, amygdala and extrahippocampal MTL were reused from our previous study (Madan et al. 2017). The prefrontal ROIs, that is, dmPFC, ACC, vmPFC and left inferior frontal gyrus ROIs, were manually traced on the mean T1 image using ITK-SNAP 3.6.0 (Yushkevich et al. 2006) following schematic drawings based on meta-analyses (Binder and Desai 2011; Dixon et al. 2017; Gilboa and Marlatte 2017).The second-level analyses based on the resulting individual β images and subject as a random factor replicated a well-established network of brain areas involved in negative emotion processing (Spalek et al. 2015): greater activity during processing negative than neutral picture pairs in the amygdala, insula, right inferior frontal gyrus, mid, and anterior cingulate cortex as well as visual areas (Fig. 2A). As in our previous study, we correlated the difference in left amygdala activity with the difference in eye movements for negative minus neutral trials, showing a significant correlation with the number of within-picture saccades (r = 0.50, P = 0.018). Thus, higher left amygdala activity was associated with increased visual search within negative pictures. We conducted a psychophysiological interaction analysis (PPI) using this amygdala region as seed and contrasted functional coupling during successful versus unsuccessful negative with successful versus unsuccessful neutral pair encoding (i.e., the interaction of valence and subsequent memory success). This PPI revealed stronger coupling during successful encoding of negative compared with neutral pairs with a (nonsignificant) cluster in the dmPFC (Z = 3.01, [−12, 38, 26]). Simple effects showed that the amygdala was more strongly coupled with the dmPFC during successful than unsuccessful negative pair encoding (Z = 3.63, [−2, 16, 42]).Open in a separate windowFigure 2.Main effects of emotion—fMRI results. (A) Greater activity during negative than neutral pair processing irrespective of subsequent memory success. (B) Greater activity during neutral than negative pairs processing. t-maps thresholded at P < 0.001 uncorrected for visualization purposes. t-value color-coded.Neutral-pair processing was associated with greater activity than negative-pair processing in the bilateral extrahippocampal MTL cortex, ventral precuneus (vPC), retrosplenial cortex (RSC), middle occipital gyrus, and putamen (Fig. 2B). In addition, we observed a general SME irrespective of valence in the left hippocampus ([−28, −16, −24], Z = 3.49, P = 0.04).An interaction between pair valence and SME with greater neutral than negative SME was observed in vmPFC (Fig. 3A), together with a (nonsignificant) cluster in right MTL cortex ([26, −24, −28], Z = 3.16, P = 0.11). We conducted a PPI using this vmPFC region as seed and contrasted functional coupling during successful vs. unsuccessful neutral with successful vs. unsuccessful negative pair encoding. This PPI revealed stronger coupling during successful encoding of neutral compared with negative pairs in a cluster at the border of the extrahippocampal MTL cortex reaching into the hippocampus ([−20, −18, −26], Z = 4.61, Fig. 3B).Open in a separate windowFigure 3.SME × Emotion interactions and PPIs. (A) Activity in the vmPFC revealed a SME only for neutral but not negative pairs. (B) This region was stronger coupled during neutral than negative pair encoding with a cluster in the border of left MTL cortex/hippocampus. (C,D) Activity in the right hippocampus and dmPFC revealed a SME only for negative pairs. (E) The dmPFC was stronger coupled during negative than neutral pairs encoding with the bilateral hippocampus. t-maps thresholded at P < 0.001 uncorrected for visualization purposes. Error bars are 95% confidence intervals around the mean, corrected for interindividual differences (Loftus and Mason 1994).Conversely, an interaction between pair valence and SME showing a greater negative than neutral SME was observed in the right hippocampal region (Fig. 3C), replicating our previous finding of compensatory hippocampal encoding, and in the insula (Z = 3.7, [38, 2, 8]). Within prefrontal cortex, the dorsal medial prefrontal cortex (dmPFC, Z = 4.14) (Fig. 3D), also showed this effect. Neutral pairs showed a subsequent forgetting effect, that is, greater activity during unsuccessful encoding of neutral pairs, in these regions (Fig. 3 C,D).Similar to the PPI with the vmPFC seed, we conducted a PPI with the dmPFC cluster as seed. This PPI revealed the bilateral hippocampus to be more strongly coupled with the dmPFC during successful negative than neutral pair encoding (Z = 3.98, [−24, −10, −18], Z = 4.71, [30, −14, −29]) (Fig. 3E). The correlational analyses of activity in the dmPFC and vmPFC (valence × encoding success interactions) with the corresponding eye-tracking measures were nonsignificant, possibly due to low reliability of difference measures (Schümann et al. 2020).The current findings, first, replicated the impairing effects of emotional arousal on association memory previously observed in six experiments across four studies (Madan et al. 2012, 2017; Caplan et al. 2019). We built on these previous findings here by identifying cortical, especially prefrontal areas involved in the associative memory advantage for neutral pairs and those involved in the compensatory mechanism for learning negative pairs. In particular, vmPFC activity more strongly supported successful encoding of neutral than negative pairs and during this process, showed stronger coupling with a cluster at the border between MTL cortex and hippocampus. Conversely, the dmPFC was more engaged and more strongly coupled with the hippocampus during successful negative than neutral pair encoding.We observed more and longer fixations, as well as more within-picture saccades for individual negative pictures compared with neutral pictures, resembling previously reported eye movement findings (Bradley et al. 2011; Dietz et al. 2011). We had previously shown that increased attention (fixation duration) to individual negative pictures is linked to centromedial amygdala activity (not measurable here due to the whole-brain scan resolution), and functionally coupled with a negative pair-specific subsequent forgetting effect in the lateral amygdala (Madan et al. 2017). These findings together suggest that increased attention attracted by individual negative pictures does not support associative memory, or may even be detrimental (cf., Hockley and Cristi 1996).The dmPFC contributed more to negative than neutral association memory and was functionally coupled to the hippocampus, which complements our interpretation of possibly compensatory activity in the hippocampus during negative pair encoding (Madan et al. 2017). The amygdala on the other hand was