Implications of animal object memory research for human amnesia

Damage to structures in the human medial temporal lobe causes severe memory impairment. Animal object recognition tests gained prominence from attempts to model ‘global’ human medial temporal lobe amnesia, such as that observed in patient HM. These tasks, such as delayed nonmatching-to-sample and spontaneous object recognition, for assessing object memory in non-human primates and rodents have proved invaluable as animal models of specific aspects of human declarative memory processes. This paper reviews research in non-human primates and rats using object recognition memory tasks to assess the neurobiological bases of amnesia. A survey of this research reveals several important implications for our understanding of the anatomical basis of memory and the medial temporal lobe amnesic syndrome. First, research with monkeys and rats reveals that the contributions of medial temporal lobe structures such as the hippocampus and perirhinal cortex to memory processes are dissociable, with particular structures contributing to specific tasks on the basis of the specific type of information that a structure is optimized to process. Second, the literature suggests that cognitive tasks requiring integration of different types of information, such as in the case of complex, multimodal declarative memory, will recruit structures of the medial temporal lobe in an interactive manner. The heterogeneity of function within the medial temporal lobe, as well as the multimodal and complex nature of human declarative memory, implies that animal tests of object recognition memory, once believed to be comprehensive models for the study of human global amnesia, model just one important facet of human declarative memory. Finally, in light of the research reviewed here, it is apparent that the specific nature of amnesia observed in an individual with medial temporal lobe damage will depend on the particular medial temporal lobe regions affected and their specific representational capacities.     

The representational-hierarchical view of amnesia: Translation from animal to human

Animal research has, in our opinion, made an invaluable contribution to our understanding of human amnesia. In this article we summarise our and others’ work in this area, focusing on a new view of amnesia we refer to as the representational-hierarchical view. According to this view—and in contrast to the prevailing paradigm in the field—the brain is best understood as a hierarchically organized continuum of representations, each of which is useful for a variety of cognitive functions. We focus our review on four visual discrimination paradigms that have been successfully translated into the human arena: configural concurrent discriminations, pair-wise “morph” discriminations, oddity discriminations, and configural oddity discriminations. The data from the animal studies are first reviewed, followed by illustrations of how the tasks have been utilized in human research. We then turn to the canonical impairment in animal models of amnesia, object recognition, and show how impairments in object recognition can be understood within the representational-hierarchical framework. This is followed by a discussion of predictions of the view related to classic issues in amnesia research, namely whether amnesia is due to a deficit of encoding, storage or retrieval, and the related issue of the role of interference in amnesia. Finally, we provide evidence from animal and human studies that even the hippocampus—almost universally regarded as a module for memory—may be better understood within the representational-hierarchical paradigm.     

KIBRA and CLSTN2 polymorphisms exert interactive effects on human episodic memory

Individual differences in episodic memory are highly heritable. Several studies have linked a polymorphism in the gene encoding the KIBRA protein to episodic memory performance. Results regarding CLSTN2, the gene encoding the synaptic protein calsyntenin 2, have been less consistent, possibly pointing to interactions with other genes. Given that both KIBRA and CLSTN2 are expressed in the medial temporal lobe and have been linked to synaptic plasticity, we investigated whether KIBRA and CLSTN2 interactively modulate episodic memory performance (n = 383). We replicated the beneficial effect of the KIBRA T-allele on episodic memory, and discovered that this effect increases with the associative demands of the memory task. Importantly, the memory-enhancing effect of the KIBRA T-allele was boosted by the presence of the CLSTN2 C-allele, which positively affected memory performance in some previous studies. In contrast, the presence of CLSTN2 C-allele led to reduced performance in subjects homozygous for the KIBRA C-allele. Overall, these findings suggest that KIBRA and CLSTN2 interactively modulate episodic memory performance, and underscore the need for delineating the interactive effects of multiple genes on brain and behavior.     

Recognition memory for faces and scenes in amnesia: dissociable roles of medial temporal lobe structures

The relative contributions of the hippocampus and the perirhinal cortex to recognition memory are currently the subject of intense debate. Whereas some authors propose that both structures play a similar role in recognition memory, others suggest that the hippocampus might mediate recollective and/or associative aspects of recognition memory, whereas the perirhinal cortex may mediate item memory. Here we investigate an alternative functional demarcation between these structures, following reports of stimulus-specific perceptual deficits in amnesics with medial temporal lobe (MTL) lesions. Using a novel recognition memory test for faces and scenes, participants with broad damage to MTL structures, which included the hippocampus and the perirhinal cortex, were impaired on both face and scene memory. By contrast, participants with damage limited to the hippocampus showed deficits only in memory for scenes. These findings imply that although both the hippocampus and surrounding cortex contribute to recognition memory, their respective roles can be distinguished according to the type of material to be remembered. This interaction between lesion site and stimulus category may explain some of the inconsistencies present in the literature.     

