Rapid memory stabilization by transient theta coherence in the human medial temporal lobe

Presenting stimuli again after presentation of intervening stimuli improves their retention, an effect known as the spacing effect. However, using event‐related potentials (ERPs), we had observed that immediate, in comparison to spaced, repetition of pictures induced a positive frontal potential at 200–300 ms. This potential appeared to emanate from the left medial temporal lobe (MTL), a structure critical for memory consolidation. In this study, we tested the behavioral relevance of this signal and explored functional connectivity changes during picture repetition. We obtained high‐density electroencephalographic recordings from 14 healthy subjects performing a continuous recognition task where pictures were either repeated immediately or after 9 intervening items. Conventional ERP analysis replicated the positive frontal potential emanating from the left MTL at 250–350 ms in response to immediately repeated stimuli. Connectivity analysis showed that this ERP was associated with increased coherence in the MTL region—left more that right—in the theta‐band (3.5–7 Hz) 200–400 ms following immediate, but not spaced, repetition. This increase was stronger in subjects who better recognized immediately repeated stimuli after 30 min. These findings indicate that transient theta‐band synchronization between the MTL and the rest of the brain at 200–400 ms reflects a memory stabilizing signal. © 2015 Wiley Periodicals, Inc.     

Neural transition from short‐ to long‐term memory and the medial temporal lobe: A human evoked‐potential study

Recent studies indicated that the human medial temporal lobe (MTL) may not only be important for long‐term memory consolidation but also for certain forms of short‐term memory. In this study, we explored the interplay between short‐ and long‐term memory using high‐density event‐related potentials. We found that pictures immediately repeated after an unfilled interval were better recognized than pictures repeated after intervening items. After 30 min, however, the immediately repeated pictures were significantly less well recognized than pictures repeated after intervening items. This processing advantage at immediate repetition but disadvantage for long‐term storage had an electrophysiological correlate: spatiotemporal analysis showed that immediate repetition induced a strikingly different electrocortical response after 200–300 ms, with inversed polarity, than new stimuli and delayed repetitions. Inverse solutions indicated that this difference reflected transient activity in the MTL. The findings demonstrate behavioral and electrophysiological dissociation between recognition during active maintenance and recognition after intervening items. Processing of novel information seems to immediately initiate a consolidation process, which remains vulnerable during active maintenance and increases its effectiveness during off‐line processing. © 2008 Wiley‐Liss, Inc.     

Rapid consolidation and the human hippocampus: Intracranial recordings confirm surface EEG

Diverse studies demonstrated that although immediately repeated stimuli are better and faster recognized than stimuli repeated after a delay, this comes at the price of less‐efficient long‐term retention. A recent‐evoked potential study using source estimation of high‐resolution scalp EEG indicated that while immediate repetition induced a strikingly different electrical activity than new items in the left‐medial temporal lobe (MTL) after 200–300 ms, delayed repetition did not. In this study, we recorded evoked potentials in two epileptic patients with intracranial depth electrodes in diverse temporal and frontal areas as they performed the same task as in the previous study. We found that immediate repetition induced increase of neural activity specifically in the left MTL between 250 and 400 ms compared to new items and items repeated after a delay. The findings are important in two ways. First, they support our previous conclusion that novel information immediately initiates a consolidation process involving the left‐hippocampal area, which remains vulnerable during active maintenance and increases its effectiveness during off‐line processing. Second, they indicate that source estimation based on high‐resolution scalp EEG correctly localizes the current source of electrical activity in midline structures like the MTL. © 2010 Wiley‐Liss, Inc.     

Differential processing of immediately repeated verbal and non‐verbal stimuli: an evoked‐potential study

Stimuli are better retained in memory if they are repeated after a delay than if they are immediately repeated. This effect is called the spacing effect (SE). Recent electroencephalographic (EEG) studies showed that delayed repetition of meaningful designs in a continuous recognition task induces an evoked response very similar to new presentations. In contrast, immediately repeated designs induced circumscribed, stronger activation of the left medio‐temporal lobe (MTL) at 200–300 ms. In amnesic subjects, this signal was missing, indicating that it has a memory‐protective effect. Here, high‐density EEG was used in humans to explore whether meaningless verbal (non‐words) and non‐verbal (geometric designs) stimuli also have a SE associated with such lateralized, temporally limited activation of the left MTL upon immediate repetition. The results revealed a SE for both materials. Timing and localization of brain activity differed as a function of stimulus material. Specific responses to immediate repetitions occurred at 200–285 ms for non‐verbal stimuli and at 285–380 ms for verbal material. Source estimations revealed increased activity in right inferior frontal areas for immediate non‐verbal repetitions and in left fronto‐parietal areas for immediate verbal repetition in comparison to new presentations. These findings show that, while the SE is a ubiquitous phenomenon, the neural processes underlying it vary according to stimulus material.     

