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.

Numerous animal studies have demonstrated that fear acquisition and expression rely on the coordinated activity of medial prefrontal cortex (mPFC) and amygdala and that theta oscillations support interregional communication within the fear network. However, it remains unclear whether these results can be generalized to fear learning in humans. We addressed this question using intracranial electroencephalography recordings in 13 patients with epilepsy during a fear conditioning paradigm. We observed increased power and inter-regional synchronization of amygdala and mPFC in theta (4 to 8 hertz) oscillations for conditioned stimulus (CS+) versus CS−. Analysis of information flow revealed that the dorsal mPFC (dmPFC) led amygdala activity in theta oscillations. Last, a computational model showed that trial-by-trial changes in amygdala theta oscillations predicted the model-based associability (i.e., learning rate). This study provides compelling evidence that theta oscillations within and between amygdala, ventral mPFC, and dmPFC constitute a general mechanism of fear learning across species.

We explored whether object behavioral priming and pupil changes occur in the absence of recognition memory. Experiment 1 found behavioral priming for unrecognized objects (Ms) regardless of whether they had been encoded perceptually or conceptually. Using the same perceptual encoding task, Experiment 2 showed greater pupil dilation for Ms than for correct rejections of unstudied objects (CRs) when reaction times were matched. In Experiment 3, there was relatively less pupil dilation for Ms than for similarly matched CRs when objects had been encoded conceptually. Mean/peak pupil dilation for CRs, but not Ms, increased in Experiment 3, in which novelty expectation was also reduced, and the pupillary time course for both Ms and CRs was distinct in the two experiments. These findings indicate that both behavioral and pupil memory occur for studied, but unrecognized stimuli, and suggest that encoding and novelty expectation modulate pupillary memory responses.

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, suggesting grid cell dysfunction as a mechanistic explanation for PI deficits in APOE ϵ4-carriers. Furthermore, 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.

The neural substrates of associative and item priming and recognition were investigated in a functional magnetic resonance imaging study over two separate sessions. In the priming session, participants decided which object of a pair was bigger during both study and test phases. In the recognition session, participants saw different object pairs and performed the same size-judgement task followed by an associative recognition memory task. Associative priming was accompanied by reduced activity in the right middle occipital gyrus as well as in bilateral hippocampus. Object item priming was accompanied by reduced activity in extensive priming-related areas in the bilateral occipitotemporofrontal cortex, as well as in the perirhinal cortex, but not in the hippocampus. Associative recognition was characterized by activity increases in regions linked to recollection, such as the hippocampus, posterior cingulate cortex, anterior medial frontal gyrus and posterior parahippocampal cortex. Item object priming and recognition recruited broadly overlapping regions (e.g., bilateral middle occipital and prefrontal cortices, left fusiform gyrus), even though the BOLD response was in opposite directions. These regions along with the precuneus, where both item priming and recognition were accompanied by activation, have been found to respond to object familiarity. The minimal structural overlap between object associative priming and recollection-based associative recognition suggests that they depend on largely different stimulus-related information and that the different directions of the effects indicate distinct retrieval mechanisms. In contrast, item priming and familiarity-based recognition seemed mainly based on common memory information, although the extent of common processing between priming and familiarity remains unclear. Further implications of these findings are discussed.

We investigated how the information that supports novel associative and item object priming differs under identical study/test conditions. In Experiments 1 and 2, participants rated the meaningfulness of sentences linking two object pictures at study. At test, they performed either a size judgement or an associative recognition memory task on intact, recombined and novel picture (Experiment 1) or word (Experiment 2) associations. Associative priming was modulated by subjective meaningfulness of the encoded links, and depended on study/test perceptual overlap. In contrast, item priming was neither affected by the meaningfulness of the sentences nor by study/test changes in the stimulus presentation format. Associative priming and recognition were behaviourally dissociated, and associative recognition was probably too slow to have seriously contaminated associative priming. In Experiment 3, participants performed a perceptually oriented task during both experimental phases, and both associative and item priming were observed. These results suggest that associative priming depends on stored associative semantic and perceptual information when the test task requires flexible retrieval of associative information. Under the same conditions, item priming may only require activation of items' semantic properties. When both study and test tasks stress perceptual processing, retrieval of perceptual information is sufficient to support both kinds of priming.

Recognition memory judgments can be influenced by a variety of signals including fluency. Here, we investigated whether the neural correlates of memory illusions (i.e., misattribution of fluency to prior study) can be modulated by fluency context. Using a masked priming/recognition memory paradigm, we found memory illusions for low confidence decisions. When fluency varied randomly across trials, we found reductions in perirhinal cortex (PrC) activity for primed trials, as well as a (pre)cuneus-PrC (BA 35) connectivity. When the fluency context was unchanging, there was increased PrC activity for primed trials, with the (pre)cuneus showing greater connectivity with PrC (BA 36). Thus, our results tentatively suggest two neural mechanisms via which fluency can lead to memory illusions.

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