stronger coupled with the dmPFC during successful encoding of negative pairs which might reflect the detection of aversive stimuli by the amygdala. The dmPFC not only plays a role in emotion regulation (Wager et al. 2008; Ochsner et al. 2012; Kohn et al. 2014; Dixon et al. 2017): It is the central node in the cognitive control network. In particular, the dmPFC regulates conflicts between goals and distracting stimuli by boosting attention toward the relevant task (Weissman 2004; Grinband et al. 2011; Ebitz and Platt 2015; Iannaccone et al. 2015). Consistent with this role in the current task, the dmPFC was functionally more strongly coupled with the bilateral hippocampus during successful negative compared with neutral pair learning. The involvement of the dmPFC during successful negative (but unsuccessful neutral) (discussed below) pair encoding may suggest that it resolves conflicts between the prepotent attention to the individual negative pictures and the current task goals, that is, their intentional associative encoding. One way to do so might involve the dmPFC''s role to regulate the negative emotions elicited by the pictures in order to focus on the associative memory task.Neutral pairs elicited more between-picture saccades than negative pairs, as in (Madan et al. 2017). The vmPFC was more strongly involved in successful associative encoding of neutral than negative pairs and more strongly coupled with the extrahippocampal MTL cortex bordering the hippocampus during successful neutral compared with negative pair encoding. Anterior vmPFC regions and their coupling with the MTL have been implicated in retrieval of consolidated memories and in anchoring new information to prior knowledge (Nieuwenhuis and Takashima 2011; van Kesteren et al. 2013; Schlichting and Preston 2015; Gilboa and Marlatte 2017; Sommer 2017; Brod and Shing 2018; Sekeres et al. 2018). We previously observed that interactive imagery (forming one instead of two images to memorize) was higher for neutral than negative pairs (Caplan et al. 2019), perhaps reflected by the increased between-picture saccades in the current study. Assuming that the anterior vmPFC subserves retrieval of prior knowledge, its engagement during successful neutral pair encoding may have supported such incidental unitization processes here as well. Negative pictures are inherently semantically more related (Barnacle et al. 2016), which implies that they may share even more prior knowledge than neutral pictures. However, the retrieval of this prior knowledge may be inhibited by the attraction of attention to individual negative pictures, not their arbitrary pairing as in the current task. Incidental unitization can occur through rather subtle manipulations (Giovanello et al. 2006; Diana et al. 2008; Bader et al. 2010; Ford et al. 2010; Li et al. 2019) or even entirely without any instruction; for example, when the items’ combination is itself meaningful or familiar (Ahmad and Hockley 2014). We suggest that similar incidental unitization processes may have occurred here as well. Memory for unitized associations is independent of hippocampal memory processes and can be based solely on the extrahippocampal MTL (Quamme et al. 2007; Haskins et al. 2008; Staresina and Davachi 2010). Our previous high-resolution fMRI study supported such a bypassing hypothesis, that is, extrahippocampal MTL cortex involvement in the successful associative encoding of neutral but not negative pairs (Madan et al. 2017). Here, this interaction did not reach significance in the MTL cortex, but the P-value of 0.11 can be considered suggestive based on our strong a priori-hypothesis. Notably, in our previous study using a scanning resolution of 1 mm³ the cluster included only 17 voxels, which would correspond to less than one voxel here. Therefore, we assume the lower sensitivity here was due to the lower spatial resolution.Unexpectedly, we observed greater activity during unsuccessful encoding of neutral pairs in the same regions that promoted successful encoding of negative pairs, that is, the dmPFC and hippocampal region. Hockley et al. (2016) previously observed that incidental but not intentional encoding of associations (for word pairs) improved for items with stronger pre-experimental associations. Perhaps using an effortful (dmPFC/hippocampal) learning strategy for neutral pairs, that is, pairs that are already more likely incidentally linked or linkable (e.g., through interactive imagery) may not have helped encoding. The forgotten neutral pairs underlying the SFE in these regions may then have been simply the hardest-to-learn neutral pairs; that is, pairs where both encoding strategies failed. Evidently, future studies should test such speculations directly.Our interpretation of the dmPFC and vmPFC as signifying in emotion regulation and unitization in this task was based on previous studies. Because we did not manipulate unitization and/or emotional regulation, these processes remain hypothetical. However, within this framework, we addressed two hypotheses regarding interactions between hippocampal/extrahippocampal MTL regions and prefrontal cortex during association memory formation. The disruption hypothesis proposes that the hippocampus is equally responsible for encoding of negative and neutral association memory but that for negative memories, hippocampal activity is inhibited by the amygdala via the prefrontal cortex (Murray and Kensinger 2013; Bisby et al. 2016). The vmPFC has known involvement in negative emotion processing (Yang et al. 2020), and the observed activity pattern in the vmPFC could appear to disrupt hippocampal association memory processes for negative pairs. However, according to the bypassing hypothesis (Madan et al. 2017), successful encoding of negative (compared with neutral) pairs requires the hippocampus since fewer extrahippocampal contributions are available. Supporting the bypassing hypothesis, we observed that the vmPFC was negatively functionally coupled with extrahippocampal MTL cortex (bordering the hippocampus), suggesting that the vmPFC decreased extrahippocampal contributions to association memory for negative pairs. The bypassing hypothesis is also supported by our finding that the hippocampus was not less but more involved in negative compared with neutral pair encoding, that is, we observed no evidence for a prefrontally (e.g., vmPFC)-mediated disruption of hippocampal activity by emotion.In conclusion, the two critical prefrontal cortex regions linked to MTL memory processes in the current study were the dmPFC, involved in successful hippocampal-dependent negative pair learning and the vmPFC, supporting successful neutral pair learning that relied on extrahippocampal MTL involvement.     