Material specific lateralization of medial temporal lobe function: An fMRI investigation

The theory of material specific lateralization of memory function posits that left and right MTL regions are asymmetrically involved in mnemonic processing of verbal and nonverbal material respectively. Lesion and functional imaging (fMRI) studies provide robust evidence for a left MTL asymmetry in the verbal memory domain. Evidence for a right MTL/nonverbal asymmetry is not as robust. A handful of fMRI studies have investigated this issue but have generally utilised nonverbal stimuli which are amenable to semantic elaboration. This fMRI study aimed to investigate the neural correlates of recognition memory processing in 20 healthy young adults (mean age = 26 years) for verbal stimuli and nonverbal stimuli that were specifically designed to minimize verbalisation. Analyses revealed that the neural correlates of recognition memory processing for verbal and nonverbal stimuli were differentiable and asymmetrically recruited the left and right MTL respectively. The right perirhinal cortex and hippocampus were preferentially involved in successful recognition memory of items devoid of semantic information. In contrast, the left anterior hippocampus was preferentially involved in successful recognition memory of stimuli which contained semantic meaning. These results suggest that the left MTL is preferentially involved in mnemonic processing of verbal/semantic information. In contrast, the right MTL is preferentially involved in visual/non‐semantic mnemonic processing. We propose that during development, the left MTL becomes specialised for verbal mnemonic processing due to its proximity with left lateralised cortical language processing areas while visual/non‐semantic mnemonic processing gets ‘crowded out’ to become predominantly, but not completely, the domain of the right MTL. Hum Brain Mapp 37:933–941, 2016. © 2015 Wiley Periodicals, Inc .     

Two P300 generators in the hippocampal formation

The presentation of rare target stimuli results in P300 scalp event‐related potentials (ERPs). Generators of this ERP component were found in various brain areas, indicating that multiple cortical and subcortical areas subserve target detection. One of these structures is the mediotemporal lobe (MTL). In the hippocampus, large negative MTL‐P300 potentials are usually observed, whereas reports concerning the rhinal cortex and subiculum are inconsistent. The aim of the present study was to investigate the topography of the mediotemporal P300. ERPs were recorded in epilepsy patients from multicontact depth electrodes, implanted along the longitudinal axis of MTL. Patients had to respond to rare visual target stimuli by a button press. ERP data from the nonfocal hemisphere of 53 patients were included in the analysis. Target detection resulted in large MTL‐P300 potentials in the hippocampus and subiculum. Their latencies did not differ. The hippocampal P300 amplitude increased linearly from anterior to posterior hippocampal body (HB). In contrast, an inverse gradient with larger mean amplitudes in anterior parts was observed for the subiculum. Our results indicate two separate generators of the MTL‐P300, one in the anterior subiculum and one in the posterior HB. Since latencies did not differ, a parallel activation via the entorhinal cortex might have initiated the simultaneous MTL‐P300. Hippocampus and subiculum are essential parts of the MTL‐memory system. Their function within target detection might be to maintain a template of previous stimuli for a comparison with incoming sensory stimuli. © 2009 Wiley‐Liss, Inc.     

Stress as a mnemonic filter: Interactions between medial temporal lobe encoding processes and post‐encoding stress

Acute stress has been shown to modulate memory for recently learned information, an effect attributed to the influence of stress hormones on medial temporal lobe (MTL) consolidation processes. However, little is known about which memories will be affected when stress follows encoding. One possibility is that stress interacts with encoding processes to selectively protect memories that had elicited responses in the hippocampus and amygdala, two MTL structures important for memory formation. There is limited evidence for interactions between encoding processes and consolidation effects in humans, but recent studies of consolidation in rodents have emphasized the importance of encoding “tags” for determining the impact of consolidation manipulations on memory. Here, we used functional magnetic resonance imaging in humans to test the hypothesis that the effects of post‐encoding stress depend on MTL processes observed during encoding. We found that changes in stress hormone levels were associated with an increase in the contingency of memory outcomes on hippocampal and amygdala encoding responses. That is, for participants showing high cortisol reactivity, memories became more dependent on MTL activity observed during encoding, thereby shifting the distribution of recollected events toward those that had elicited relatively high activation. Surprisingly, this effect was generally larger for neutral, compared to emotionally negative, memories. The results suggest that stress does not uniformly enhance memory, but instead selectively preserves memories tagged during encoding, effectively acting as mnemonic filter. © 2016 Wiley Periodicals, Inc.     

