The Hippocampus is Preferentially Associated with Memory for Spatial Context

<p>Healthy aging is associated with episodic memory decline, particularly in the ability to encode and retrieve object-context associations (context memory). Neuropsychological and neuroimaging studies have highlighted the importance of the medial temporal lobes (MTL) in supporting episodic memory across the lifespan. However, given the functional heterogeneity of the MTL, volumetric declines in distinct regions may impact performance on specific episodic memory tasks, and affect the function of the large-scale neurocognitive networks supporting episodic memory encoding and retrieval. In the current study, we investigated how MTL structure may mediate age-related differences in performance on spatial and temporal context memory tasks, in a sample of 125 healthy adults aged 19-76 years old. Standard T1-weighted MRIs were segmented into the perirhinal, entorhinal and parahippocampal cortices, as well as the anterior and posterior hippocampal subregions. We observed negative linear and quadratic associations between age and volume of the parahippocampal cortex, and anterior and posterior hippocampal subregions. We also found that volume of the posterior hippocampus fully mediated the association between age and spatial, but not temporal context memory performance. Further, we employed a multivariate behavior partial-least-squares analysis to assess how age and regional MTL volumes correlated with brain activity during the encoding and retrieval of spatial context memories. We found that greater activity within lateral prefrontal, parietal, and occipital regions, as well as within the anterior MTL was related to older age and smaller volume of the posterior hippocampus. Our results highlight the heterogeneity of MTL contributions to episodic memory across the lifespan and provide support for the posterior-anterior shift in aging, and scaffolding theory of aging and cognition.</p>

A functional gradient has been proposed across the medial temporal lobes (MTL) such that the anterior MTL is thought to support processing of individual items (e.g., item memory and complex object perception), whereas the posterior MTL is thought to support item-context retrieval (e.g., source memory). Whereas functional imaging studies have provided evidence supporting this anatomical organization, results from structural analyses remain inconclusive. The current study examined the relationship between volume of MTL regions of interest (ROIs), and performance on a source memory task and a fine-grain complex object perception task, in healthy young adults (mean age = 21.5, range = 18-29). Using a semiautomated procedure, we segmented the parahippocampal and perirhinal cortices (PHC, PRC), posteromedial and anterolateral entorhinal cortices (pmERC, alERC), and posterior and anterior hippocampus (postHC, antHC) on high-resolution T2-weighted MRIs. Regional volumes were computed as proportions of intracranial volume, and as posterior-anterior volumetric ratios (PHC:PRC, pmERC:alERC, postHC:antHC). Partial-least squares regressions were applied to predict source and item memory, and perceptual discrimination accuracy, based on ROI and ratio volumes. In our ROI regressions, we found that postHC volume was positively correlated with a latent factor predicting source memory, and PRC and antHC volumes were negatively correlated to this latent factor. In our ratio regressions, we observed an effect relating the posterior-anterior distribution of gray matter across the MTL with source memory. Our results demonstrate differential associations between anterior and posterior MTL and source memory performance. Findings from this study highlight the importance of considering patterns of structure-behavior associations in the neurobiology of episodic memory.

Dissecting medial temporal lobe contributions to item and associative memory formation

The human entorhinal-hippocampal circuitry is characterized by an information-specific functional organization where two routes, that are preferentially connected to the parahippocampal cortex or the perirhinal and retrosplenial cortices, divide the entorhinal cortex as well as hippocampal subiculum and CA1 subregions.

