Rapid neocortical acquisition of long-term arbitrary associations independent of the hippocampus

Anterograde amnesia following hippocampal damage involves the loss of the capacity to form new declarative memories but leaves nondeclarative memory processes intact. Current theories of declarative memory suggest the existence of two complementary memory systems: a hippocampal-based system that specializes in rapid acquisition of specific events and a neocortical system that slowly learns through environmental statistical regularities and requires the initial support of the hippocampal system. Contrary to this notion, we demonstrate a neurocognitive mechanism that enables rapid acquisition of novel arbitrary associations independently of the hippocampus. This mechanism has been dubbed "fast mapping" (FM) and is believed to support the rapid acquisition of vocabulary in children as young as 16 mo of age. We used FM to teach novel word-picture associations to four profoundly amnesic patients with hippocampal system damage. Patients were able to acquire arbitrary associations through FM normally, despite profound impairment on a matched standard associative memory task. Most importantly, they retained what they learned through FM after a week's delay, when they were around chance level on the standard task. By contrast, two patients with unilateral damage to the left polar temporal neocortex were impaired on FM, suggesting that this cortical region is critical for associative learning through FM. Left perirhinal and entorhinal cortices might also play a role in learning through FM. Contrary to current theories, these findings indicate that rapid acquisition of declarative-like (relational) memory can be accomplished independently of the hippocampus and that neocortical plasticity can be induced rapidly to support novel arbitrary associations.     

Neural basis of the cognitive map: path integration does not require hippocampus or entorhinal cortex

The hippocampus and entorhinal cortex have been linked to both memory functions and to spatial cognition, but it has been unclear how these ideas relate to each other. An important part of spatial cognition is the ability to keep track of a reference location using self-motion cues (sometimes referred to as path integration), and it has been suggested that the hippocampus or entorhinal cortex is essential for this ability. Patients with hippocampal lesions or larger lesions that also included entorhinal cortex were led on paths while blindfolded (up to 15 m in length) and were asked to actively maintain the path in mind. Patients pointed to and estimated their distance from the start location as accurately as controls. A rotation condition confirmed that performance was based on self-motion cues. When demands on long-term memory were increased, patients were impaired. Thus, in humans, the hippocampus and entorhinal cortex are not essential for path integration.     

Impaired capacity for familiarity after hippocampal damage

Recognition memory is thought to consist of two components: recollection and familiarity. Whereas it is widely agreed that the hippocampus supports recollection (remembering the episode in which an item was learned), there is uncertainty about whether it also supports familiarity (simply knowing that an item was encountered but without remembering the learning episode). We tested a counterintuitive prediction that follows from the idea that the hippocampus selectively supports recollection. Patients with hippocampal lesions should have strong experiences of familiarity as often as controls do; however, unlike controls, these experiences should not be accompanied by recollection. Accordingly, with methods that allow participants to report whether they remember an item as encountered previously or whether they simply know it is familiar, patients should express strong familiarity (in the absence of recollection) more often than controls. We indexed strong familiarity and recollection for previously studied words by obtaining confidence ratings together with Remember-Know judgments. The result was that patients provided fewer high-confidence Know responses than controls rather than more. Furthermore, the number of Know responses made by patients was substantially less than was predicted if recollection were impaired. This was true regardless of whether the prediction was based on the assumption that recollection and familiarity are independent or dependent processes. These results suggest that hippocampal lesions impair both recollection and familiarity. Unlike many previous studies of these constructs, the prediction (and the result) is independent of any particular theoretical model, and it holds even if Remember-Know judgments are not process-pure indicators of recollection and familiarity.     

Recognition memory signals in the macaque hippocampus

The hippocampus plays a critical role in recognition memory in both monkeys and humans. However, neurophysiological studies have rarely reported recognition memory signals among hippocampal neurons. The majority of these previous studies used variants of the delayed match-to-sample task; however, studies of the effects of hippocampal damage in monkey and humans have shown that another task of recognition memory, the visual paired-comparison, or visual preferential looking task (VPLT), is more sensitive to hippocampal damage than the delayed matching tasks. Accordingly, to examine possible recognition memory signals in the hippocampus, we recorded the activity of 131 hippocampal neurons in two monkeys performing the VPLT. Eighty-eight neurons (67%) responded significantly to stimulus presentation relative to the baseline prestimulus period. A substantial proportion of these visually responsive neurons (36%) showed significant firing-rate modulations that reflected whether stimuli were novel or familiar. Additionally, these firing-rate modulations were correlated with recognition memory performance on the VPLT such that larger modulations by stimulus novelty were associated with better performance. Together, these results provide evidence for a neural signal in the hippocampus that may support recognition memory performance.     