Absence of an early hippocampal encoding signal after medial temporal lesions: No consequence for the spacing effect

Immediately repeated meaningful pictures in a continuous recognition task induce a positive frontal potential at about 200–300 ms, which appears to emanate from the medial temporal lobe (MTL) centered on the hippocampus, as concluded from inverse solutions, coherence measurements, and depth electrode recordings in humans. In this study, we tested patients with unilateral MTL lesions due to stroke to verify the provenance of this signal and its association with the spacing effect (SE)—the improved learning of material encountered in spaced rather than massed presentation. We found that unilateral left or right MTL lesions abolished the early frontal MTL‐mediated signal but not the spacing effect. We conclude that the SE does not depend on MTL integrity. We suggest that the early frontal signal at 200–300 ms after immediate picture repetition may serve as a direct biomarker of MTL integrity that may be useful in the early stages of diseases like Alzheimer's.     

Complementary roles of medial temporal lobes and mid‐dorsolateral prefrontal cortex for working memory for novel and familiar trial‐unique visual stimuli

It has been suggested that working memory (WM) for novel information requires the medial temporal lobes (MTL), but is not necessary for WM for familiar stimuli. In previous studies that directly compared WM for novel and familiar stimuli, only the novel stimuli were trial‐unique. Here, 16 young human subjects performed a Sternberg WM task with visual scenes while in a functional magnetic resonance imaging scanner. All task stimuli were trial‐unique, but were either new (Novel condition) or previously learned (Familiar condition). This design allowed investigation of whether MTL and prefrontal cortex (PFC) activity is related specifically to the novelty/familiarity of the stimuli or to their trial‐unique status during WM. We observed greater hippocampal and parahippocampal activity during encoding and maintenance for novel than for familiar stimuli. In contrast, right mid‐dorsolateral PFC (dlPFC) activity was greater during encoding of familiar than novel stimuli. The mid‐dlPFC was not recruited during maintenance or for retrieval when the Familiar condition was contrasted with the Novel condition. However, left mid‐dlPFC activity was present at retrieval when correct Match trials (i.e. hits) were contrasted with correct Non‐match trials (i.e. correct rejections) for the Novel condition. The results support the hypothesis that MTL regions are required for the encoding and maintenance of novel stimuli during WM, demonstrating that the observed MTL activity is not related to the trial‐uniqueness of the stimuli per se. Furthermore, the observed activation pattern in mid‐dlPFC suggests a role for the mid‐dlPFC in executive control‐associated processes related to monitoring of scene familiarity at encoding and retrieval during WM.     

Differential roles for medial prefrontal and medial temporal cortices in schema-dependent encoding: From congruent to incongruent

Information that is congruent with prior knowledge is generally remembered better than incongruent information. This effect of congruency on memory has been attributed to a facilitatory influence of activated schemas on memory encoding and consolidation processes, and hypothesised to reflect a shift between processing in medial temporal lobes (MTL) towards processing in medial prefrontal cortex (mPFC). To investigate this shift, we used functional magnetic resonance imaging (fMRI) to compare brain activity during paired-associate encoding across three levels of subjective congruency of the association with prior knowledge. Participants indicated how congruent they found an object-scene pair during scanning, and were tested on item and associative recognition memory for these associations one day later. Behaviourally, we found a monotonic increase in memory performance with increasing congruency for both item and associative memory. Moreover, as hypothesised, encoding-related activity in mPFC increased linearly with increasing congruency, whereas MTL showed the opposite pattern of increasing encoding-related activity with decreasing congruency. Additionally, mPFC showed increased functional connectivity with a region in the ventral visual stream, presumably related to the binding of visual representations. These results support predictions made by a recent neuroscientific framework concerning the effects of schema on memory. Specifically, our findings show that enhanced memory for more congruent information is mediated by the mPFC, which is hypothesised to guide integration of new information into a pre-existing schema represented in cortical areas, while memory for more incongruent information relies instead on automatic encoding of arbitrary associations by the MTL.     

