Dynamic changes in the medial temporal lobe during incidental learning of object-location associations

The role of the medial temporal lobe (MTL) in associative memory encoding has been the focus of many memory experiments. However, there has been surprisingly little investigation of whether the contributions of different MTL subregions (amygdala, hippocampus [HPC], parahippocampal [PHc], perirhinal cortex [PRc], and temporal polar cortex [TPc]) shift across multiple presentations during associative encoding. We examined this issue using event-related functional magnetic resonance imaging and a multivoxel pattern classification analysis. Subjects performed a visual search task, becoming faster with practice to locate objects whose locations were held constant across trials. The classification analysis implicated right HPC and amygdala early in the task when the speed-up from trial to trial was greatest. The same analysis implicated right PRc and TPc late in learning when speed-up was minimal. These results suggest that associative encoding relies on complex patterns of neural activity in MTL that cannot be expressed by simple increases or decreases of blood oxygenation level-dependent signal during learning. Involvement of MTL subregions during encoding of object-location associations depends on the nature of the learning phase. Right HPC and amygdala support active integration of object and location information, while right PRc and TPc are involved when object and spatial representations become unitized into a single representation.     

Medial temporal lobe involvement in an implicit memory task: evidence of collaborating implicit and explicit memory systems from FMRI and Alzheimer's disease

We used a prototype extraction task to assess implicit learning of a meaningful novel visual category. Cortical activation was monitored in young adults with functional magnetic resonance imaging. We observed occipital deactivation at test consistent with perceptually based implicit learning, and lateral temporal cortex deactivation reflecting implicit acquisition of the category's semantic nature. Medial temporal lobe (MTL) activation during exposure and test suggested involvement of explicit memory as well. Behavioral performance of Alzheimer's disease (AD) patients and healthy seniors was also assessed, and AD performance was correlated with gray matter volume using voxel-based morphometry. AD patients showed learning, consistent with preserved implicit memory, and confirming that AD patients' implicit memory is not limited to abstract patterns. However, patients were somewhat impaired relative to healthy seniors. Occipital and lateral temporal cortical volume correlated with successful AD patient performance, and thus overlapped with young adults' areas of deactivation. Patients' severe MTL atrophy precluded involvement of this region. AD patients thus appear to engage a cortically based implicit memory mechanism, whereas their relative deficit on this task may reflect their MTL disease. These findings suggest that implicit and explicit memory systems collaborate in neurologically intact individuals performing an ostensibly implicit memory task.     

Repetition suppression and reactivation in auditory-verbal short-term recognition memory

The neural response to stimulus repetition is not uniform across brain regions, stimulus modalities, or task contexts. For instance, it has been observed in many functional magnetic resonance imaging (fMRI) studies that sometimes stimulus repetition leads to a relative reduction in neural activity (repetition suppression), whereas in other cases repetition results in a relative increase in activity (repetition enhancement). In the present study, we hypothesized that in the context of a verbal short-term recognition memory task, repetition-related "increases" should be observed in the same posterior temporal regions that have been previously associated with "persistent activity" in working memory rehearsal paradigms. We used fMRI and a continuous recognition memory paradigm with short lags to examine repetition effects in the posterior and anterior regions of the superior temporal cortex. Results showed that, consistent with our hypothesis, the 2 posterior temporal regions consistently associated with working memory maintenance, also show repetition increases during short-term recognition memory. In contrast, a region in the anterior superior temporal lobe showed repetition suppression effects, consistent with previous research work on perceptual adaptation in the auditory-verbal domain. We interpret these results in light of recent theories of the functional specialization along the anterior and posterior axes of the superior temporal lobe.     

