Sandra N. Moses

The hippocampus supports multiple cognitive processes through relational binding and comparison.

It has been well established that the hippocampus plays a pivotal role in explicit long-term recognition memory. However, findings from amnesia, lesion and recording studies with non-human animals, eye-movement recording studies, and functional neuroimaging have recently converged upon a similar message: the functional reach of the hippocampus extends far beyond explicit recognition memory. Damage to the hippocampus affects performance on a number of cognitive tasks including recognition memory after short and long delays and visual discrimination. Additionally, with the advent of neuroimaging techniques that have fine spatial and temporal resolution, findings have emerged that show the elicitation of hippocampal responses within the first few 100 ms of stimulus/task onset. These responses occur for novel and previously viewed information during a time when perceptual processing is traditionally thought to occur, and long before overt recognition responses are made. We propose that the hippocampus is obligatorily involved in the binding of disparate elements across both space and time, and in the comparison of such relational memory representations. Furthermore, the hippocampus supports relational binding and comparison with or without conscious awareness for the relational representations that are formed, retrieved and/or compared. It is by virtue of these basic binding and comparison functions that the reach of the hippocampus extends beyond long-term recognition memory and underlies task performance in multiple cognitive domains.

A complementary analytic approach to examining medial temporal lobe sources using magnetoencephalography

Neuropsychological and neuroimaging findings reveal that the hippocampus is important for recognition memory. However, it is unclear when and whether the hippocampus contributes differentially to recognition of previously studied items (old) versus novel items (new), or contributes to a general processing requirement that is necessary for recognition of both types of information. To address this issue, we examined the temporal dynamics and spectral frequency underlying hippocampal activity during recognition of old/new complex scenes using magnetoencephalography (MEG). In order to provide converging evidence to existing literature in support of the potential of MEG to localize the hippocampus, we reconstructed brain source activity using the beamformer method and analyzed three types of processing-related signal changes by applying three different analysis methods: (1) Synthetic aperture magnetometry (SAM) revealed event related and non-event-related spectral power changes; (2) Inter-trial coherence (ITC) revealed time-locked changes in neural synchrony; and (3) Event-related SAM (ER-SAM) revealed averaged event-related responses over time. Hippocampal activity was evident for both old and new information within the theta frequency band and during the first 250 ms following stimulus onset. The early onset of hippocampal responses suggests that general comparison processes related to recognition of new/old information may occur obligatorily.

Differential involvement of amygdala and hippocampus in responding to novel objects and contexts

Different medial temporal lobe structures are involved in memory for different types of novel cues and novel relationships among familiar cues. We measured the behavior of rats with amygdala or hippocampal damage, when confronted with novelty in an incidental learning paradigm. We examined both direct and indirect measures of memory. Following habituation to an environment, proximal objects or distal cues were manipulated in several ways. We found that rats with hippocampal damage exhibited a deficit on direct measures of memory, but performed normally on all indirect measures. Rats with amygdala damage exhibited a deficit on a direct measure, and performed normally on an indirect measure, of memory for proximal object identity. Thus, the hippocampus may be necessary for success on direct measures of memory for distal cues and proximal objects and the relationships among them. Likewise, the amygdala may be necessary for success on some direct measures of memory, such as memory for aspects of proximal object identity. Neither the amygdala nor the hippocampus functions as a generalized novelty detection system. To the extent that we tap implicit and explicit knowledge using this paradigm, we suggest that in the rat, the amygdala and hippocampal systems are necessary for at least some types of explicit knowledge.

Semantic information alters neural activation during transverse patterning performance.