A role for the hippocampus in encoding simulations of future events

The role of the hippocampus in imagining the future has been of considerable interest. Preferential right hippocampal engagement is observed for imagined future events relative to remembered past events, and patients with hippocampal damage are impaired when imagining detailed future events. However, some patients with hippocampal damage are not impaired at imagining, suggesting that there are conditions in which the hippocampus may not be necessary for episodic simulation. Given the known hippocampal role in memory encoding, the hippocampal activity associated with imagining may reflect the encoding of simulations rather than event construction per se. The present functional (f)MRI study investigated this possibility. Participants imagined future events in response to person, place, and object cues. A postscan cued-recall test probing memory for detail sets classified future events as either successfully encoded or not. A contrast of successfully versus unsuccessfully encoded events revealed anterior and posterior right hippocampal clusters. When imagined events were successfully encoded, both anterior and posterior hippocampus showed common functional connectivity to a network including parahippocampal gyrus, medial parietal and cingulate cortex, and medial prefrontal cortex. However, when encoding was unsuccessful, only the anterior hippocampus, and not the posterior, exhibited this pattern of connectivity. These findings demonstrate that right hippocampal activity observed during future simulation may reflect the encoding of the simulations into memory. This function is not essential for constructing coherent scenarios and may explain why some patients with hippocampal damage are still able to imagine the future.     

Recollection versus strength as the primary determinant of hippocampal engagement at retrieval

We examined whether hippocampal activity in recognition relates to the strength of the memory or to recollective experience, a subject of considerable current debate. Participants studied word pairs and then made two successive recognition decisions on each item: first on the uncued target and then on the target presented with the studied cue word. We compared recollection and familiarity patterns of activation in fMRI for these decisions. Critically, our analyses attempted in two ways to equate perceived memory strength while varying the associative information available. First, activity for targets judged familiar before cueing was contrasted with activity for the same items in the second decision as a function of whether the targets converted to recollection or remained familiar when the context cues were provided. We found increased hippocampal activity following cueing only with recollective conversion. Second, we investigated whether hippocampal activity was modulated by the rated familiarity strength of cued items or whether it increased uniquely in recollection. Hippocampal activation was not modulated parametrically by familiarity strength and recollected items were associated with greater activity relative to highly familiar items. Together, our results support the notion that it is recollection of context, rather than memory strength, that underlies hippocampal engagement at retrieval.     

Age-related memory deficits linked to circuit-specific disruptions in the hippocampus

Converging data from rodents and humans have demonstrated an age-related decline in pattern separation abilities (the ability to discriminate among similar experiences). Several studies have proposed the dentate and CA3 subfields of the hippocampus as the potential locus of this change. Specifically, these studies identified rigidity in place cell remapping in similar environments in the CA3. We used high-resolution fMRI to examine activity profiles in the dentate gyrus and CA3 in young and older adults as stimulus similarity was incrementally varied. We report evidence for "representational rigidity" in older adults' dentate/CA3 that is linked to behavioral discrimination deficits. Using ultrahigh-resolution diffusion imaging, we quantified both the integrity of the perforant path as well as dentate/CA3 dendritic changes and found that both were correlated with dentate/CA3 functional rigidity. These results highlight structural and functional alterations in the hippocampal network that predict age-related changes in memory function and present potential targets for intervention.     

Human single-neuron responses at the threshold of conscious recognition

We studied the responses of single neurons in the human medial temporal lobe while subjects viewed familiar faces, animals, and landmarks. By progressively shortening the duration of stimulus presentation, coupled with backward masking, we show two striking properties of these neurons. (i) Their responses are not statistically different for the 33-ms, 66-ms, and 132-ms stimulus durations, and only for the 264-ms presentations there is a significantly higher firing. (ii) These responses follow conscious perception, as indicated by the subjects' recognition report. Remarkably, when recognized, a single snapshot as brief as 33 ms was sufficient to trigger strong single-unit responses far outlasting stimulus presentation. These results suggest that neurons in the medial temporal lobe can reflect conscious recognition by "all-or-none" responses.     

A demonstration that the hippocampus supports both recollection and familiarity

Recognition memory is thought to depend on two distinct processes: recollection and familiarity. There is debate as to whether damage to the hippocampus selectively impairs recollection or whether it impairs both recollection and familiarity. If hippocampal damage selectively impairs recollection but leaves familiarity intact, then patients with circumscribed hippocampal lesions should exhibit the full normal range of low-confidence and high-confidence familiarity-based recognition. High-confidence, familiarity-based decisions are ordinarily accompanied by successful recollection (when memory is intact). However, patients with hippocampal lesions, if recollection is impaired, should frequently experience high-confidence, familiarity-based recognition in the absence of recollection, and this circumstance (termed the “butcher-on-the-bus” phenomenon) should occur more often in patients than in healthy controls. We tested five patients with circumscribed hippocampal damage, asking them to recognize recently studied words as well as to remember the context in which the items were studied. Relative to controls, the patients exhibited no increased tendency to experience the butcher-on-the-bus phenomenon. The simplest explanation of the results is that hippocampal damage impairs familiarity as well as recollection. The same conclusion was suggested when two competing models of recognition memory were used to analyze the data.     