Interaction of working memory and long-term memory in the medial temporal lobe

Recent findings indicate that regions in the medial temporal lobe (MTL) do not only play a crucial role in long-term memory (LTM) encoding, but contribute to working memory (WM) as well. However, very few studies investigated the interaction between these processes so far. In a new functional magnetic resonance imaging paradigm comprising both a complex WM task and an LTM recognition task, we found not only that some items were successfully processed in WM but later forgotten, but also that a significant number of items which were not successfully processed in the WM task were subsequently recognized. Activation in the parahippocampal cortex (PHC) during successful WM was predictive of subsequent LTM, but was correlated with subsequent forgetting if the WM task was not successfully solved. The contribution of the PHC to LTM encoding thus crucially depends on whether an item was successfully processed in the WM task. Functional connectivity analysis revealed that across-trial fluctuations in PHC activity were correlated with activation in extensive regions if WM and LTM tasks were correctly solved, whereas connectivity broke down during unsuccessful attempts to do the task, suggesting that activity in the PHC during WM has to be well controlled to support LTM formation.     

Learning the exception to the rule: model-based FMRI reveals specialized representations for surprising category members

Category knowledge can be explicit, yet not conform to a perfect rule. For example, a child may acquire the rule "If it has wings, then it is a bird," but then must account for exceptions to this rule, such as bats. The current study explored the neurobiological basis of rule-plus-exception learning by using quantitative predictions from a category learning model, SUSTAIN, to analyze behavioral and functional magnetic resonance imaging (fMRI) data. SUSTAIN predicts that exceptions require formation of specialized representations to distinguish exceptions from rule-following items in memory. By incorporating quantitative trial-by-trial predictions from SUSTAIN directly into fMRI analyses, we observed medial temporal lobe (MTL) activation consistent with 2 predicted psychological processes that enable exception learning: item recognition and error correction. SUSTAIN explains how these processes vary in the MTL across learning trials as category knowledge is acquired. Importantly, MTL engagement during exception learning was not captured by an alternate exemplar-based model of category learning or by standard contrasts comparing exception and rule-following items. The current findings thus provide a well-specified theory for the role of the MTL in category learning, where the MTL plays an important role in forming specialized category representations appropriate for the learning context.     

Neural correlates of true memory, false memory, and deception

We used functional magnetic resonance imaging (fMRI) to determine whether neural activity can differentiate between true memory, false memory, and deception. Subjects heard a series of semantically related words and were later asked to make a recognition judgment of old words, semantically related nonstudied words (lures for false recognition), and unrelated new words. They were also asked to make a deceptive response to half of the old and unrelated new words. There were 3 main findings. First, consistent with the notion that executive function supports deception, 2 types of deception (pretending to know and pretending not to know) recruited prefrontal activity. Second, consistent with the sensory reactivation hypothesis, the difference between true recognition and false recognition was found in the left temporoparietal regions probably engaged in the encoding of auditorily presented words. Third, the left prefrontal cortex was activated during pretending to know relative to correct rejection and false recognition, whereas the right anterior hippocampus was activated during false recognition relative to correct rejection and pretending to know. These findings indicate that fMRI can detect the difference in brain activity between deception and false memory despite the fact that subjects respond with "I know" to novel events in both processes.     

Distinct patterns of functional and effective connectivity between perirhinal cortex and other cortical regions in recognition memory and perceptual discrimination

Traditionally, the medial temporal lobe (MTL) is thought to be dedicated to declarative memory. Recent evidence challenges this view, suggesting that perirhinal cortex (PrC), which interfaces the MTL with the ventral visual pathway, supports highly integrated object representations in recognition memory and perceptual discrimination. Even with comparable representational demands, perceptual and memory tasks differ in numerous task demands and the subjective experience they evoke. Here, we tested whether such differences are reflected in distinct patterns of connectivity between PrC and other cortical regions, including differential involvement of prefrontal control processes. We examined functional magnetic resonance imaging data for closely matched perceptual and recognition memory tasks for faces that engaged right PrC equivalently. Multivariate seed analyses revealed distinct patterns of interactions: Right ventrolateral prefrontal and posterior cingulate cortices exhibited stronger functional connectivity with PrC in recognition memory; fusiform regions were part of the pattern that displayed stronger functional connectivity with PrC in perceptual discrimination. Structural equation modeling revealed distinct patterns of effective connectivity that allowed us to constrain interpretation of these findings. Overall, they demonstrate that, even when MTL structures show similar involvement in recognition memory and perceptual discrimination, differential neural mechanisms are reflected in the interplay between the MTL and other cortical regions.     