Memory tasks can be performed using multiple cognitive strategies, which are mediated by different brain systems. The transverse patterning (TP) task is dependent upon the integrity of the hippocampal system, however, we previously demonstrated successful TP following hippocampal damage using meaningful stimuli and relations (Moses, S.N., Ostreicher, M.L., Rosenbaum, R.S., Ryan, J.D., 2008. Successful transverse patterning in amnesia using semantic knowledge. Hippocampus 18, 121-124). Here, we used magnetoencephalgraphy (MEG) to directly observe the neural underpinnings of TP, and the changes that occur as stimuli and relations become more meaningful. In order to optimize our ability to detect signal from deep, non-dominant, brain sources we implemented the event-related synthetic aperture magnetometry minimum-variance beamformer algorithm (ER-SAM; Cheyne, D., Bakhtazad, L., Gaetz, W., 2006. Spatiotemporal mapping of cortical activity accompanying voluntary movements using an event-related beamforming approach. Human Brain Mapping 27, 213-229) coupled with the partial least squares (PLS) multivariate statistical approach (McIntosh, A.R., Bookstein, F.L., Haxby, J.V., Grady, C.L., 1996. Spatial pattern analysis of function brain images using partial least squares. NeuroImage 3, 143-157; McIntosh, A.R., Lobaugh, N.J., 2004. Partial least squares analysis of neuroimaging data: Applications and advances. NeuroImage 23, S250-S263). We found that increased meaningfulness elicited reduced bilateral hippocampal activation, along with increased activation of left prefrontal and temporal cortical structures, including inferior frontal (IFG), as well as anterior temporal and perirhinal cortices. These activation patterns may represent a shift towards reliance upon existing semantic knowledge. This shift likely permits successful TP performance with meaningful stimuli and relations following hippocampal damage.

Techniques for Detection and Localization of Weak Hippocampal and Medial Frontal Sources Using Beamformers in MEG

Magnetoencephalography provides precise information about the temporal dynamics of brain activation and is an ideal tool for investigating rapid cognitive processing. However, in many cognitive paradigms visual stimuli are used, which evoke strong brain responses (typically 40–100xa0nAm in V1) that may impede the detection of weaker activations of interest. This is particularly a concern when beamformer algorithms are used for source analysis, due to artefacts such as “leakage” of activation from the primary visual sources into other regions. We have previously shown (Quraan et al. 2011) that we can effectively reduce leakage patterns and detect weak hippocampal sources by subtracting the functional images derived from the experimental task and a control task with similar stimulus parameters. In this study we assess the performance of three different subtraction techniques. In the first technique we follow the same post-localization subtraction procedures as in our previous work. In the second and third techniques, we subtract the sensor data obtained from the experimental and control paradigms prior to source localization. Using simulated signals embedded in real data, we show that when beamformers are used, subtraction prior to source localization allows for the detection of weaker sources and higher localization accuracy. The improvement in localization accuracy exceeded 10xa0mm at low signal-to-noise ratios, and sources down to below 5xa0nAm were detected. We applied our techniques to empirical data acquired with two different paradigms designed to evoke hippocampal and frontal activations, and demonstrated our ability to detect robust activations in both regions with substantial improvements over image subtraction. We conclude that removal of the common-mode dominant sources through data subtraction prior to localization further improves the beamformer’s ability to project the n-channel sensor-space data to reveal weak sources of interest and allows more accurate localization.

Impaired relational organization of propositions, but intact transitive inference, in aging: Implications for understanding underlying neural integrity

The ability to perform relational proposition-based reasoning was assessed in younger and older adults using the transitive inference task in which subjects learned a series of premise pairs (A>B, B>C, C>D, D>E, E>F) and were asked to make inference judgments (B?D, B?E, C?E). Learning of premise pairs was related to subsequent inference performance and conscious awareness of the stimulus hierarchy (A>B>C>D>E>F). Despite extended training, age-related deficits were observed for response times, accurate learning of the premise pairs, making inference judgments, and articulating the hierarchy. When performance for younger and older adults was examined with respect to whether they were subsequently considered aware of the hierarchy, older and younger adults still significantly differed on their accuracy for studied premise pairs, but performance between the age groups was similar for the inference pairs. Successful transitive inference performance is contingent upon the relational organization of propositions within memory and such processes are impaired in aging, potentially leading to disruptions in conscious access to the stimulus hierarchy. Such findings, in concert with previous neuropsychological and neuroimaging studies, implicate an age-related deficit in the functioning of frontal and medial temporal lobe structures, with particular emphasis on the hippocampus.