Self‐initiated learning reveals memory performance and electrophysiological differences between younger,older and older adults with relative memory impairment

Older adults display difficulties in encoding and retrieval of information, resulting in poorer memory. This may be due to an inability of older adults to engage elaborative encoding strategies during learning. This study examined behavioural and electrophysiological effects of explicit cues to self‐initiate learning during encoding and subsequent recognition of words in younger adults (YA), older control adults (OA) and older adults with relative memory impairment (OD). The task was a variation of the old/new paradigm, some study items were preceded by a cue to learn the word (L) while others by a do not learn cue (X). Behaviourally, YA outperformed OA and OD on the recognition task, with no significant difference between OA and OD. Event‐related potentials at encoding revealed enhanced early visual processing (70–140 ms) for L‐ versus X‐words in young and old. Only YA exhibited a greater late posterior positivity (LPP; 200–500 ms) for all words during encoding perhaps reflecting superior encoding strategy. During recognition, only YA differentiated L‐ versus X‐words with enhanced frontal P200 (150–250 ms) suggesting impaired early word selection for retrieval in older groups; however, OD had enhanced P200 activity compared to OA during L‐word retrieval. The LPP (250–500 ms) was reduced in amplitude for L‐words compared to both X‐ and new words. However, YA showed greater LPP amplitude for all words compared to OA. For older groups, we observed reduced left parietal hemispheric asymmetry apparent in YA during encoding and recognition, especially for OD. Findings are interpreted in the light of models of compensation and dedifferentiation associated with age‐related changes in memory function.     

Characterization of brain network supporting episodic memory in the absence of one medial temporal lobe

How the brain supports normal episodic memory function without medial temporal lobe (MTL) structures has not been well characterized, which could provide clues for new therapeutic targets for people with MTL dysfunction‐related memory impairment. To characterize brain network supporting effective episodic memory function in the absence of unilateral MTL, we investigated the whole‐brain cortical interactions during functional magnetic resonance imaging memory encoding paradigms of words and figures in patients who showed a normal range of memory capacity following unilateral MTL resection and healthy controls (HC). Compared to the HC, the patients showed less activation in the left inferior frontal areas and right thalamus together with greater activation in the many cortical areas including the medial prefrontal cortex (mPFC). Task‐based functional connectivity (FC) analysis revealed that the mPFC showed stronger interactions with widespread brain areas in both patient groups, including the hippocampus contralateral to the resection. Moreover, the strength of the mPFC FC predicts the individual memory capacity of the patients. Our data suggest that hyperconnectivity of distributed brain areas, especially the mPFC, is a neural mechanism for memory function in the absence of one MTL.     

Memory lateralization in medial temporal lobe epilepsy assessed by functional MRI

PURPOSE: To determine the utility of functional magnetic resonance imaging (fMRI) in preoperative lateralization of memory function in patients with medial temporal lobe epilepsy (MTLE). METHODS: Nine patients with MTLE underwent standard preoperative assessment including video-EEG and intracarotid amytal testing (IAT). fMRI was performed while subjects encoded four types of stimuli (patterns, faces, scenes, and words). Activation maps were created for each subject representing areas more active for novel than for repeated stimuli. Regions of interest were drawn around the MTL in individual subjects, suprathreshold voxels were counted, and an asymmetry index was calculated. RESULTS: In eight of nine subjects, lateralization of memory encoding by fMRI was concordant with that obtained from the IAT. Group-level analysis demonstrated greater activation in the MTL contralateral to the seizure focus such that in the left MTLE group, verbal encoding engaged the right MTL, whereas in the right MTLE group, nonverbal encoding engaged the left MTL. CONCLUSIONS: fMRI is a valid tool for assessing of memory lateralization in patients with MTLE and may therefore allow noninvasive preoperative evaluation of memory lateralization. FMRI revealed that memory encoding may be reorganized to the contralateral MTL in patients with MTLE.     

Perspectives on fear generalization and its implications for emotional disorders

Although generalization to conditioned stimuli is not a new phenomenon, renewed interest in understanding its biological underpinning has stemmed from its association with a number of anxiety disorders. Generalization as it relates to fear processing is a temporally dynamic process in which animals, including humans, display fear in response to similar yet distinct cues or contexts as the time between training and testing increases. This Review surveys the literature on contextual fear generalization and its relation to several views of memory, including systems consolidation, forgetting, and transformation hypothesis, which differentially implicate roles of the hippocampus and neocortex in memory consolidation and retrieval. We discuss recent evidence on the neurobiological mechanisms contributing to the increase in fear generalization over time and how generalized responding may be modulated by acquisition, consolidation, and retrieval mechanisms. Whereas clinical perspectives of generalization emphasize a lack of fear inhibition to CS^– cues or fear toward intermediate CS cues, the time‐dependent nature of generalization and its relation to traditional views on memory consolidation and retrieval are often overlooked. Understanding the time‐dependent increase in fear generalization has important implications not only for understanding how generalization contributes to anxiety disorders but also for understanding basic long‐term memory function. © 2016 Wiley Periodicals, Inc.     

