Elizabeth Murray

Post-study caffeine administration enhances memory consolidation in humans

It is currently not known whether caffeine has an enhancing effect on long-term memory in humans. We used post-study caffeine administration to test its effect on memory consolidation using a behavioral discrimination task. Caffeine enhanced performance 24 h after administration according to an inverted U-shaped dose-response curve; this effect was specific to consolidation and not retrieval. We conclude that caffeine enhanced consolidation of long-term memories in humans.

Spatial discrimination deficits as a function of mnemonic interference in aged adults with and without memory impairment

It is well established that aging is associated with declines in episodic memory. In recent years, an emphasis has emerged on the development of behavioral tasks and the identification of biomarkers that are predictive of cognitive decline in healthy as well as pathological aging. Here, we describe a memory task designed to assess the accuracy of discrimination ability for the locations of objects. Object locations were initially encoded incidentally, and appeared in a single space against a 5 × 7 grid. During retrieval, subjects viewed repeated object‐location pairings, displacements of 1, 2, 3, or 4 grid spaces, and maximal corner‐to‐opposite‐corner displacements. Subjects were tasked with judging objects in this second viewing as having retained their original location, or having moved. Performance on a task such as this is thought to rely on the capacity of the individual to perform hippocampus‐mediated pattern separation. We report a performance deficit associated with a physically healthy aged group compared to young adults specific to trials with low mnemonic interference. Additionally, for aged adults, performance on the task was correlated with performance on the delayed recall portion of the Rey Auditory Verbal Learning Test (RAVLT), a neuropsychological test sensitive to hippocampal dysfunction. In line with prior work, dividing the aged group into unimpaired and impaired subgroups based on RAVLT Delayed Recall scores yielded clearly distinguishable patterns of performance, with the former subgroup performing comparably to young adults, and the latter subgroup showing generally impaired memory performance even with minimal interference. This study builds on existing tasks used in the field, and contributes a novel paradigm for differentiation of healthy from possible pathological aging, and may thus provide an avenue for early detection of age‐related cognitive decline.

Greater loss of object than spatial mnemonic discrimination in aged adults

Previous studies across species have established that the aging process adversely affects certain memory‐related brain regions earlier than others. Behavioral tasks targeted at the function of vulnerable regions can provide noninvasive methods for assessing the integrity of particular components of memory throughout the lifespan. The present study modified a previous task designed to separately but concurrently test detailed memory for object identity and spatial location. Memory for objects or items is thought to rely on perirhinal and lateral entorhinal cortices, among the first targets of Alzheimers related neurodegeneration. In line with prior work, we split an aged adult sample into “impaired” and “unimpaired” groups on the basis of a standardized word‐learning task. The “impaired” group showed widespread difficulty with memory discrimination, whereas the “unimpaired” group showed difficulty with object, but not spatial memory discrimination. These findings support the hypothesized greater age‐related impacts on memory for objects or items in older adults, perhaps even with healthy aging.

Perceptual versus conceptual interference and pattern separation of verbal stimuli in young and older adults

Recently, several studies have strongly suggested that age‐related decline in episodic memory is associated with deficits in hippocampal pattern separation (orthogonalizing overlapping experiences using distinct neural codes). The same studies also link these deficits to neurobiological features such as dentate/CA3 representational rigidity and perforant path loss. This decline in pattern separation is thought to underlie behavioral deficits in discriminating similar stimuli on pictorial tasks. Similar pictorial stimuli invoke interference both in the perceptual and conceptual domains, and do not allow one to be disentangled from another. For example, it is very difficult to design a set of pictorial stimuli that are perceptually similar yet conceptually unrelated. Verbal stimuli, on the other hand, allow experimenters to independently manipulate conceptual and perceptual interference. We tested discrimination on conceptually similar (semantically related) and perceptually similar (phonologically related) verbal stimuli in young (mean age 20) and older adults (mean age 69), and find that older adults are selectively impaired in perceptual pattern separation. This deficit was not secondary to failure in working memory, attention, or visual processing. Based on past studies, we suggest that perceptual discrimination relies on recollection while conceptual discrimination relies more on gist. Our results fit well within the notion that recollection but not familiarity (i.e. gist) is impaired in older adults, and suggests that the impairment observed in pictorial tasks may be driven mostly by failure in perceptual and not conceptual pattern separation.

Age-related individual variability in memory performance is associated with amygdala-hippocampal circuit function and emotional pattern separation

While aging is generally associated with episodic memory decline, not all older adults exhibit memory loss. Furthermore, emotional memories are not subject to the same extent of forgetting and appear preserved in aging. We conducted high-resolution fMRI during a task involving pattern separation of emotional information in older adults with and without age-related memory impairment (characterized by performance on a word-list learning task: low performers: LP vs. high performers: HP). We found signals consistent with emotional pattern separation in hippocampal dentate (DG)/CA3 in HP but not in LP individuals, suggesting a deficit in emotional pattern separation. During false recognition, we found increased DG/CA3 activity in LP individuals, suggesting that hyperactivity may be associated with overgeneralization. We additionally observed a selective deficit in basolateral amygdala-lateral entorhinal cortex-DG/CA3 functional connectivity in LP individuals during pattern separation of negative information. During negative false recognition, LP individuals showed increased medial temporal lobe functional connectivity, consistent with overgeneralization. Overall, these results suggest a novel mechanistic account of individual differences in emotional memory alterations exhibited in aging.