Dorsolateral prefrontal cortex mediates working memory processes in motor skill learning

Neuroimaging studies have shown that the dorsolateral prefrontal cortex (DLPFC) is recruited during motor skill learning, which suggests the involvement of the DLPFC in working memory (WM) processes, such as selection and integration of motor representations temporarily stored in WM. However, direct evidence linking activation of the DLPFC to WM storage and manipulation during motor skill learning in real-time is rare. In this study, we conducted two experiments to investigate the causal role of DLPFC activity in WM storage and manipulation during motor skill learning under low and high WM-demand conditions. Participants received continuous theta burst stimulation (cTBS) and sham stimulation (crossover design) over the left DLPFC (experiment 1) or right DLPFC (experiment 2). Before and after stimulation, participants in both experiments performed a sequential finger-tapping (SFT) task containing repeated sequence (low-WM demand) and non-repeated sequence (high-WM demand) conditions which are used to study WM processes. The number of correct sequences (NoCS) and reproduction error rate were analyzed. Learning gains in NoCS improved significantly with the practice for both sequence types in the presence of either stimulation type. Compared to sham stimulation, cTBS over the left DLPFC resulted in significantly reduced learning gains in NoCS for non-repeated sequences. These results suggest that the left DLPFC contributes to WM manipulation during motor skill learning.     