Role of the medial temporal lobes in relational memory: neuropsychological evidence from a cued recognition paradigm

In this study, we examined the role of the hippocampus in relational memory by comparing item recognition performance in amnesic patients with medial temporal lobe (MTL) damage and their matched controls. Specifically, we investigated the contribution of associative memory to item recognition using a cued recognition paradigm. Control subjects studied cue-target pairs once, whereas amnesic patients studied cue-target pairs six times. Following study, subjects made recognition judgments about targets that were presented either alone (no cue), with the originally presented cue (same cue), or with a cue that had been presented with a different target (recombined cue). Controls had higher recognition scores in the same cue than in the recombined cue condition, indicating that they benefited from the associative information provided by the same cue. By contrast, amnesic patients did not. This was true even for a subgroup of patients whose recognition performance in the no cue condition was matched to that of the controls. These data provide further support for the idea that the hippocampus plays a critical role in relational memory, even when associative information need not be retrieved intentionally.     

Reward mechanisms in the brain and their role in dependence: evidence from neurophysiological and neuroimaging studies

This article reviews neuronal activity related to reward processing in primate and human brains. In the primate brain, neurophysiological methods provide a differentiated view of reward processing in a limited number of brain structures. Dopamine neurons respond to unpredictable rewards and produce a global reinforcement signal. Some neurons in the striatum also react to the expectation and detection of reward. Other striatal neurons show reward-related activities related to the preparation, initiation and execution of movement. Orbitofrontal neurons discriminate among different rewards and code reward preferences. In the human brain, regions belonging to a meso-striatal and meso-corticolimbic loop respond to reinforcement stimuli in control subjects. These observations corroborate results obtained in primates. Additionally, reward induces activation in regions specific to task performance. Our results also show a similar pattern of reward-related activation in nicotine and opiate addicts. Thus, in contrast to healthy subjects, typical reward-related regions respond in addicts to monetary reward but not to nonmonetary reinforcement. Reduced activation in performance-related regions is also observed in both groups of dependent subjects. The results of animal and human studies suggest that dopamine and dopamine-related regions are associated with the integration of motivational information and movement execution. Dopamine-related pathological disorders can be associated with movement disorders, such as Parkinson’s disease or with false motivational attributions such as drug dependence.     

Stress and the engagement of multiple memory systems: Integration of animal and human studies

Learning and memory can be controlled by distinct memory systems. How these systems are coordinated to optimize learning and behavior has long been unclear. Accumulating evidence indicates that stress may modulate the engagement of multiple memory systems. In particular, rodent and human studies demonstrate that stress facilitates dorsal striatum‐dependent “habit” memory, at the expense of hippocampus‐dependent “cognitive” memory. Based on these data, a model is proposed which states that the impact of stress on the relative use of multiple memory systems is due to (i) differential effects of hormones and neurotransmitters that are released during stressful events on hippocampal and dorsal striatal memory systems, thus changing the relative strength of and the interactions between these systems, and (ii) a modulatory influence of the amygdala which biases learning toward dorsal striatum‐based memory after stress. This shift to habit memory after stress can be adaptive with respect to current performance but might contribute to psychopathology in vulnerable individuals. © 2013 Wiley Periodicals, Inc.     

Automated and manual segmentation of the hippocampus in human infants

The hippocampus, critical for learning and memory, undergoes substantial changes early in life. Investigating the developmental trajectory of hippocampal structure and function requires an accurate method for segmenting this region from anatomical MRI scans. Although manual segmentation is regarded as the “gold standard” approach, it is laborious and subjective. This has fueled the pursuit of automated segmentation methods in adults. However, little is known about the reliability of these automated protocols in infants, particularly when anatomical scan quality is degraded by head motion or the use of shorter and quieter infant-friendly sequences. During a task-based fMRI protocol, we collected quiet T1-weighted anatomical scans from 42 sessions with awake infants aged 4–23 months. Two expert tracers first segmented the hippocampus in both hemispheres manually. The resulting inter-rater reliability (IRR) was only moderate, reflecting the difficulty of infant segmentation. We then used four protocols to predict these manual segmentations: average adult template, average infant template, FreeSurfer software, and Automated Segmentation of Hippocampal Subfields (ASHS) software. ASHS generated the most reliable hippocampal segmentations in infants, exceeding the manual IRR of experts. Automated methods thus provide robust hippocampal segmentations of noisy T1-weighted infant scans, opening new possibilities for interrogating early hippocampal development.     

