Acute Angiotensin II Receptor Blockade Facilitates Parahippocampal Processing During Memory Encoding in High-Trait-Anxious Individuals.

Background: Angiotensin II receptor blockers (ARBs) have been associated with preventing posttraumatic stress disorder symptom development and improving memory. However, the underlying neural mechanisms are poorly understood. This study investigated ARB effects on memory encoding and hippocampal functioning that have previously been implicated in posttraumatic stress disorder development. Methods: In a double-blind randomized design, 40 high-trait-anxious participants (33 women) received the ARB losartan (50 mg) or placebo. At drug peak level, participants encoded images of animals and landscapes before undergoing functional magnetic resonance imaging, where they viewed the encoded familiar images and unseen novel images to be memorized and classified as animals/landscapes. Memory recognition was assessed 1 hour after functional magnetic resonance imaging. To analyze neural effects, whole-brain analysis, hippocampus region-of-interest analysis, and exploratory multivariate pattern similarity analysis were employed. Results: ARBs facilitated parahippocampal processing. In the whole-brain analysis, losartan enhanced brain activity for familiar images in the parahippocampal gyrus (PHC), anterior cingulate cortex, and caudate. For novel images, losartan enhanced brain activity in the PHC only. Pattern similarity analysis showed that losartan increased neural stability in the PHC when processing novel and familiar images. However, there were no drug effects on memory recognition or hippocampal activation. Conclusions: Given that the hippocampus receives major input from the PHC, our findings suggest that ARBs may modulate higher-order visual processing through parahippocampal involvement, potentially preserving intact memory input. Future research needs to directly investigate whether this effect may underlie the preventive effects of ARBs in the development of posttraumatic stress disorder.

Age differences in neural distinctiveness during memory encoding, retrieval, and reinstatement.

Robust evidence points to mnemonic deficits in older adults related to dedifferentiated, i.e. less distinct, neural responses during memory encoding. However, less is known about retrieval-related dedifferentiation and its role in age-related memory decline. In this study, younger and older adults were scanned both while incidentally learning face and house stimuli and while completing a surprise recognition memory test. Using pattern similarity searchlight analyses, we looked for indicators of neural dedifferentiation during encoding, retrieval, and encoding-retrieval reinstatement. Our findings revealed age-related reductions in neural distinctiveness during all memory phases in visual processing regions. Interindividual differences in retrieval- and reinstatement-related distinctiveness were strongly associated with distinctiveness during memory encoding. Both item- and category-level distinctiveness predicted trial-wise mnemonic outcomes. We further demonstrated that the degree of neural distinctiveness during encoding tracked interindividual variability in memory performance better than both retrieval- and reinstatement-related distinctiveness. All in all, we contribute to meager existing evidence for age-related neural dedifferentiation during memory retrieval. We show that neural distinctiveness during retrieval is likely tied to recapitulation of encoding-related perceptual and mnemonic processes.

Age-related declines in neural selectivity manifest differentially during encoding and recognition.

One important factor contributing to age-related memory decline is the loss of distinctiveness with which information is represented in brain activity. This loss in neural selectivity may be driven by neural attenuation (i.e., reduced activation to target stimuli) or neural broadening (i.e., increased activation to nontarget stimuli). In this fMRI study, we assessed age differences in neural selectivity during first encoding, repeated encoding, and recognition, as well as the underlying pattern (broadening vs. attenuation). We found lower neural selectivity in older compared to younger adults during all memory stages. Crucially, while reduced selectivity in older adults was due to neural broadening during first encoding, it was driven by neural attenuation during recognition, but revealed no clear pattern during repeated encoding. Our findings suggest that intrinsic differences between memory stages may interact with neural activity to manifest as either neural broadening or attenuation. Moreover, despite these differential patterns, neural selectivity was highly correlated across memory stages, indicating that one common mechanism may underly distinct expressions of age-related neural dedifferentiation.

Tracking Age Differences in Neural Distinctiveness across Representational Levels.

The distinctiveness of neural information representation is crucial for successful memory performance but declines with advancing age. Computational models implicate age-related neural dedifferentiation on the level of item representations, but previous studies mostly focused on age differences of categorical information representation in higher-order visual regions. In an age-comparative fMRI study, we combined univariate analyses and whole-brain searchlight pattern similarity analyses to elucidate age differences in neural distinctiveness at both category and item levels and their relation to memory. Thirty-five younger (18-27 years old) and 32 older (67-75 years old) women and men incidentally encoded images of faces and houses, followed by an old/new recognition memory task. During encoding, age-related neural dedifferentiation was shown as reduced category-selective processing in ventral visual cortex and impoverished item specificity in occipital regions. Importantly, successful subsequent memory performance built on high item stability, that is, high representational similarity between initial and repeated presentation of an item, which was greater in younger than older adults. Overall, we found that differences in representational distinctiveness coexist across representational levels and contribute to interindividual and intraindividual variability in memory success, with item specificity being the strongest contributor. Our results close an important gap in the literature, showing that older adults' neural representation of item-specific information in addition to categorical information is reduced compared with younger adults.SIGNIFICANCE STATEMENT A long-standing hypothesis links age-related cognitive decline to a loss of neural specificity. While previous evidence supports the notion of age-related neural dedifferentiation of category-level information in ventral visual cortex, whether or not age differences exist at the item level was a matter of debate. Here, we observed age group differences at both levels as well as associations between both categorical distinctiveness and item specificity to memory performance, with item specificity being the strongest contributor. Importantly, age differences in occipital item specificity were largely due to reduced item stability across repetitions in older adults. Our results suggest that age differences in neural representations can be observed across the entire cortical hierarchy and are not limited to category-level information.