Dissociated Signals in Human Dentate Gyrus and CA3 Predict Different Facets of Recognition Memory

A wealth of evidence has implicated the hippocampus and surrounding medial temporal lobe cortices in support of recognition memory. However, the roles of the various subfields of the hippocampus are poorly understood. In this study, we concurrently varied stimulus familiarization and repetition to engage different facets of recognition memory. Using high-resolution fMRI (1.5 mm isotropic), we observed distinct familiarity and repetition-related recognition signal profiles in the dentate gyrus (DG)/CA3 subfield in human subjects. The DG/CA3 demonstrated robust response suppression with repetition and familiarity-related facilitation. Both of these discrete responses were predictive of different aspects of behavioral performance. Consistent with previous work, we observed novelty responses in CA1 consistent with “match/mismatch detection,” as well as mixed recognition signaling distributed across medial temporal lobe cortices. Additional analyses indicated that the repetition and familiarity-related signals in the DG/CA3 were strikingly dissociated along the hippocampal longitudinal axis and that activity in the posterior hippocampus was strongly correlated with the retrosplenial cortex. These data provide novel insight into the roles of hippocampal subfields in support of recognition memory and further provide evidence of a functional heterogeneity in the human DG/CA3, particularly along the longitudinal axis.

Repetition reveals ups and downs of hippocampal, thalamic, and neocortical engagement during mnemonic decisions

The extent to which current information is consistent with past experiences and our capacity to recognize or discriminate accordingly are key factors in flexible memory‐guided behavior. Despite a wealth of evidence linking hippocampal and neocortical computations to these phenomena, many important factors remain poorly understood. One such factor is repeated encoding of learned information. In this experiment, participants completed a task in which study stimuli were incidentally encoded either once or three separate times during high‐resolution fMRI scanning. We asked how repetition influenced recognition and discrimination memory judgments, and how this affects engagement of hippocampal and neocortical regions. Repetition revealed shifts in engagement in an anterior (ventral) CA1‐thalamic‐medial prefrontal network related to true and false recognition. Conversely, repetition revealed shifts in a posterior (dorsal) dentate/CA3‐parahippocampal‐restrosplenial network related to accurate discrimination. These differences in engagement were accompanied by task‐related correlations in respective anterior and posterior networks. In particular, the anterior thalamic region observed during recognition judgments is functionally and anatomically consistent with nucleus reuniens in humans, and was found to mediate correlations between the anterior CA1 and medial prefrontal cortex. These findings offer new insights into how repeated experience affects memory and its neural substrates in hippocampal‐neocortical networks.

Disruption of amygdala-entorhinal-hippocampal network in late-life depression: MEDIAL TEMPORAL LOBE DYSFUNCTION IN LATE-LIFE DEPRESSION

Episodic memory deficits are evident in late‐life depression (LLD) and are associated with subtle synaptic and neurochemical changes in the medial temporal lobes (MTL). However, the particular mechanisms by which memory impairment occurs in LLD are currently unknown. We tested older adults with (DS+) and without (DS−) depressive symptoms using high‐resolution fMRI that is capable of discerning signals in hippocampal subfields and amygdala nuclei. Scanning was conducted during performance of an emotional discrimination task used previously to examine the relationship between depressive symptoms and amygdala‐mediated emotional modulation of hippocampal pattern separation in young adults. We found that hippocampal dentate gyrus (DG)/CA3 activity was reduced during correct discrimination of negative stimuli and increased during correct discrimination of neutral items in DS+ compared to DS− adults. The extent of the latter increase was correlated with symptom severity. Furthermore, DG/CA3 and basolateral amygdala (BLA) activity predicted discrimination performance on negative trials, a relationship that depended on symptom severity. The impact of the BLA on depressive symptom severity was mediated by the DG/CA3 during discrimination of neutral items, and by the lateral entorhinal cortex (LEC) during false recognition of positive items. These results shed light on a novel mechanistic account for amygdala–hippocampal network changes and concurrent alterations in emotional episodic memory in LLD. The BLA‐LEC‐DG/CA3 network, which comprises a key pathway by which emotion modulates memory, is specifically implicated in LLD.

Anterolateral entorhinal-hippocampal imbalance in older adults disrupts object pattern separation

The entorhinal cortex (EC) is among the earliest brain areas to deteriorate in Alzheimer’s disease (AD). However, the extent to which functional properties of the EC are altered in the aging brain, even in the absence of clinical symptoms, is not understood. Recent human fMRI studies have identified a functional dissociation within the EC, similar to what is found in rodents. Here, we used high-resolution fMRI to identify a specific hypoactivity in the anterolateral EC (alEC) commensurate with major behavioral deficits on an object pattern separation task in asymptomatic older adults. Only subtle deficits were found in a comparable spatial condition, with no associated differences in posteromedial EC between young and older adults. We additionally link this condition to previously reported dentate/CA3 hyperactivity, both of which were associated with object mnemonic discrimination impairment. These results provide novel evidence of alEC-dentate/CA3 circuit dysfunction in cognitively normal aged humans.

Functional Imbalance of Anterolateral Entorhinal Cortex and Hippocampal Dentate/CA3 Underlies Age-Related Object Pattern Separation Deficits

The entorhinal cortex (EC) is among the earliest brain areas to deteriorate in Alzheimers disease (AD). However, the extent to which functional properties of the EC are altered in the aging brain, even in the absence of clinical symptoms, is not understood. Recent human fMRI studies have identified a functional dissociation within the EC, similar to what is found in rodents. Here, we used high-resolution fMRI to identify a specific hypoactivity in the anterolateral EC (alEC) commensurate with major behavioral deficits on an object pattern separation task in asymptomatic older adults. Only subtle deficits were found in a comparable spatial condition, with no associated differences in posteromedial EC between young and older adults. We additionally linked this condition to dentate/CA3 hyperactivity, and the ratio of activity between the regions was associated with object mnemonic discrimination impairment. These results provide novel evidence of alEC-dentate/CA3 circuit dysfunction in cognitively normal aged humans.