颞叶癫痫大鼠学习记忆障碍与海马病理变化的相关性研究

目的 探讨大鼠颞叶癫痫发作后不同时问学习、记忆障碍程度与海马病理变化的相关性。方法 采用立体定向技术在大鼠右侧海马注射红藻氨酸诱发颡叶癫痫发作,观察其行为学表现、脑电图变化,Morris水迷宫评价不同时间段学习、记忆障碍程度,以及海马、皮质病理变化。结果 注射红藻氨酸大鼠出现颞叶癫痫发作,随发作时间延长出现不同程度学习、记忆障碍,定位航行实验示逃避潜伏期延长,空间搜索实验示原平台象限内游泳时问百分比下降,与对照组比较均有显著性差异（P〈0．05）,发作后2个月达到高峰。右侧海马锥体细胞逐渐出现变性、坏死,由CA3区向CA4、CA2、CA1区扩展,2个月达到高峰;对侧海马锥体细胞也出现变性、坏死。但程度明显低于注射侧。结论 大鼠颡叶癫痫发作后,其学习、记忆障碍程度与海马变性、坏死程度具有一定相关性。     

Effects of cholinergic deafferentation of the rhinal cortex on visual recognition memory in monkeys

Excitotoxic lesion studies have confirmed that the rhinal cortex is essential for visual recognition ability in monkeys. To evaluate the mnemonic role of cholinergic inputs to this cortical region, we compared the visual recognition performance of monkeys given rhinal cortex infusions of a selective cholinergic immunotoxin, ME20.4-SAP, with the performance of monkeys given control infusions into this same tissue. The immunotoxin, which leads to selective cholinergic deafferentation of the infused cortex, yielded recognition deficits of the same magnitude as those produced by excitotoxic lesions of this region, providing the most direct demonstration to date that cholinergic activation of the rhinal cortex is essential for storing the representations of new visual stimuli and thereby enabling their later recognition.     

Neuronal code for extended time in the hippocampus

The time when an event occurs can become part of autobiographical memories. In brain structures that support such memories, a neural code should exist that represents when or how long ago events occurred. Here we describe a neuronal coding mechanism in hippocampus that can be used to represent the recency of an experience over intervals of hours to days. When the same event is repeated after such time periods, the activity patterns of hippocampal CA1 cell populations progressively differ with increasing temporal distances. Coding for space and context is nonetheless preserved. Compared with CA1, the firing patterns of hippocampal CA3 cell populations are highly reproducible, irrespective of the time interval, and thus provide a stable memory code over time. Therefore, the neuronal activity patterns in CA1 but not CA3 include a code that can be used to distinguish between time intervals on an extended scale, consistent with behavioral studies showing that the CA1 area is selectively required for temporal coding over such periods.     

Two kinds of memory signals in neurons of the human hippocampus

Prior studies of the neural representation of episodic memory in the human hippocampus have identified generic memory signals representing the categorical status of test items (novel vs. repeated), whereas other studies have identified item specific memory signals representing individual test items. Here, we report that both kinds of memory signals can be detected in hippocampal neurons in the same experiment. We recorded single-unit activity from four brain regions (hippocampus, amygdala, anterior cingulate, and prefrontal cortex) of epilepsy patients as they completed a continuous recognition task. The generic signal was found in all four brain regions, whereas the item-specific memory signal was detected only in the hippocampus and reflected sparse coding. That is, for the item-specific signal, each hippocampal neuron responded strongly to a small fraction of repeated words, and each repeated word elicited strong responding in a small fraction of neurons. The neural code was sparse, pattern-separated, and limited to the hippocampus, consistent with longstanding computational models. We suggest that the item-specific episodic memory signal in the hippocampus is fundamental, whereas the more widespread generic memory signal is derivative and is likely used by different areas of the brain to perform memory-related functions that do not require item-specific information.