Prefrontal selection and medial temporal lobe reactivation in retrieval of short-term verbal information

Both the prefrontal cortex (PFC) and medial temporal lobe (MTL) are involved in memory retrieval. Here we distinguish between their roles by manipulating demand for interference resolution and reactivation of maintained information. Subjects were tested on a letter working memory task with distractors. When the memory delay was interrupted with letter distractors, there was higher activity in the middle frontal gyrus at retrieval compared to when the delay was interrupted by number distractors, suggesting the role of the PFC in interference resolution. By contrast, activity in the parahippocampal gyrus did not differ between the two conditions. The two structures were then compared using the dataset of our previous study on memory reactivation, where subjects performed a letter working memory task with arithmetic distractors or non-distractors. The activity in the parahippocampal gyrus at retrieval was higher when distractors interrupted rehearsal than when the intervening task was non-distracting and subjects continued to rehearse, suggesting the role of the MTL in reactivating the stored information. By contrast, the activity in the middle frontal gyrus did not differ between the two conditions. Taking these results together, we have shown the double dissociation between the PFC and MTL in memory retrieval.     

Volumetric correlates of spatiotemporal working and recognition memory impairment in aged rhesus monkeys

Spatiotemporal and recognition memory are affected by aging in humans and macaque monkeys. To investigate whether these deficits are coupled with atrophy of memory-related brain regions, T(1)-weighted magnetic resonance images were acquired and volumes of the cerebrum, ventricles, prefrontal cortex (PFC), calcarine cortex, hippocampus, and striatum were quantified in young and aged rhesus monkeys. Subjects were tested on a spatiotemporal memory procedure (delayed response [DR]) that requires the integrity of the PFC and a medial temporal lobe-dependent recognition memory task (delayed nonmatching to sample [DNMS]). Region of interest analyses revealed that age inversely correlated with striatal, dorsolateral prefrontal cortex (dlPFC), and anterior cingulate cortex volumes. Hippocampal volume predicted acquisition of the DR task. Striatal volume correlated with DNMS acquisition, whereas total prefrontal gray matter, prefrontal white matter, and dlPFC volumes each predicted DNMS accuracy. A regional covariance analysis revealed that age-related volumetric changes could be captured in a distributed network that was coupled with declining performance across delays on the DNMS task. This volumetric analysis adds to growing evidence that cognitive aging in primates arises from region-specific morphometric alterations distributed across multiple memory-related brain systems, including subdivisions of the PFC.     

Neural correlates of availability and accessibility in memory

Failure to remember can be due to not having information available in memory or to an inability to access information that is available. We used functional magnetic resonance imaging to examine brain responses during encoding and successive cued recall and associative recognition tests of paired associates. Items were classified into 3 categories based on performance on the 2 retrieval tests: 1) successfully remembered (both recalled and recognized), 2) inaccessible (not recalled but later recognized), and 3) forgotten (neither recalled nor recognized). During cued recall, availability in memory was signaled in a network of regions including bilateral medial temporal lobe, left middle temporal cortex, and the parietal cortex. Memory access resulted in heightened activity in these regions as well as in left inferior frontal cortex. Encoding-related activity in hippocampus and inferior temporal cortex predicted subsequent availability and left inferior frontal activity predicted subsequent access. These results suggest that failure to access information that is available in memory may reflect weaker memory representations.     