Understanding medial temporal activation in memory tasks: evidence from fMRI of encoding and recognition in a case of transient global amnesia

We used fMRI to examine the activation patterns of patient AE during encoding and recognition of visual scenes during an episode of transient global amnesia (TGA) and 3 months later. Controls (n = 5) showed bilateral (R > L) activation in parahippocampal and fusiform gyri during encoding and right-sided activation in the same regions associated with recognition of previously viewed scenes. AE showed a similar pattern at follow-up. During acute TGA, when performance was profoundly impaired, AE showed no medial temporal activation associated with encoding of new scenes or recognition of old scenes. In both contrasts, the percent signal change in relevant medial temporal regions was more than three standard deviations below the control sample mean. She did, however, show striking bilateral hippocampal activation for recognition attempts (old + new scenes > baseline) even though retrieval was unsuccessful (55% recognition accuracy). This finding was unique to AE on this occasion. This is the first study to document normalization of both encoding and recognition activation patterns in TGA. Furthermore, the strong hippocampal activation during unsuccessful retrieval highlights important issues in interpreting memory-related activations, particularly in dysfunctional systems.     

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.     

Development of cognitive control and executive functions from 4 to 13 years: evidence from manipulations of memory, inhibition, and task switching

Predictions concerning development, interrelations, and possible independence of working memory, inhibition, and cognitive flexibility were tested in 325 participants (roughly 30 per age from 4 to 13 years and young adults; 50% female). All were tested on the same computerized battery, designed to manipulate memory and inhibition independently and together, in steady state (single-task blocks) and during task-switching, and to be appropriate over the lifespan and for neuroimaging (fMRI). This is one of the first studies, in children or adults, to explore: (a) how memory requirements interact with spatial compatibility and (b) spatial incompatibility effects both with stimulus-specific rules (Simon task) and with higher-level, conceptual rules. Even the youngest children could hold information in mind, inhibit a dominant response, and combine those as long as the inhibition required was steady-state and the rules remained constant. Cognitive flexibility (switching between rules), even with memory demands minimized, showed a longer developmental progression, with 13-year-olds still not at adult levels. Effects elicited only in Mixed blocks with adults were found in young children even in single-task blocks; while young children could exercise inhibition in steady state it exacted a cost not seen in adults, who (unlike young children) seemed to re-set their default response when inhibition of the same tendency was required throughout a block. The costs associated with manipulations of inhibition were greater in young children while the costs associated with increasing memory demands were greater in adults. Effects seen only in RT in adults were seen primarily in accuracy in young children. Adults slowed down on difficult trials to preserve accuracy; but the youngest children were impulsive; their RT remained more constant but at an accuracy cost on difficult trials. Contrary to our predictions of independence between memory and inhibition, when matched for difficulty RT correlations between these were as high as 0.8, although accuracy correlations were less than half that. Spatial incompatibility effects and global and local switch costs were evident in children and adults, differing only in size. Other effects (e.g., asymmetric switch costs and the interaction of switching rules and switching response-sites) differed fundamentally over age.     

A compensatory role for declarative memory in neurodevelopmental disorders

Most research on neurodevelopmental disorders has focused on their abnormalities. However, what remains intact may also be important. Increasing evidence suggests that declarative memory, a critical learning and memory system in the brain, remains largely functional in a number of neurodevelopmental disorders. Because declarative memory remains functional in these disorders, and because it can learn and retain numerous types of information, functions, and tasks, this system should be able to play compensatory roles for multiple types of impairments across the disorders. Here, we examine this hypothesis for specific language impairment, dyslexia, autism spectrum disorder, Tourette syndrome, and obsessive–compulsive disorder. We lay out specific predictions for the hypothesis and review existing behavioral, electrophysiological, and neuroimaging evidence. Overall, the evidence suggests that declarative memory indeed plays compensatory roles for a range of impairments across all five disorders. Finally, we discuss diagnostic, therapeutic and other implications.