The hippocampus is essential for the formation of declarative (conscious) memory (1, 2), including both episodic memory (memory for events) and semantic memory (factual knowledge). Episodic memories represent the “what, when, and where” information about remembered events (3). Here, we focus on the neural representation of episodic memory for events, specifically words presented and later repeated in a continuous recognition memory format (4).Bilateral hippocampal lesions result in substantial anterograde amnesia for new events, whether memory is tested by recall or recognition (5). By contrast, bilateral lesions to a more anterior medial temporal lobe structure―the amygdala―have no such effect (6). One might therefore expect to find single-unit activity associated with episodic memory in the hippocampus but not in the amygdala. Yet, the earliest single-neuron studies failed to detect hippocampal neurons that fired differentially to recently presented test items vs. novel items. This was true in studies with humans (7, 8) and monkeys (9–11). One early study with monkeys identified a few such neurons in the hippocampus (12), and other studies found them in areas other than the hippocampus (e.g., inferomedial temporal cortex or inferotemporal temporal cortex) (9–11, 13, 14). Overall, this was not the pattern anticipated from lesion studies.Subsequent studies successfully detected some memory-related neural activity (15–17), observing that ∼10% of hippocampal neurons exhibited differential firing rates based on item status, with some firing more for repeated items and others firing more for novel items. Surprisingly, similar “memory-selective” neurons were also reliably detected in the amygdala at approximately the same frequency. Yet, these memory-selective neurons responded differentially to the generic, categorical status of test items (repeated vs. novel) and thus are not episodic memory signals (i.e., signals representing memory for specific events). According to neurocomputational models dating back to Marr (18), episodic memory representations in the hippocampus are supported by sparse neural codes (19–21). If memories for individual items are sparsely coded in largely nonoverlapping (pattern-separated) neural assemblies, it should be possible to find neurons that respond to particular repeated items, rather than to an item’s generic status. Two recent single-unit studies with humans detected such neurons in the hippocampus, but not in the amygdala (22, 23), apparently reflecting sparsely coded episodic memories. In the present study, we tested 1) whether the generic and the item-specific signals coexist in neural firing patterns recorded during the same memory task, and 2) whether the two kinds of signals are present exclusively in the hippocampus or are also evident in other brain regions.During a continuous recognition memory procedure, neurons were simultaneously recorded from four brain regions: hippocampus, amygdala, anterior cingulate cortex, and prefrontal cortex. Altogether, 55 continuous recognition memory sessions were completed by 34 epilepsy patients who had implanted clinical depth electrodes with microwires measuring single-unit activity (SUA) and multiunit activity bilaterally (24). We limited the present analyses to SUA. Words were presented consecutively and repeated once after varying lags; patients judged each word as either “novel” or “repeated.” Thus, repeated words differed from their earlier presentations as novel words only with respect to their combined “what, when, and where” episodic status (3).     

Memory,scene construction,and the human hippocampus

We evaluated two different perspectives about the function of the human hippocampus–one that emphasizes the importance of memory and another that emphasizes the importance of spatial processing and scene construction. We gave tests of boundary extension, scene construction, and memory to patients with lesions limited to the hippocampus or large lesions of the medial temporal lobe. The patients were intact on all of the spatial tasks and impaired on all of the memory tasks. We discuss earlier studies that associated performance on these spatial tasks to hippocampal function. Our results demonstrate the importance of medial temporal lobe structures for memory and raise doubts about the idea that these structures have a prominent role in spatial cognition.Two traditions of work have influenced discussion about the function of the hippocampus (1). One tradition is based on work with memory-impaired patients and the idea that the hippocampus is important for a particular kind of memory (2, 3). The other tradition is based on work with rodents and the idea that the hippocampus is critical for spatial mapping (4). Its possible role in spatial processing has been recently explored in humans as well (5), and it has been proposed that the human hippocampus is essential for the ability to construct spatially coherent scenes (6, 7).This view of hippocampal function has depended on evidence from two kinds of tasks: boundary extension and scene construction (6, 8). Boundary extension refers to the tendency to reconstruct a scene such that it has a larger background than was actually presented (9). In the Mullally et al. (8) study, memory-impaired patients exhibited boundary extension less strongly than controls. Scene construction refers to the ability to imagine and describe spatially coherent scenes. In two studies, memory-impaired patients made few references to space when visualizing and describing imagined scenes (6, 8).It is unclear how to reconcile such findings with the view that the hippocampus chiefly supports memory functions. In particular, the idea that the construction and visualization of scenes involves the hippocampus seems at odds with the historic distinction between short-term (working) memory and long-term memory and the related idea that short-term memory is independent of the hippocampus (10–12). According to this perspective, hippocampal damage should not impair performance on spatial tasks, so long as testing puts no burden on long-term memory. In an attempt to clarify these issues, we gave tests of boundary extension, scene construction, and memory to patients with well-characterized lesions limited to the hippocampus or large lesions of the medial temporal lobe.     