Contextual processing in episodic future thought

Remembering events from one's past (i.e., episodic memory) and envisioning specific events that could occur in one's future (i.e., episodic future thought) invoke highly overlapping sets of brain regions. The present study employed functional magnetic resonance imaging to test the hypothesis that one source of this shared architecture is that episodic future thought--much like episodic memory--tends to invoke memory for known visual-spatial contexts. That is, regions of posterior cortex (within posterior cingulate cortex [PCC], parahippocampal cortex [PHC], and superior occipital gyrus [SOG]) elicit indistinguishable activity during remembering and episodic future thought, and similar regions have been identified as important for establishing visual-spatial contextual associations. In the present study, these regions were similarly engaged when participants thought about personal events in familiar contexts, irrespective of temporal direction (past or future). The same regions, however, exhibited very little activity when participants envisioned personal future events in unfamiliar contextual settings. These findings suggest that regions within PCC, PHC, and SOG support the activation of well-known contextual settings that people tend to imagine when thinking about personal events, whether in the past or future. Hence, this study pinpoints an important similarity between episodic future thought and episodic memory.     

Activating the medial temporal lobe during oddity judgment for faces and scenes

Impairments in visual discrimination beyond long-term declarative memory have been found in amnesic individuals, with hippocampal lesions resulting in deficits in scene discrimination and perirhinal cortex damage affecting object discrimination. To complement these findings, the present functional magnetic resonance imaging study found that in healthy participants oddity judgment for novel trial-unique scenes, compared with face or size oddity, was associated with increased posterior hippocampus and parahippocampal cortex activity. In contrast, perirhinal and anterior hippocampus activity was observed during unfamiliar trial-unique face oddity judgment, when contrasted with scene or size oddity tasks. Activity in all of these regions decreased as the stimuli were repeated across trials, reflecting the participants' increasing familiarity with the stimuli. This change was significant in all areas, with the exception of the perirhinal cortex, right anterior hippocampus, and to a lesser extent the left anterior hippocampus during face oddity judgment. One possibility is that the activity in these regions may not reflect entirely episodic memory encoding but, in part, processes beyond the mnemonic domain. Thus, the perirhinal cortex, and possibly anterior hippocampus, may play a more generic role in the discrimination and processing of objects.     

Anterior prefrontal cortex mediates rule learning in humans

Despite a need for rule learning in everyday life, the brain regions involved in explicit rule induction remain undetermined. Here we use event-related functional magnetic resonance imaging to measure learning-dependent neuronal responses during an explicit categorization task. Subjects made category decisions, with feedback, to exemplar letter strings for which the rule governing category membership was periodically changed. Bilateral fronto-polar prefrontal cortices were selectively engaged following rule change. This activation pattern declined with improving task performance reflecting rule acquisition. The vocabulary of letters comprising the exemplars was also periodically changed, independently of rule changes. This exemplar change modulated activation in left anterior hippocampus. Our finding that fronto-polar cortex mediates rule learning supports a functional contribution of this region to generic reasoning and problem-solving behaviours.     

The relationship between aging, performance, and the neural correlates of successful memory encoding

The present functional magnetic resonance imaging (fMRI) study investigated whether age-related differences in the neural correlates of successful memory encoding are modulated by memory performance. Young (mean age 22 years; N = 16) and older (mean age 69 years; N = 32) subjects were scanned while making animacy decisions on visually presented words. Memory for the words was later assessed in a recognition test, allowing fMRI activity elicited by study words to be contrasted according to subsequent memory performance. Young and older adults exhibited equivalent subsequent memory effects (enhanced activity for later remembered items) in an extensive network that included left inferior prefrontal cortex and anterior hippocampus. In posterior cingulate cortex, reversed subsequent memory effects (greater activity for later forgotten items) were of greater magnitude in young subjects. A voxel-of-interest analysis conducted on left and right prefrontal subsequent memory effects revealed that the effects were distributed more bilaterally in older than in young subjects, replicating previous findings. This age-related difference was confined to older subjects with relatively poor recognition performance, who were also the only group to demonstrate statistically significant right prefrontal subsequent memory effects. The findings suggest that relative preservation of memory performance with increasing age does not depend upon right prefrontal "over-recruitment."     