Review of: Watrous AJ, Tandon N, Conner CR, Pieters T, Ekstrom AD. Frequency-specific network connectivity increases underlie accurate spatiotemporal memory retrieval. Nat Neurosci 2013 doi:10.1038/nn.3315. Humans depend on a memory system to rapidly and veraciously store the massive stream of incoming information documenting their experiences, and faithfully represent and recall that information for future use. Devastating dysfunction in the system is observed in schizophrenia and Alzheimer’s disease. While the medial temporal lobe (MTL), prefrontal cortex (PFC), and parietal lobe have been implicated in an episodic memory retrieval network, the processes underlying successful retrieval remain undetermined, particularly regarding simultaneous recall of different classes of information represented by shared neuronal ensembles. Leading hypotheses propose that retrieval may be defined by changes in connectivity and activity of one region in the network, connections throughout the network, or phase-synchronized activity at specific frequencies. In a recent study, Watrous et al. tested these theories with simultaneous electrocortigraphical (ECoG) recordings from these regions during episodic memory retrieval. Six patients with medically intractable epilepsy underwent invasive monitoring, and the derived data were used for this study. Electrodes were localized to subregions of the MTL, PFC, and parietal cortex. Patients performed a spatiotemporal memory-dependent task with a virtual taxi game, in which they drove passengers to five irregularly spaced stores in a specific sequential order. Once patients reached criteria levels of accuracy or training time, retrieval of spatial and temporal information was tested separately. Phase synchronization was utilized as a measure of functional connectivity to test the different hypotheses. Pairwise phase consistency (PPC) index, which is based on phase angle difference between signals from different electrodes, was used to quantify the phase synchronization across electrode pairs. Two subregions, termed nodes within the network, were considered functionally connected when the PPC between them differed significantly depending on the condition (correct vs. incorrect responses, spatial vs. temporal memory retrieval). The node degree, a node’s total number of connections, also marked the magnitude of connectivity. Nodes with the highest node degree were defined as hubs. With the greatest connectivity, a hub is thought to play a central role in mediating interactions across the network for retrieval. The percent connectivity was also calculated as the number of connections a node has in a given condition out of the total possible connections. The authors found that functional connectivity, derived by measuring phase-synchronized low-frequency oscillations, was augmented both globally and in the parahippocampal gyrus (PHG) with successful retrieval of spatiotemporal memory. PPC of delta-theta frequency (1-10 Hz) range was greater for correct responses than incorrect. While percent connectivity increased throughout the network with successful retrieval, a disproportionately greater increase in the PHG node was also observed. PHG was designated a hub in the retrieval network. According to these findings, both network-wide and regional, but not frequency-specific, increases in functional connectivity occur for retrieval of spatiotemporal information. Comparing spatial versus temporal memory retrieval uncovered spectral, temporal, and regional segregation of functional connectivity within the retrieval network. For retrieval of spatial information, PPC and percent connectivity were increased between PHG, superior frontal gyrus (SFG), and middle frontal gyrus (MFG), and precuneus areas, at 1-4 Hz, and early in memory retrieval. Temporal memory retrieval was characterized by greater PPC and percent connectivity between PHG, SFG, MFG, and the inferior parietal lobule, at 7-10 Hz, and later in memory retrieval. The PHG was a hub in both conditions, making the same number of overall connections with other nodes, and with differential clustering of connectivity (Figure 1).Figure 1: Frequency-specific synchronization occurs among several components of the human memory system during context retrieval. (G-J) Correct spatial and temporal retrieval networks (within the context of the virtual taxi game task) in the 1–4-Hz and 7–10-Hz bands.This work has notable implications for neuroscience and neurosurgery. The role of mesial temporal lobe structures (particularly the hippocampus) in memory recall remains controversial, particularly after memory consolidation. The hippocampus’s role in memory encoding is well established. Theories of consolidation typically argue that retrieval of consolidated information is independent of the hippocampus, while the Multiple Trace Theory (MTT) proposes that memory recall is hippocampus-dependent. The identification of the PHG, which is intimately connected with the hippocampus, as a hub, lends indirect support for MTT. Since the PHG includes connections from entorhinal, parahippocampal, and perirhinal cortices, but not the hippocampus proper, the evidence does not directly indicate specific action of the hippocampus but rather the MTL in general. Additionally, processes supporting functional connectivity and recall of distinct types of information were elucidated by the authors. This discovery could lead to clinical interventions targeting specific types of cognitive processes including memory retrieval. As neurosurgery continues to expand toward treating cognitive disorders, a network-level understanding of mechanisms and components of memory systems will prove invaluable.

How the different elements of our experiences are encoded into episodic memories has remained one of the major questions in memory research. Although the pivotal role of the medial temporal lobe as a whole for memory formation is well established, much controversy surrounds the precise contributions of the subregions in the medial temporal lobe cortex (MTLC), most notably the perirhinal cortex (PrC) and the parahippocampal cortex (PhC). While one prominent view links PrC processes with familiarity-based memory and PhC with recollection, an alternative organizing principle is the representational domain critical for successful memory performance, e.g., object- vs. scene-related information. In this fMRI study, we directly compared successful source encoding during object- vs. scene-imagery, holding perceptual input constant across the two representational domains. While the hippocampus contributed to associative encoding of both object and scene information, our results revealed a clear double dissociation between PrC and PhC for object- vs. scene-related source encoding. In particular, PrC, but not PhC, encoding activation predicted later source memory for the object imagery task, whereas PhC, but not PrC, encoding activation predicted later source memory for the scene imagery task. Interestingly, the transitional zone between PrC and posterior PhC contributed to both object and scene source encoding, possibly reflecting a gradient in domain-preference along MTLC. In sum, these results strongly point to representational domain as a key factor determining the involvement of different MTLC subregions during successful episodic memory formation.

