Representational formats of human memory traces.

Neural representations are internal brain states that constitute the brain's model of the external world or some of its features. In the presence of sensory input, a representation may reflect various properties of this input. When perceptual information is no longer available, the brain can still activate representations of previously experienced episodes due to the formation of memory traces. In this review, we aim at characterizing the nature of neural memory representations and how they can be assessed with cognitive neuroscience methods, mainly focusing on neuroimaging. We discuss how multivariate analysis techniques such as representational similarity analysis (RSA) and deep neural networks (DNNs) can be leveraged to gain insights into the structure of neural representations and their different representational formats. We provide several examples of recent studies which demonstrate that we are able to not only measure memory representations using RSA but are also able to investigate their multiple formats using DNNs. We demonstrate that in addition to slow generalization during consolidation, memory representations are subject to semantization already during short-term memory, by revealing a shift from visual to semantic format. In addition to perceptual and conceptual formats, we describe the impact of affective evaluations as an additional dimension of episodic memories. Overall, these studies illustrate how the analysis of neural representations may help us gain a deeper understanding of the nature of human memory.

Deep-brain stimulation of the human nucleus accumbens-medial septum enhances memory formation.

Deep-brain stimulation (DBS) is a potential novel treatment for memory dysfunction. Current attempts to enhance memory focus on stimulating human hippocampus or entorhinal cortex. However, an alternative strategy is to stimulate brain areas providing modulatory inputs to medial temporal memory-related structures, such as the nucleus accumbens (NAc), which is implicated in enhancing episodic memory encoding. Here, we show that NAc-DBS improves episodic and spatial memory in psychiatric patients. During stimulation, NAc-DBS increased the probability that infrequent (oddball) pictures would be subsequently recollected, relative to periods off stimulation. In a second experiment, NAc-DBS improved performance in a virtual path-integration task. An optimal electrode localization analysis revealed a locus spanning postero-medio-dorsal NAc and medial septum predictive of memory improvement across both tasks. Patient structural connectivity analyses, as well as NAc-DBS-evoked hemodynamic responses in a rat model, converge on a central role for NAc in a hippocampal-mesolimbic circuit regulating encoding into long-term memory. Thus, short-lived, phasic NAc electrical stimulation dynamically improved memory, establishing a critical on-line role for human NAc in episodic memory and providing an empirical basis for considering NAc-DBS in patients with loss of memory function.

Dissociating effects of aging and genetic risk of sporadic Alzheimer's disease on path integration.

Path integration is a spatial navigation ability that requires the integration of information derived from self-motion cues and stable landmarks, when available, to return to a previous location. Path integration declines with age and Alzheimer's disease (AD). Here, we sought to separate the effects of age and AD risk on path integration, with and without a landmark. Overall, 279 people participated, aged between 18 and 80 years old. Advanced age impaired the appropriate use of a landmark. Older participants furthermore remembered the location of the goal relative to their starting location and reproduced this initial view without considering that they had moved in the environment. This lack of adaptative behavior was not associated with AD risk. In contrast, participants at genetic risk of AD (apolipoprotein E ε4 carriers) exhibited a pure path integration deficit, corresponding to difficulty in performing path integration in the absence of a landmark. Our results show that advanced-age impacts landmark-supported path integration, and that this age effect is dissociable from the effects of AD risk impacting pure path integration.

Acute stress impairs visual path integration.

Acute stress exerts substantial effects on episodic memory, which are often mediated by glucocorticoids, the end-product of the hypothalamic-pituitary-adrenal axis. Surprisingly little is known, however, about the influence of acute stress on human spatial navigation. One specific navigational strategy is path integration, which is linked to the medial entorhinal cortex, a region harboring glucocorticoid receptors and thus susceptible for stress effects. Here, we investigated effects of acute stress on path integration performance using a virtual homing task. We divided a sample of healthy young male participants into a stress group (nstress = 32) and a control group (ncontrol = 34). The stress group underwent the socially evaluated cold-pressor test, while the control group underwent a non-stressful control procedure. Stress induction was confirmed via physiological and subjective markers, including an increase of salivary cortisol concentrations. We applied linear mixed models to investigate the effect of acute stress on path integration depending on task difficulty and the presence or absence of spatial cues. These analyses revealed that stress impaired path integration especially in trials with high difficulty and led to greater decline of performance upon removal of spatial cues. Stress-induced deficits were strongly related to impaired distance estimation, and to a lesser extent to compromised rotation estimation. These behavioral findings are in accordance with the hypothesis that acute stress impairs path integration processes, potentially by affecting the entorhinal grid cell system. More generally, the current data suggests acute stress to impair cognitive functions mediated by medial temporal lobe regions outside the hippocampus.