Longitudinal structure-function correlates in elderly reveal MTL dysfunction with cognitive decline

By integrating behavioral measures and imaging data, previous investigations have explored the relationship between biological markers of aging and cognitive functions. Evidence from functional and structural neuroimaging has revealed that hippocampal volume and activation patterns in the medial temporal lobe (MTL) may predict cognitive performance in old age. Most past demonstrations of age-related differences in brain structure-function were based on cross-sectional comparisons. Here, the relationship between 6-year intraindividual change in functional magnetic resonance imaging (fMRI) signal and change in memory performance over 2 decades was examined. Correlations between intraindividual change in fMRI signal during episodic encoding and change in memory performance measured outside of scanning were used as an estimate for relating brain-behavior changes. The results revealed a positive relationship between activation change in the hippocampus (HC) and change in memory performance, reflecting reduced hippocampal activation in participants with declining performance. Using a similar analytic approach as for the functional data, we found that individuals with declining performance had reduced HC volume compared with individuals with intact performance. These observations provide a strong link between cognitive change in older adults and MTL structure and function and thus provide insights into brain correlates of individual variability in aging trajectories.     

Temporal and cerebellar brain regions that support both declarative memory formation and retrieval

Using event-related fMRI, we scanned young healthy subjects while they memorized real-world photographs and subsequently tried to recognize them within a series of new photographs. We confirmed that activity in the medial temporal lobe (MTL) and inferior prefrontal cortex correlates with declarative memory formation as defined by the subsequent memory effect, stronger responses to subsequently remembered than forgotten items. Additionally, we confirmed that activity in specific regions within the parietal lobe, anterior prefrontal cortex, anterior cingulate and cerebellum correlate with recognition memory as measured by the conventional old/new effect, stronger responses for recognized old items (hits) than correctly identified new items (correct rejections). To obtain a purer measure of recognition success, we introduced two recognition effects by comparing brain responses to hits and old items misclassified as new (misses). The positive recognition effect (hits > misses) revealed prefrontal, parietal and cerebellar contributions to recognition, and in line with electrophysiological findings, the negative recognition effect (hits < misses) revealed an anterior medial temporal contribution. Finally, by inclusive masking, we identified temporal and cerebellar brain areas that support both declarative memory formation and retrieval. For matching operations during recognition, these areas may re-use representations formed and stored locally during encoding.     

Attenuated brain response to auditory word stimulation with sevoflurane: a functional magnetic resonance imaging study in humans

BACKGROUND: Functional magnetic resonance imaging offers a compelling, new perspective on altered brain function but is sparsely used in studies of anesthetic effect. To examine effects on verbal memory encoding, the authors imaged human brain response to auditory word stimulation using functional magnetic resonance imaging at different concentrations of an agent not previously studied, and tested memory after recovery. METHODS: Six male volunteers were studied breathing 0.0, 2.0, and 1.0% end-tidal sevoflurane (awake, deep, and light states, respectively) via laryngeal mask. In each condition, they heard 15 two-syllable English nouns via closed headphones. Each word was repeated 15 times (1/s), followed by 15 s of rest. Blood oxygenation level-dependent brain activations during blocks of stimulation versus rest were assessed with a 3-T Siemens Trio scanner and a 20-voxel spatial extent threshold. Memory was tested approximately 1.5 h after recovery with an auditory recognition task (chance performance = 33% correct). RESULTS: Scans showed widespread activations (P < 0.005, uncorrected) in the awake state, including bilateral superior temporal, frontal, and parietal cortex, right occipital cortex, bilateral thalamus, striatum, hippocampus, and cerebellum; more limited activations in the light state (bilateral superior temporal gyrus, right thalamus, bilateral parietal cortex, left frontal cortex, and right occipital cortex); and no significant auditory-related activation in the deep state. During recognition testing, subjects correctly selected 77 +/- 12% of words presented while they were awake as "old," versus 32 +/- 15 and 42 +/- 8% (P < 0.01) correct for the light and deep stages, respectively. CONCLUSIONS: Sevoflurane induces dose-dependent suppression of auditory blood oxygenation level-dependent signals, which likely limits the ability of words to be processed during anesthesia and compromises memory.     