Functional inactivation of the rat hippocampus disrupts avoidance of a moving object

The hippocampus is well known for its critical involvement in spatial memory and information processing. In this study, we examined the effect of bilateral hippocampal inactivation with tetrodotoxin (TTX) in an "enemy avoidance" task. In this paradigm, a rat foraging on a circular platform (82 cm diameter) is trained to avoid a moving robot in 20-min sessions. Whenever the rat is located within 25 cm of the robot's center, it receives a mild electrical foot shock, which may be repeated until the subject makes an escape response to a safe distance. Seventeen young male Long-Evans rats were implanted with cannulae aimed at the dorsal hippocampus 14 d before the start of the training. After 6 d of training, each rat received a bilateral intrahippocampal infusion of TTX (5 ng in 1 μL) 40 min before the training session on day 7. The inactivation severely impaired avoidance of a moving robot (n = 8). No deficit was observed in a different group of rats (n = 9) that avoided a stable robot that was only displaced once in the middle of the session, showing that the impairment was not due to a deficit in distance estimation, object-reinforcement association, or shock sensitivity. This finding suggests a specific role of the hippocampus in dynamic cognitive processes required for flexible navigation strategies such as continuous updating of information about the position of a moving stimulus.     

Attention promotes episodic encoding by stabilizing hippocampal representations

Attention influences what is later remembered, but little is known about how this occurs in the brain. We hypothesized that behavioral goals modulate the attentional state of the hippocampus to prioritize goal-relevant aspects of experience for encoding. Participants viewed rooms with paintings, attending to room layouts or painting styles on different trials during high-resolution functional MRI. We identified template activity patterns in each hippocampal subfield that corresponded to the attentional state induced by each task. Participants then incidentally encoded new rooms with art while attending to the layout or painting style, and memory was subsequently tested. We found that when task-relevant information was better remembered, the hippocampus was more likely to have been in the correct attentional state during encoding. This effect was specific to the hippocampus, and not found in medial temporal lobe cortex, category-selective areas of the visual system, or elsewhere in the brain. These findings provide mechanistic insight into how attention transforms percepts into memories.Why do we remember some things and not others? Consider a recent experience, such as the last movie complex you visited, flight you took, or restaurant at which you ate. More information was available to your senses than was stored in memory, such as the theater number of the movie, the faces of other passengers, and the color of the napkins. The selective nature of memory is adaptive, because encoding carries a cost: newly stored memories can interfere with existing ones and with our ability to learn new information in the future. What is the mechanism by which information gets selected for encoding?Attention offers a means of prioritizing information in the environment that is most relevant to behavioral goals. Attended information, in turn, has stronger control over behavior and is represented more robustly in the brain (1, 2). If attention gates which information we perceive and act upon, then it may also determine what information we remember. Indeed, attention during encoding affects both subsequent behavioral expressions of memory (3) and the extent to which activity levels in the brain predict memory formation (4–7). Although these findings suggest that attention modulates processes related to memory, how it does so is unclear.According to biased competition and other theories of attention (1, 8), task-relevant stimuli are more robustly represented in sensory systems, and thus fare better in competition with task-irrelevant stimuli for downstream processing. Indeed, there is extensive evidence that attention enhances overall activity in visual areas that represent attended vs. unattended features and locations (2, 9). Moreover, attention modulates cortical areas of the medial temporal lobe that provide input to the hippocampus (10–12).Attention can also modulate the hippocampus itself. Specifically, there is growing evidence that attention stabilizes distributed hippocampal representations of task-relevant information (10, 13, 14). For example, in rodents, distinct ensembles of hippocampal place cells activate when different spatial reference frames are task-relevant (15, 16; see also ref. 17) and place fields are more reliable when animals engage in a task for which spatial information is important (18, 19). Such representational stability has been found in the hippocampus more generally, such as for olfactory representations when odor information is task-relevant (19). In humans, attention similarly modulates patterns of hippocampal activity, but over voxels measured with functional magnetic resonance imaging (fMRI); for example, attention to different kinds of information induces distinct activity patterns in all hippocampal subfields (10).Thus, attention can modulate sensory cortex, medial temporal lobe cortex, and the hippocampus. Here, we explored which of these neural signatures of attention is most closely linked to the formation of memory. We hypothesized that attention induces state-dependent patterns of activity in the cortex and hippocampus, but that representational stability in the hippocampus itself may be the mechanism by which attention enhances memory. That is, attention serves to focus and maintain