Common pathway in the medial temporal lobe for storage and recovery of words as revealed by event-related functional MRI

Lesion studies have provided compelling evidence that episodic memory is dependent on the integrity of the medial temporal lobe (MTL). This role of the MTL in episodic memory has been supported by several neuroimaging studies during both episodic encoding and retrieval. After two meta-analyses of positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) studies, we investigated a possible dissociation within the MTL memory system in relation to encoding and retrieval processes. Based on previous reports that specifically related the function of the MTL in episodic memory to successful encoding and actual recovery of information, we applied event-related fMRI to compare successful encoding of words (ES) directly with successful recognition of those same words (RS). Our results did not indicate a clear dissociation between encoding and retrieval activations in the MTL. Instead, a region in the left MTL, covering the parahippocampal cortex and hippocampal formation, which was activated during ES almost completely overlapped with the area that was activated during RS. An additional region in the left anterior MTL, including the entorhinal cortex, was found to be activated exclusively during ES. Research has indicated that a large percentage of cells in this region are particularly sensitive to the relative novelty of stimuli. Our results, therefore, suggest that the parahippocampal/hippocampal region is involved in the formation and subsequent reactivation of memory traces, whereas the activity observed in the entorhinal cortex may reflect elementary memory processes related to novelty detection.     

Functional connectivity in category‐selective brain networks after encoding predicts subsequent memory

Activity in category selective regions of the temporal and parietal lobes during encoding has been associated with subsequent memory for face and scene stimuli. Reactivation theories of memory consolidation predict that after encoding connectivity between these category‐selective regions and the hippocampus should be modulated and predict recognition memory. However, support for this proposal has been limited in humans. Here, participants completed a resting‐state functional MRI (fMRI) scan, followed by face‐ and place‐encoding tasks, followed by another resting‐state fMRI scan during which they were asked to think about the stimuli they had previously encountered. Individual differences in face recognition memory were predicted by the degree to which connectivity between face‐responsive regions of the fusiform gyrus and perirhinal cortex increased following the face‐encoding task. In contrast, individual differences in scene recognition were predicted by connectivity between the hippocampus and a scene‐selective region of the retrosplenial cortex before and after the place‐encoding task. Our results provide novel evidence for category specificity in the neural mechanisms supporting memory consolidation.     

Peri-encoding predictors of memory encoding and consolidation

We review reports of brain activations that occur immediately prior to the onset or following the offset of to-be-remembered information and can predict subsequent mnemonic success. Memory-predictive pre-encoding processes, occurring from fractions of a second to minutes prior to event onset, are mainly associated with activations in the medial temporal lobe (MTL), amygdala and midbrain, and with enhanced theta oscillations. These activations may be considered as the neural correlates of one or more cognitive operations, including contextual processing, attention, and the engagement of distinct computational modes associated with prior encoding or retrieval. Post-encoding activations that correlate with subsequent memory performance are mainly observed in the MTL, sensory cortices and frontal regions. These activations may reflect binding of elements of the encoded information and initiation of memory consolidation. In all, the findings reviewed here illustrate the importance of brain states in the immediate peri-encoding time windows in determining encoding success. Understanding these brain states and their specific effects on memory may lead to optimization of the encoding of desired memories and mitigation of undesired ones.     

Representational demands modulate involvement of perirhinal cortex in face processing