Brain activation during episodic memory retrieval: sex differences

Behavioral studies have shown a tendency for women to outperform men on episodic memory tasks. Here, data from a series of positron emission tomography (PET) studies were analyzed to examine sex differences in brain activity associated with episodic memory retrieval (yes/no recognition). A total of 17 women and 17 men were included in the analyses. The strongest effect of the design was a retrieval-related increase in activity, involving right prefrontal and anterior cingulate regions, that was common to women and men. In addition, a significant task-by-sex interaction effect was observed which involved a distributed set of brain regions, including several frontal areas. These results suggest that while the neural correlate of episodic memory retrieval is largely the same for men and women, some differences do exist. Possible explanations for the observed differences are discussed, and it is concluded that biological and experiential factors jointly contribute to sex differences in brain activity.     

Medial prefrontal cortex and hippocampal activity differentially contribute to ordinal and temporal context retrieval during sequence memory

Remembering sequences of events defines episodic memory, but retrieval can be driven by both ordinality and temporal contexts. Whether these modes of retrieval operate at the same time or not remains unclear. Theoretically, medial prefrontal cortex (mPFC) confers ordinality, while the hippocampus (HC) associates events in gradually changing temporal contexts. Here, we looked for evidence of each with BOLD fMRI in a sequence task that taxes both retrieval modes. To test ordinal modes, items were transferred between sequences but retained their position (e.g., AB3). Ordinal modes activated mPFC, but not HC. To test temporal contexts, we examined items that skipped ahead across lag distances (e.g., ABD). HC, but not mPFC, tracked temporal contexts. There was a mPFC and HC by retrieval mode interaction. These current results suggest that the mPFC and HC are concurrently engaged in different retrieval modes in support of remembering when an event occurred.