hippocampal processing on one particular aspect of a complex stimulus, strengthening the resulting memory trace and improving later recognition. We also hypothesized that the interplay between the hippocampus and visual processing regions would be closely related to memory formation, and thus examined the coupling of attentional states across these regions and its relationship to memory.To test these hypotheses, we designed a three-part study that allowed us to identify attentional-state representations in the hippocampus (phase 1) and then examine whether more evidence for the goal-relevant attentional state during the encoding of new information (phase 2) predicted later success in remembering that information (phase 3). We describe each of these three phases in more detail below.Phase 1 took place during fMRI and consisted of an “art gallery” paradigm (10). Participants were cued to attend to either the paintings or room layouts in a rendered gallery (Fig. 1A). After the cue, they were shown a “base image” (a room with a painting) and then searched a stream of other images for a painting from the same artist as the painting in the base image (art state) or for a room with the same layout as the room in the base image (room state). After the search stream, participants were probed about whether there had been a matching painting or room. The comparison of valid trials (e.g., cued for painting, probed for painting) vs. invalid trials (e.g., cued for painting, probed for layout) provided a behavioral measure of attention. Specifically, if attention was engaged by the cue, participants should be better at detecting matches on valid trials. Importantly, identical images were used for both tasks, allowing us to isolate the effects of top-down attention. We used phase 1 to identify neural representations of the two attentional states in each hippocampal subfield—that is, “template” patterns of activity for each of the art and room states.Open in a separate windowFig. 1.Task design and behavioral results. The study consisted of three phases. In phase 1 (A, Upper), participants performed a task in which they paid attention to paintings or rooms on different trials. One room trial is illustrated. For visualization, the cued match is outlined in green and the uncued match in red. Task performance (A, Lower) is shown as sensitivity in making present/absent judgments as a function of attentional state and probe type. Error bars depict ±1 SEM of the within-participant valid vs. invalid difference. In phase 2 (B, Upper), participants performed an incidental encoding task in which they viewed trial-unique images and looked for one-back repetitions of artists or room layouts in different blocks. Task performance (B, Lower) is shown as sensitivity in detecting one-back repetitions as a function of attentional state. Error bars depict ±1 SEM. In phase 3 (C, Upper), participants’ memory for the attended aspect of phase 2 images was tested. Memory performance (C, Lower) is shown as sensitivity in identifying previously studied items, as a function of response confidence and attentional state. Error bars depict ±1 SEM of the within-participant high- vs. low-confidence difference. Dashed line indicates chance performance. **P < 0.01, ***P < 0.001.Phase 2 also took place during fMRI and consisted of an incidental encoding paradigm. Participants performed a cover task while being exposed to a new set of trial-unique images (rooms with paintings). The cover task was used to manipulate art vs. room states (Fig. 1B): in art blocks, participants looked for two paintings in a row painted by the same artist; in room blocks, participants looked for two rooms in a row with the same layout. Because each image contained both a painting and a layout, top-down attention was needed to select the information relevant for the current block and to ignore irrelevant information. The demands for selection and comparison were thus similar to those of the art and room states in phase 1. For each phase 2 encoding trial, we quantified the match between the state of the hippocampus on that trial and the attentional-state representations defined from phase 1. Specifically, we correlated the activity pattern on each trial with the template that was relevant for the current block (e.g., art state during art block) and with the template that was irrelevant for the current block (e.g., room state during art block). We measured the extent to which the hippocampus was in the correct attentional state by calculating the difference of the relevant minus irrelevant pattern correlations.Phase 3 was conducted outside the scanner and involved a recognition memory test. Task-relevant aspects of the images from phase 2 (i.e., paintings in the art block, layouts in the room block) were presented one at a time and participants made memory judgments on a four-point scale: old or new, with high or low confidence (Fig. 1C). The test was divided into blocks: in the art block, old and new paintings were presented in isolation without background rooms; in the room block, old and new rooms were presented without paintings. To increase reliance on the kind of detailed episodic memory supported by the hippocampus, the memory test included a highly similar lure for each encoded item (20, 21): a novel painting from the same artist or the same layout from a novel perspective, for the art and room blocks, respectively. We used memory performance on this task to sort the fMRI data from phase 2, which allowed us to relate attentional states during encoding to subsequent memory (22, 23).To summarize our hypothesis: (i) Attention should modulate representational stability in the hippocampus, inducing distinct activity patterns for each of the art and room states (10). (ii) If attention is properly oriented during encoding, the