GENERAL COMMENTARY article Front. Hum. Neurosci., 06 August 2012Sec. Cognitive Neuroscience Volume 6 - 2012 | https://doi.org/10.3389/fnhum.2012.00231

Introduction Remembering relationships between items (information) and the contexts (sources) in which they are framed is crucial for everyday functioning. Total sleep deprivation (TSD) impairs this ability, with evidence suggesting that TSD affects source memory even when items are remembered. Source memory deficits imply problems with associative memory, which relies on hippocampal functioning, known to be altered by TSD. Serotonin is highly expressed in the hippocampus, is influenced by TSD, and may be part of a mechanism by which TSD degrades source memory. We investigated the association between 5-HTTLPR, a functional length polymorphism of the human serotonin transporter gene (SLC6A4), and item and source memory during TSD. Methods N=34 healthy adults (ages 27.3±4.9y; 18 female) participated in a 4-day/3-night laboratory TSD study. Participants underwent 38h TSD, preceded and followed by 10h sleep opportunities. At baseline and 24h later during TSD, they completed an item/source memory task. Participants listened to a list of 60 words each presented by a male or female speaker (study phase). They were then tested for recognition of the words (items) out of 60 old and 60 new words presented visually, and were asked to identify the corresponding speakers (sources, male or female). Results The genotype distribution was in Hardy-Weinberg equilibrium (P=0.34), with 35.3% long/long, 41.2% long/short, 23.5% short/short. Mixed-effects ANOVA showed a significant adverse effect of TSD for both item recognition (P< 0.001) and source recognition (P< 0.001), where TSD degraded source memory even when item recognition was accurate. There were no 5-HTTLPR genotype effects on item memory. However, there was a significant main effect for genotype on source memory (P=0.019), and a genotype by TSD interaction (P=0.018). For accurately recognized items, source memory was largely preserved for the short/short genotype but impaired for carriers of the long allele, and especially the long/long genotype. Conclusion 5-HTTLPR genotype predicted source memory deficits from TSD, distinct from item memory deficits unaffected by genotype, which confirms that item and source memory deficits due to TSD are dissociable. Furthermore, TSD’s impact on binding of items and sources in memory may be mediated by hippocampal serotonin. Support (if any) NIH R21CA167691, WSU Anthony Marchionne and Foundry10 Bridge fellowships

The essential role of the medial temporal lobe (MTL) in long-term memory for individual events is well established, yet important questions remain regarding the mnemonic functions of the component structures that constitute the region. Within the hippocampus, recent functional neuroimaging findings suggest that formation of new memories depends on the dentate gyrus and the CA(3) field, whereas the contribution of the subiculum may be limited to retrieval. During encoding, it has been further hypothesized that structures within MTL cortex contribute to encoding in a content-sensitive manner, whereas hippocampal structures may contribute to encoding in a more domain-general manner. In the current experiment, high-resolution fMRI techniques were utilized to assess novelty and subsequent memory effects in MTL subregions for two classes of stimuli--faces and scenes. During scanning, participants performed an incidental encoding (target detection) task with novel and repeated faces and scenes. Subsequent recognition memory was indexed for the novel stimuli encountered during scanning. Analyses revealed voxels sensitive to both novel faces and novel scenes in all MTL regions. However, similar percentages of voxels were sensitive to novel faces and scenes in perirhinal cortex, entorhinal cortex, and a combined region comprising the dentate gyrus, CA(2), and CA(3), whereas parahippocampal cortex, CA(1), and subiculum demonstrated greater sensitivity to novel scene stimuli. Paralleling these findings, subsequent memory effects in perirhinal cortex were observed for both faces and scenes, with the magnitude of encoding activation being related to later memory strength, as indexed by a graded response tracking recognition confidence, whereas subsequent memory effects were scene-selective in parahippocampal cortex. Within the hippocampus, encoding activation in the subiculum correlated with subsequent memory for both stimulus classes, with the magnitude of encoding activation varying in a graded manner with later memory strength. Collectively, these findings suggest a gradient of content sensitivity from posterior (parahippocampal) to anterior (perirhinal) MTL cortex, with MTL cortical regions differentially contributing to successful encoding based on event content. In contrast to recent suggestions, the present data further indicate that the subiculum may contribute to successful encoding irrespective of event content.