Chronic stress is associated with specific path integration deficits.

Repeated exposure to stress (chronic stress) can cause excess levels of circulating cortisol and has detrimental influences on various cognitive functions including long-term memory and navigation. However, it remains an open question whether chronic stress affects path integration, a navigational strategy that presumably relies on the functioning of grid cells in the medial entorhinal cortex. The entorhinal cortex is a brain region in the medial temporal lobe, which contains multiple cell types involved in spatial navigation (and episodic memory), and a high number of corticosteroid receptors, predisposing it as a potential target of cortisol effects. Here, our goal was to investigate the association between chronic stress and path integration performance. We assessed chronic stress via hair cortisol concentration (physiological measure) and the Perceived Stress Questionnaire (subjective measure) in 52 female participants aged 22-65 years. Path integration was measured using a virtual homing task. Linear mixed models revealed selective impairments associated with chronic stress that depended on error type and environmental features. When focusing on distance estimations in the path integration task, we observed a significant relationship to hair cortisol concentrations indicating impaired path integration particularly during trials with higher difficulty in participants with high hair cortisol concentrations. This relationship especially emerged in the absence of spatial cues (a boundary or a landmark), and particularly in participants who reported high levels of subjectively experienced chronic stress. The findings are in line with the hypothesis that chronic stress compromises path integration, possibly via an effect on the entorhinal grid cell system.

The memory trace of a stressful episode.

Stress influences episodic memory formation via noradrenaline and glucocorticoid effects on amygdala and hippocampus. A common finding is the improvement of memory for central aspects of a stressful episode. This is putatively related to changes in the neural representations of specific experiences, i.e., their memory traces. Here we show that the memory improvement for objects that were encountered in a stressful episode relates to differences in the neural representations of these objects in the amygdala. Using functional magnetic resonance imaging, we found that stress specifically altered the representations of central objects: compared to control objects, they became more similar to one another and more distinct from objects that were not part of this episode. Furthermore, higher similarity of central objects to the main stressor-the faces of the stress-inducing committee members-predicted better memory. This suggests that the central objects were closely integrated into a stressor-centered memory representation. Our findings provide mechanistic insights into how stress shapes the memory trace and have profound implications for neurocognitive models of stressful and emotional memory.

Unmasking selective path integration deficits in Alzheimer's disease risk carriers.

Alzheimer's disease (AD) manifests with progressive memory loss and spatial disorientation. Neuropathological studies suggest early AD pathology in the entorhinal cortex (EC) of young adults at genetic risk for AD (APOE ε4-carriers). Because the EC harbors grid cells, a likely neural substrate of path integration (PI), we examined PI performance in APOE ε4-carriers during a virtual navigation task. We report a selective impairment in APOE ε4-carriers specifically when recruitment of compensatory navigational strategies via supportive spatial cues was disabled. A separate fMRI study revealed that PI performance was associated with the strength of entorhinal grid-like representations when no compensatory strategies were available, suggesting grid cell dysfunction as a mechanistic explanation for PI deficits in APOE ε4-carriers. Furthermore, posterior cingulate/retrosplenial cortex was involved in the recruitment of compensatory navigational strategies via supportive spatial cues. Our results provide evidence for selective PI deficits in AD risk carriers, decades before potential disease onset.

Hippocampal theta phases organize the reactivation of large-scale electrophysiological representations during goal-directed navigation.

Humans are adept in simultaneously following multiple goals, but the neural mechanisms for maintaining specific goals and distinguishing them from other goals are incompletely understood. For short time scales, working memory studies suggest that multiple mental contents are maintained by theta-coupled reactivation, but evidence for similar mechanisms during complex behaviors such as goal-directed navigation is scarce. We examined intracranial electroencephalography recordings of epilepsy patients performing an object-location memory task in a virtual environment. We report that large-scale electrophysiological representations of objects that cue for specific goal locations are dynamically reactivated during goal-directed navigation. Reactivation of different cue representations occurred at stimulus-specific hippocampal theta phases. Locking to more distinct theta phases predicted better memory performance, identifying hippocampal theta phase coding as a mechanism for separating competing goals. Our findings suggest shared neural mechanisms between working memory and goal-directed navigation and provide new insights into the functions of the hippocampal theta rhythm.