hippocampus should be more strongly in the task-relevant state. (iii) This will result in a greater difference in correlation between the pattern of activity at encoding and the predefined template patterns for the task-relevant vs. task-irrelevant states. (iv) A greater correlation difference should be associated with better processing of task-relevant stimulus information, better encoding of that information into long-term memory, and a higher likelihood of later retrieval.We also explored the roles of different hippocampal subfields. In our prior study, one hippocampal subfield region of interest (ROI) in particular—comprising subfields CA2/3 and dentate gyrus (DG)—showed behaviorally relevant attentional modulation (10). This finding, together with work linking univariate activity and pattern similarity in CA2/CA3/DG to memory encoding (24–27), raised the possibility that this region might be especially important for the attentional modulation of episodic memory behavior. Thus, we hypothesized that the attentional state of CA2/CA3/DG during encoding would predict the formation of memory. Another candidate for the attentional modulation of memory is CA1. Activity in the CA1 subfield is modulated by goal states during memory retrieval (28), and this region serves as a “comparator” of expectations—which may be induced by attentional cues—and percepts (29, 30).To test these hypotheses, we acquired high-resolution fMRI data and manually segmented CA1 and a combined CA2/CA3/DG ROI in the hippocampus (Fig. 2). We also defined an ROI for the remaining subfield, the subiculum, for completeness and to mirror prior high-resolution fMRI studies of the hippocampus (31). We report results for these three subfield ROIs, as well as for a single hippocampal ROI collapsing across subfield labels. Moreover, motivated by computational theories and work with animal models, which highlight different roles for CA3 and DG in memory (32), as well as recent human neuroimaging studies that have examined these regions separately (33, 34), we report supplemental exploratory analyses for separate CA2/3 and DG ROIs (Fig. S1). To test the specificity of effects in the hippocampus, we also defined ROIs in the medial temporal lobe (MTL) cortex, including entorhinal cortex (ERc), perirhinal cortex (PRc), and parahippocampal cortex (PHc), and in category-selective areas of occipitotemporal and parietal cortices. Finally, in follow-up analyses of which other regions support attentional modulation of hippocampal encoding, we examined functional connectivity of multivariate representations in the hippocampus with those in MTL cortex and category-selective areas.Open in a separate windowFig. 2.MTL ROIs. Example segmentation from one participant is depicted for one anterior and one posterior slice. ROIs consisted of three hippocampal regions [subiculum (Sub), CA1, and CA2/CA3/DG], and three MTL cortical regions (ERc, PRc, and PHc). We also conducted analyses across the hippocampus as a single ROI, and exploratory analyses with separate CA2/3 and DG ROIs (Fig. S1). For segmentation guide, see ref. 10.Open in a separate windowFig. S1.Comparison of attention and memory effects in CA2/3 and DG. (A) We conducted exploratory analyses with separate ROIs for CA2/3 and DG, shown here for an example participant. We conducted these analyses because of reported dissociations across CA2/3 and DG with 3T fMRI (33, 34). These analyses should be interpreted with caution, however, because separation of CA2/3 and DG signals is difficult, even with the 1.5-mm isotropic voxels used in the present study. Specifically, the intertwined nature of these subfields means that a functional voxel could include both CA2/3 and DG. Thus, in the main text, we used the standard approach of collapsing across CA2, CA3, and DG in a single ROI (31). Here we report separated analyses for completeness and to contribute data to the discussion of this issue in the field. (B) In the phase 1 attention task, both regions showed state-dependent patterns of activity, with more similar patterns of activity for trials of the same vs. different states (CA2/3: t₃₁ = 7.97, P < 0.0001; DG: t₃₁ = 6.53, P < 0.0001) (compare with Fig. 3C). Error bars depict ±1 SEM of the within-participant same vs. different state difference. (C) In the phase 1 attention task, individual differences in room-state pattern similarity in CA2/3 were correlated with individual differences in behavioral performance (A′) on valid trials of the room task (r₂₃ = 0.39, P = 0.05). This effect was not found in DG [r₂₅ = 0.20, P = 0.31; note that degrees-of-freedom differ because of the robust correlation methods used (60)]. Additionally, the CA2/3 correlation was specific to room-state pattern similarity and room-state behavior: room-state activity did not predict room-state behavior (r₂₉ = −0.03, P = 0.87) and room-state pattern similarity did not predict art-state behavior (r₂₇ = 0.11, P = 0.58). Finally, controlling for room-state pattern similarity, art-state pattern similarity did not predict room-state behavior (r₂₃ = 0.12, P = 0.58). (D) During the phase 2 encoding task, there was greater pattern similarity with the task-relevant vs. task-irrelevant state template for subsequent hits vs. misses in CA2/3 (F_1,30 = 7.86, P = 0.009), but this effect was not reliable in DG (F_1,30 = 2.82, P = 0.10) (compare with Fig. 4D). Error bars depict ±1 SEM of the within-participant hits vs. misses difference. (E) Individual differences in room memory were positively correlated with the match between CA2/3 encoding activity patterns and the room- vs. art-state template (r₂₃ = 0.44, P = 0.03). This correlation was not reliable in DG [r₂₄ = 0.15, P = 0.46; note that degrees-of-freedom differ because of the robust correlation methods used (60)]. *P = 0.05, **P < 0.01, ***P < 0.001.     