These experiments investigated the involvement of several temporal lobe regions in consolidation of recognition memory. Anisomycin, a protein synthesis inhibitor, was infused into the hippocampus, perirhinal cortex, insular cortex, or basolateral amygdala of rats immediately after the sample phase of object or object-in-context recognition memory training. Anisomycin infused into perirhinal or insular cortices blocked long-term (24 h), but not short-term (90 min) object recognition memory. Infusions into the hippocampus or amygdala did not impair object recognition memory. Anisomycin infused into the hippocampus blocked long-term, but not short-term object-in-context recognition memory, whereas infusions administered into the perirhinal cortex, insular cortex, or amygdala did not affect object-in-context recognition memory. These results clearly indicate that distinct regions of the temporal lobe are differentially involved in long-term object and object-in-context recognition memory. Whereas perirhinal and insular cortices are required for consolidation of familiar objects, the hippocampus is necessary for consolidation of contextual information of recognition memory. Altogether, these results suggest that temporal lobe structures are differentially involved in recognition memory consolidation.

Individuals in preclinical and clinical stages of Huntington's disease (HD) demonstrate impairments in olfactory functioning. In addition, HD patients are impaired in source memory for verbal stimuli. A task combining both source and odor memory may be particularly sensitive to early changes in HD. The present study examined source and item memory for olfactory and visual stimuli in 10 individuals with HD, 10 asymptomatic HD gene carriers, 8 nongene carriers who had a parent with HD, and 20 normal controls. During the study phase, a male and a female experimenter (sources) presented odors and objects to the participant in an alternating sequence. To assess item memory, a stimulus from the study phase (target) and a novel stimulus (distractor) were presented, and the participant was asked to choose the target. To assess source memory, the experimenter presented a stimulus and asked whether the male or female experimenter had previously presented the stimulus. Results indicate that source memory for both visual and olfactory stimuli was impaired in HD patients compared to normal controls. In asymptomatic gene carriers, however, source memory for olfactory stimuli, but not visual stimuli, was more impaired than in nongene carriers and normal controls. Furthermore, gene carriers and HD patients showed a similar degree of impairment in source memory for olfactory stimuli. The only significant impairment found in item memory was for olfactory stimuli in HD patients. These results suggest that source memory for olfactory stimuli may be particularly sensitive to neuropathological changes in preclinical stages of HD.

Findings reported in the memory literature suggest that the emotional components of an encoding episode can be dissociated from nonemotional memory. In particular, it has been found that the previous association with threatening events can be retrieved in aversive conditioning even in the absence of item identification. In the present study, we test whether emotional source memory can be independent of item recognition. Participants saw pictures of snakes paired with threatening and nonthreatening context information (poisonousness or nonpoisonousness). In the source memory test, participants were required to remember whether a snake was associated with poisonousness or nonpoisonousness. A simple extension of a well-established multinomial source monitoring model was used to measure source memory for unrecognized items. By using this model, it was possible to assess directly whether participants were able to associate a previously seen snake with poisonousness or nonpoisonousness even if the snake itself was not recognized as having been presented during the experiment. In 3 experiments, emotional source memory was only found for recognized items. While source memory for recognized items differed between emotional and nonemotional information, source memory for unrecognized items was equally absent for emotional and nonemotional information. We conclude that emotional context information is bound to item representations and cannot be retrieved in the absence of item recognition. (PsycINFO Database Record

The present study examined the role of enactment in source memory in a cognitively impaired population. As seen in healthy older adults, it was predicted that source memory in people with mild cognitive impairment due to Alzheimer's disease (MCI-AD) would benefit from the self-reference aspect of enactment. Seventeen participants with MCI-AD and 18 controls worked in small groups to pack a picnic basket and suitcase and were later tested for their source memory for each item. For item memory, self-referencing improved corrected recognition scores for both MCI-AD and control participants. The MCI-AD group did not demonstrate the same benefit as controls in correct source memory for self-related items. However, those with MCI-AD were relatively less likely to misattribute new items to the self and more likely to misattribute new items to others when committing errors, compared with controls. The enactment effect and self-referencing did not enhance accurate source memory more than other referencing for patients with MCI-AD. However, people with MCI-AD benefited in item memory and source memory, being less likely to falsely claim new items as their own, indicating some self-reference benefit occurs for people with MCI-AD.

P3-081 Development of automated identification of cortical regions on MRI scans in AD patients

Functional connectivity based parcellation of the human medial temporal lobe