Impairment and facilitation of transverse patterning after lesions of the perirhinal cortex and hippocampus, respectively

We have recently suggested that certain effects of perirhinal cortex removals in monkeys can be attributed to the lesion compromising complex configural representations of visual stimuli. On this view, monkeys with perirhinal cortex lesions will be impaired on acquisition of discrimination problems that possess high "feature ambiguity," that is, those in which many of the same features belong to both rewarded and unrewarded stimuli. A subclass of feature-ambiguous problems includes "configural" discrimination problems in which all features are ambiguous. In the present study, we tested control monkeys and monkeys with bilateral lesions of perirhinal cortex on a configural discrimination problem, the transverse-patterning task (i.e., A+ vs. B-, B+ vs. C-, C+ vs. A-), using complex 2-dimensional visual stimuli. In addition, we investigated the effects of lesions to another structure that has been implicated in configural learning, the hippocampus. Monkeys with perirhinal cortex lesions were impaired, whereas monkeys with selective hippocampal lesions were facilitated, on acquisition of the transverse-patterning task. These data do not provide support for mass action theories of medial temporal lobe function, which cannot account for the opposing effects of the 2 lesions. These results are, however, compatible with a view that perirhinal cortex, and not the hippocampus, contains complex configural representations of visual stimuli critical to the solution of the transverse-patterning task.     

Inhibitory and excitatory responses of single neurons in the human medial temporal lobe during recognition of faces and objects

The medial temporal lobe (MTL) plays a critical role in transforming complex stimuli into permanent memory traces, yet little is known on how the activity of neurons in the human brain mediates this process. Recording from single neurons in the human MTL during visual encoding and retrieval of faces and objects, we found that in the hippocampus faces evoked predominantly suppression of neuronal firing below prestimulus baseline ('inhibitory responses'). These responses were also prevalent in the entorhinal cortex but were absent in the amygdala during the first second of stimulus encoding when all responses to faces were 'excitatory' (neuronal firing increased above the prestimulus baseline). Inhibitory responses were more prevalent during recognition than encoding and were also present during processing of objects, albeit less frequently than during processing of faces. Despite the prevalence in the hippocampus of cells with inhibitory responses and their relative specificity to faces, it was mainly the activity of the cells with excitatory responses that was selective for stimulus features such as gender and emotional expression of faces. These findings suggest that a large population of cells with inhibitory responses is engaged in the hippocampal memory network, but primarily cells with excitatory responses process feature-specific information.     

Not all false memories are created equal: the neural basis of false recognition

False recognition, a type of memory distortion where one claims to remember something that never happened, can occur in response to items that are similar but not identical to previously seen items (i.e., related false recognition) or in response to novel items (i.e., unrelated false recognition). It is unknown whether these 2 types of memory errors arise from the same or distinct neural substrates. Using functional magnetic resonance imaging, we compared the neural activity associated with true recognition, related false recognition, and unrelated false recognition for abstract shapes. True recognition and related false recognition were associated with similar patterns of neural activity, including activity in the prefrontal cortex, the parietal cortex, and the medial temporal lobe. By contrast, unrelated false recognition was associated with activity in language-processing regions. These results indicate that false recognition is not a unitary phenomenon, but rather can reflect the operation of 2 distinct cognitive and neural processes.