Prior Experience Supports New Learning of Relations in Aging

This work examined whether semantically relevant schemas could facilitate learning in the transverse patterning (TP) task, which requires participants to learn the value of each stimulus in relation to the stimulus with which it is paired (e.g., A wins over B, B wins over C, C wins over A). Younger and older adults received the standard TP in isolation (alone condition), with additional sessions (practice condition), or with 2 TP sessions, which used familiar stimuli with known relations (e.g., rock-paper-scissors, semantic condition). Accuracy improved when training was provided within the context of a previously known relational framework, beyond the benefits obtained with extended practice with the task. When levels of education and vocabulary scores were considered as covariates, age-related deficits in accuracy were observed in the alone and practice conditions but were eliminated in the semantic condition. Extended practice and appealing to prior knowledge improved explicit awareness for the stimulus contingencies for each age-group. Thus, age-related deficits in learning relations among items may be remediated using existing relational information within semantic memory as an analog for new learning.

Relational framework improves transitive inference across age groups

Transitive inference is a complex task, conducive to the use of multiple strategies. We investigated whether transitive inference accuracy can be improved by biasing strategy choice towards a proposition-based approach that relies on the extraction of relations among stimuli. We biased strategy choice by using familiar stimuli with known relations that tap prior knowledge. Semantic information led to increased accuracy for younger and older adults, and increased awareness of stimulus relations. Increased age was associated with reduced awareness. Awareness accounted for the variability in performance accuracy to a greater extent than age, as aware older and younger adults showed similar accuracies on all conditions. The current work indicates that age differences in performance can be minimized by providing semantically meaningful stimuli that bias participants to use a relational proposition-based approach.

Relational learning and transitive expression in aging and amnesia

Aging has been associated with a decline in relational memory, which is critically supported by the hippocampus. By adapting the transitivity paradigm (Bunsey and Eichenbaum (1996) Nature 379:255‐257), which traditionally has been used in nonhuman animal research, this work examined the extent to which aging is accompanied by deficits in relational learning and flexible expression of relational information. Older adults performance was additionally contrasted with that of amnesic case DA to understand the critical contributions of the medial temporal lobe, and specifically, the hippocampus, which endures structural and functional changes in healthy aging. Participants were required to select the correct choice item (B versus Y) based on the presented sample item (e.g., A). Pairwise relations must be learned (A‐>B, B‐>C, C‐>D) so that ultimately, the correct relations can be inferred when presented with a novel probe item (A‐>C?Z?). Participants completed four conditions of transitivity that varied in terms of the degree to which the stimuli and the relations among them were known pre‐experimentally. Younger adults, older adults, and DA performed similarly when the condition employed all pre‐experimentally known, semantic, relations. Older adults and DA were less accurate than younger adults when all to‐be‐learned relations were arbitrary. However, accuracy improved for older adults when they could use pre‐experimentally known pairwise relations to express understanding of arbitrary relations as indexed through inference judgments. DA could not learn arbitrary relations nor use existing knowledge to support novel inferences. These results suggest that while aging has often been associated with an emerging decline in hippocampal function, prior knowledge can be used to support novel inferences. However, in case DA, significant damage to the hippocampus likely impaired his ability to learn novel relations, while additional damage to ventromedial prefrontal and anterior temporal regions may have resulted in an inability to use prior knowledge to flexibly express indirect relational knowledge.

Dynamic Imaging of Deep Brain Structures with MEG: Contributions to Understanding Human Memory

Sandra N. Moses1,2,3, Faith M. Hanlon4,5 and Jennifer D. Ryan3,6,7 1Department of Diagnostic Imaging, Hospital for Sick Children, Toronto, 2Department of Medical Imaging, University of Toronto, Toronto, 3Rotman Research Institute, Baycrest, Toronto, 4The Mind Research Network, Albuquerque, NM, 5Department of Psychology, University of New Mexico, Albuquerque, NM, 6Department of Psychology, University of Toronto, Toronto, 7Department of Psychiatry, University of Toronto, Toronto, 1,2,3,6,7Canada 4,5USA