Human hippocampus represents space and time during retrieval of real-world memories

Memory stretches over a lifetime. In controlled laboratory settings, the hippocampus and other medial temporal lobe brain structures have been shown to represent space and time on the scale of meters and seconds. It remains unclear whether the hippocampus also represents space and time over the longer scales necessary for human episodic memory. We recorded neural activity while participants relived their own experiences, cued by photographs taken with a custom lifelogging device. We found that the left anterior hippocampus represents space and time for a month of remembered events occurring over distances of up to 30 km. Although previous studies have identified similar drifts in representational similarity across space or time over the relatively brief time scales (seconds to minutes) that characterize individual episodic memories, our results provide compelling evidence that a similar pattern of spatiotemporal organization also exists for organizing distinct memories that are distant in space and time. These results further support the emerging view that the anterior, as opposed to posterior, hippocampus integrates distinct experiences, thereby providing a scaffold for encoding and retrieval of autobiographical memories on the scale of our lives.The hippocampus plays a critical role in remembering the events of our lives (1). Direct evidence from single-neuron recordings in rats indicates that cells in the hippocampus fire in specific spatial locations (2–6) or at specific times during a temporal delay (7, 8). Single-neuron and functional MRI (fMRI) studies in individuals navigating virtual environments have confirmed that cells coding for spatial location are also present in the human hippocampus (9–11). Similarly, place-responsive cell activity recorded in the hippocampus of patients with epilepsy during navigation of a virtual town was shown to reinstate during episodic memory retrieval of the previous virtual navigation (12). Together, these studies provide evidence that the same neurons in the medial temporal lobe (MTL) that are active during an experience also help represent the memory for that experience. These results, however, are limited to simple events in laboratory settings that occur on the scale of minutes and meters, thereby leaving unanswered whether we harness similar mechanisms in more natural settings and over larger temporal and spatial scales.Recent studies have used more naturalistic designs with incidentally acquired memories recorded via lifelogging devices that automatically capture photographs from the participants’ lives (13, 14). The typical finding is increased hippocampal activation when participants view images from their cameras as opposed to images from other participants’ cameras (15–17), and this activation decays over the course of months (14). Still, there is no evidence to date that the hippocampus or other MTL structures actually represent space or time of autobiographical experiences. We addressed this question by having participants relive their own real-life experiences in the fMRI scanner. We then used multivariate pattern analysis (18) to identify regions of the MTL that represent space and time of these remembered experiences. If a brain region represented either space or time of personal experiences, the distances between neural activity patterns would correlate with the spatial or temporal proximity of the original experiences.     

Beyond the K-hole: a 3-year longitudinal investigation of the cognitive and subjective effects of ketamine in recreational users who have substantially reduced their use of the drug

RATIONALE: Ketamine is a dissociative anaesthetic that is also a drug of abuse. Previous studies have demonstrated persisting episodic and semantic memory impairments in recreational ketamine users 3 days after taking ketamine. However, the degree to which these deficits might be reversible upon reduction or cessation of ketamine use was not known. OBJECTIVE: To follow-up a population of ketamine users tested 3 years previously and examine whether impairments observed 3 days after drug use are enduring or reversible. METHODS: Eighteen ketamine users and 10 polydrug controls from studies conducted between 3 and 4 years earlier were re-tested on the same battery of cognitive tasks and subjective measures. These tapped episodic, semantic and working memory and executive and attentional functioning. Subjective schizotypal, dissociative, mood and bodily symptoms were also examined and a drug use history recorded. RESULTS: The ketamine users had reduced their frequency of use of ketamine by an average of 88.3%. Performance of ketamine users on tasks tapping semantic memory had improved and this improvement was correlated with their reduction in ketamine use. On tasks tapping episodic memory and attentional functioning, ketamine users still showed deficits compared to polydrug controls. Higher levels of schizotypal symptoms and perceptual distortions were exhibited by the ketamine group, although dissociative symptoms were similar to controls. CONCLUSIONS: These findings indicate that semantic memory impairments associated with recreational ketamine are reversible upon marked reduction of use; however, impairments to episodic memory and possibly attentional functioning appear long-lasting. In addition, schizotypal symptoms and perceptual distortions may persist after cessation of ketamine use. Ketamine users, or potential users, should be aware of the enduring effects of this drug on aspects of memory and subjective experience.     

Neural correlates of access to short-term memory

Behavioral research has led to the view that items in short-term memory can be parsed into two categories: a single item in the focus of attention that is available for immediate cognitive processing and a small set of other items that are in a heightened state of activation but require retrieval for further use. We examined this distinction by using an item-recognition task. The results show that the item in the focus of attention is represented by increased activation in inferior temporal representational cortices relative to other information in short-term memory. Functional connectivity analyses suggest that activation of these inferior temporal regions is maintained via frontal- and posterior-parietal contributions. By contrast, other items in short-term memory demand retrieval mechanisms that are represented by increased activation in the medial temporal lobe and left mid-ventrolateral prefrontal cortex. These results show that there are two distinctly different sorts of access to information in short-term memory, and that access by retrieval operations makes use of neural machinery similar to that used in long-term memory retrieval.