The classic view holds that the medial temporal lobes (MTL) are dedicated to declarative memory functioning. Recent evidence, however, suggests that perirhinal cortex (PrC), a structure within the anterior MTL, may also play a role in perceptual discriminations when representations of complex conjunctions of features, or of gestalt‐characteristics of objects must be generated. Interestingly, neuroimaging and electrophysiological recordings in nonhuman primates have also revealed a face patch in the anterior collateral sulcus with preferential responses to face stimuli in various task contexts. In the present fMRI study, we investigated the representational demands that influence PrC involvement in different types of judgments on human faces. Holding stimulus complexity constant, we independently manipulated the nature of the task and the orientation of the stimuli presented (through face inversion). Aspects of right PrC showed increased responses in a forced‐choice recognition‐memory and a perceptual‐oddity task, as compared to a feature‐search task that was included to probe visual detection of an isolated face feature. Effects of stimulus orientation in right PrC were observed when the recognition‐memory condition for upright faces was compared with all other experimental conditions, including recognition‐memory for inverted faces‐a result that can be related to past work on the role of PrC in object unitization. Notably, both effects in right PrC paralleled activity patterns in broader networks of regions that also included the right fusiform gyrus and the amygdala, regions frequently implicated in face processing in prior research. As such, the current findings do not support the view that reference to a prior study episode clearly distinguishes the role of PrC from that of more posterior ventral visual pathway regions. They add to a growing body of evidence suggesting that the functional role of specific MTL structures may be best understood in terms of the representations that are required by the task and the stimuli at hand. © 2013 Wiley Periodicals, Inc.     

Patterns of hippocampal–neocortical interactions in the retrieval of episodic autobiographical memories across the entire life‐span of aged adults

We previously demonstrated that episodic autobiographical memories (EAMs) rely on a network of brain regions comprising the medial temporal lobe (MTL) and distributed neocortical regions regardless of their remoteness. The findings supported the model of memory consolidation, which proposes a permanent role of MTL during EAM retrieval (multiple‐trace theory or MTT) rather than a temporary role (standard model). Our present aim was to expand the results by examining the interactions between the MTL and neocortical regions (or MTL–neocortical links) during EAM retrieval with varying retention intervals. We used an experimental paradigm specially designed to engage aged participants in the recollection of EAMs, extracted from five different time‐periods, covering their whole life‐span, in order to examine correlations between activation in the MTL and neocortical regions. The nature of the memories was checked at debriefing by means of behavioral measures to control the degree of episodicity and properties of memories. Targeted correlational analyses carried out on the MTL, frontal, lateral temporal, and posterior regions revealed strong links between the MTL and neocortex during the retrieval of both recent and remote EAMs, challenging the standard model of memory consolidation and supporting MTT instead. Further confirmation was given by results showing that activation in the left and right hippocampi significantly correlated during the retrieval of both recent and remote memories. Correlations among extra‐MTL neocortical regions also emerged for all time‐periods, confirming the critical role of the prefrontal, temporal (lateral temporal cortex and temporal pole), precuneus, and posterior cingulate regions in EAM retrieval. Overall, this paper emphasizes the role of a bilateral network of MTL and neocortical areas whose activation correlate during the recollection of rich phenomenological recent and remote EAMs. © 2009 Wiley‐Liss, Inc.     

Encoding of novel picture pairs activates the perirhinal cortex: an fMRI study

It is well established in nonhuman primates that the medial temporal lobe (MTL) structures, the hippocampus and the entorhinal and perirhinal cortices, are necessary for declarative memory encoding. In humans, the neuropathological and neuropsychological changes in early Alzheimer's disease (AD) further support a role for the rhinal cortex in the consolidation of new events into long-term memory. Little is known, however, regarding the function of the rhinal cortex in humans in vivo. To examine the participation of the interconnected MTL structures as well as the whole-brain network of activated brain areas in visual associative long-term memory, functional magnetic resonance imaging (fMRI) was used to determine the brain regions that are activated during encoding and retrieval of paired pictures in 12 young control subjects. The most striking finding in the MTL activation pattern was the consistent activation of the perirhinal cortex in the encoding-baseline and encoding-retrieval comparisons with a strict statistical threshold (P < 0.00001). In contrast, no perirhinal cortex activation was detected in the retrieval-baseline or retrieval-encoding comparisons even with a low statistical threshold (P < 0.05). The location of the perirhinal activation area was in the transentorhinal part of the perirhinal cortex, in the medial bank of the collateral sulcus. The hippocampus and the more posterior parahippocampal gyrus were activated in both encoding and retrieval conditions. During the encoding processing, MTL activations were more consistent and the hippocampal activation area located more anteriorly than during retrieval. The frontal, parietal, temporal, and occipital association cortices were also activated in the encoding-baseline and retrieval-baseline comparisons. The data suggest that encoding, but not retrieval, of novel picture pairs activates the perirhinal cortex. To our knowledge, this is the first fMRI study reporting encoding activation in this transentorhinal part of the perirhinal cortex, the site of the very earliest neuropathological changes in AD.