Memory for sequences of events is a fundamental component of episodic memory (Tulving 1984, 2002; Allen and Fortin 2013; Howard and Eichenbaum 2013; Eichenbaum 2017). While different experiences share overlapping elements, the sequence of events is unique. Remembering the order of events allows us to disambiguate episodes with similar content and make detailed predictions supporting decision-making.At least two complementary memory processes contribute to the retrieval of events in the correct sequence: ordinal (Orlov et al. 2002) and temporal context (Howard and Kahana 2002) retrieval modes. Whether these disparate retrieval modes operate coincidently or not remains an open question with consequences for understanding basic mechanisms of how we remember the events that unfold throughout our day. According to an ordinal retrieval mode, items are remembered by their position within an event sequence (DuBrow and Davachi 2013; Allen et al. 2014; Long and Kahana 2019), providing sequential memory through well-established semantic or abstracted relationships (first, second, third, etc.). While for a temporal context retrieval mode, events are remembered through a gradually changing temporal context within which specific items have been associated. According to temporal contexts, when an element of a sequence is presented or retrieved (e.g., “C” in ABCDEF), items that are more proximal in the sequence (e.g., the “D” in the sequence) have a higher retrieval rate compared with items that are further away (e.g., the “F” in the sequence). These temporal contexts result from item associations that are dependent on time varying neural activity (e.g., Eichenbaum 2014), and contribute to sequence memory through the reactivation of neighboring items during retrieval (DuBrow and Davachi 2013; Long and Kahana 2019).The medial prefrontal cortex (mPFC) and hippocampus (HC) are thought to contribute to sequence memory through ordinal representations and temporal contexts, respectively (Agster et al. 2002; Fortin et al. 2002; Kesner et al. 2002; DeVito and Eichenbaum 2011; Allen et al. 2016; Jenkins and Ranganath 2016). In rodents, mPFC disruptions impair sequence memory (DeVito and Eichenbaum 2011; Jayachandran et al. 2019), mPFC “time cells” are evident (Tiganj et al. 2017), and positions within a sequence can be the main determinant of differential activity in mPFC neurons during spatial sequences (Euston and McNaughton 2006). In humans, mPFC activation is sensitive to temporal order memory (Preston and Eichenbaum 2013), and codes for information about temporal positions within image sequences regardless of the image itself (Hsieh and Ranganath 2015). HC activations are also generally associated with temporal order memory (Kumaran and Maguire 2006; Ekstrom and Bookheimer 2007; Lehn et al. 2009; Ross et al. 2009; Jenkins and Ranganath 2010; Tubridy and Davachi 2011; Kalm et al. 2013; Hsieh et al. 2014; Goyal et al. 2018). Prior evidence further shows that the medial temporal lobe, specifically the HC formation, plays a critical role in the use of a TCM retrieval mode in the brain (Manns et al. 2007; Hsieh et al. 2014; Bladon et al. 2019). The HC binds events within temporal contexts (Eichenbaum et al. 2007; DuBrow and Davachi 2013; Bladon et al. 2019) through a gradually changing neural context (Manns et al. 2007; Mankin et al. 2012). Similarly, medial temporal lobe neuronal and BOLD activations in humans have demonstrated evidence for gradually evolving temporal contexts (Howard et al. 2012; Kalm et al. 2013; Kragel et al. 2015).Here we tested the contributions of the mPFC and HC during a visual sequence memory task that provides behavioral evidence of both ordinal and temporal context retrieval modes (see Fig. 1A; task modified from Allen et al. 2014). Briefly, participants first memorized six visual sequences (six images each) in a single passive viewing phase, and then were instructed to make judgments as to whether individual items were subsequently presented in sequence (InSeq) or out of sequence (OutSeq) over 240 self-paced presentations of each of the six items from each sequence. In the task, the two retrieval modes are parsed using probe trials that place conflicting demands on ordinal (Orlov et al. 2000; Allen et al. 2014, 2015) and temporal context modes (Jayachandran et al. 2019). We first evaluated ordinal retrieval modes using items that were transferred from one sequence to another while retaining their ordinal position (Ordinal Transfers) (Fig. 1B). Evidence for an ordinal-based retrieval mode occurs when these probes are identified as in sequence, because they occur in the same ordinal position as their original sequence. mPFC activations (but not HC) was strongest for these ordinal retrievals. Second, we evaluated a temporal context retrieval mode using items that skipped ahead (Skips) (Fig. 1B) with shorter lag distances (ABCFEF) compared with larger lag distances (AFCDEF). Skips should be most difficult to detect on the shortest lag distances because proximal items in a sequence are more likely to be retrieved (Howard and Kahana 2002; Kragel et al. 2015) and thus judged as InSeq. HC activations (but not mPFC) tracked with lag distance, providing evidence the HC is more reflective of a temporal context-based retrieval mode. Importantly, a significant interaction was observed such that mPFC and HC differentially activated for ordinal and temporal context retrievals. Altogether, our data show that sequence memory involves both retrieval modes. In line with these results, we suggest that understanding episodic memory requires more insight into the neurobiology of ordinal processing, in addition to the more often studied temporal contexts, in the mPFC and HC system.Open in a separate windowFigure 1.Sequence memory task and overall performance levels. Participants were tested on a sequence memory task that differentially burdens different retrieval modes using different out of sequence probe trial types. (A) An example sequence set that included six sequences. Two sequences were low memory demand sequences and four were high memory demand sequences. (B) There were three out of sequence probe trial types: items that were repeated in the sequence (Repeats), items that were presented too early in the sequence (Skips), and items that transferred from one sequence to another, while remaining in their ordinal position (Ordinal Transfers). Repeats and Skips occurred throughout the whole task, whereas Ordinal Transfers occurred during the second half only. (C) Accuracy throughout the task (error bars = ±1SD). Participants performed best on Repeats, then Skips, and poorest on Ordinal Transfers. (D,E) Distributions of response times for all InSeq trials (D, gray bars) and for all OutSeq trials (E, gray bars) for all participants with a fitted two-term Gaussian curve (black line). (F) A bimodal Gaussian curve fit better than a unimodal curve for InSeq and OutSeq trials. A trimodal curve did not improve the fit and increased the root mean squared error (not shown), suggesting distinct decisions decision-making between two decisions. It was rare to observe responses outside of the two distributions.     

Noradrenergic action in prefrontal cortex in the late stage of memory consolidation

These experiments investigated the role of the noradrenergic system in the late stage of memory consolidation and in particular its action at beta receptors in the prelimbic region (PL) of the prefrontal cortex in the hours after training. Rats were trained in a rapidly acquired, appetitively motivated foraging task based on olfactory discrimination. They were injected with a beta adrenergic receptor antagonist into the PL 5 min or 2 h after training and tested 48 h later. Rats injected at 2 h showed amnesia, whereas those injected at 5 min had good retention, equivalent to saline-injected controls. Monitoring extracellular noradrenaline efflux in PL by in vivo microdialysis during the first hours after training revealed a significant increase shortly after training, with a rapid return to baseline, and then another increase around the 2-h posttraining time window. Pseudo-trained rats showed a smaller early efflux and did not show the second wave of efflux at 2 h. These results confirm earlier pharmacological and immunohistochemical studies suggesting a delayed role of noradrenaline in a late phase of long-term memory consolidation and the engagement of the PL during these consolidation processes.