Older adults' difficulty in distinguishing between old and new information contributes to memory decline, which may occur because older adults are less likely than young adults to retrieve specific sensory details necessary to distinguish between similar items. In male and female human subjects, the present study measured the extent of age differences in the specificity of memory representations using a false memory paradigm in which studied items were linked to retrieval items at multiple levels of similarity. Older adults showed poorer behavioral discrimination than young adults, driven primarily by false recognition of lures that differed from targets only in perceptual details. Patterns of activation across several regions within ventral visual cortex could be used to distinguish between targets and lures when they differed in both perceptual details and a semantic label. However, of ventral visual regions, only signals in the midline occipital cortex could be used to distinguish targets from lures when they differed only in perceptual details. Although there was an overall age deficit for this neural discrimination in this region, the positive relationship between neural and behavioral discriminability did not differ across age groups. In contrast, age moderated the relationship between neural and behavioral discriminability in lateral occipital and fusiform cortices, suggesting that activation patterns within these regions represent different types of information in each age group. Therefore, the quality of perceptual signals is a key contributor to memory discrimination across age groups, with evidence that age differences in the nature of representations emerges outside early visual cortex.Age-related memory decline is due in part to older adults' difficulties in discriminating between old and new information. We tested whether this deficit arises from lack of specificity in the sensory representations underlying older adults' recognition judgments. Using pattern classification analyses in ventral visual cortices, we found that signals in a region early in the visual stream could distinguish between targets and lures at the highest level of similarity. The discriminability of targets and lures in this region was positively related to behavioral discriminability across age groups despite an overall age deficit in classification accuracy. Together, results showed that older adults' memory deficits are related to reduced discriminability of cognitive processes (old/new recognition) in portions of visual cortex.

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Background Aging is often associated with behavioral impairments, but some people age more gracefully than others. Why? One factor that may play a role is individual differences in the distinctiveness of neural representations. Previous research has found that neural activation patterns in visual cortex in response to different visual stimuli are often more similar (i.e., less distinctive) in older vs. young participants, a phenomenon referred to as age-related neural dedifferentiation. Furthermore, older people whose neural representations are less distinctive tend to perform worse on a wide range of behavioral tasks. The Michigan Neural Distinctiveness (MiND) project aims to investigate the scope of neural dedifferentiation (e.g., does it also occur in auditory, motor, and somatosensory cortex?), one potential cause (age-related reductions in the inhibitory neurotransmitter gamma-aminobutyric acid (GABA)), and the behavioral consequences of neural dedifferentiation. This protocol paper describes the study rationale and methods being used in complete detail, but not the results (data collection is currently underway). Methods The MiND project consists of two studies: the main study and a drug study. In the main study, we are recruiting 60 young and 100 older adults to perform behavioral tasks that measure sensory and cognitive function. They also participate in functional MRI (fMRI), MR spectroscopy, and diffusion weighted imaging sessions, providing data on neural distinctiveness and GABA concentrations. In the drug study, we are recruiting 25 young and 25 older adults to compare neural distinctiveness, measured with fMRI, after participants take a placebo or a benzodiazepine (lorazepam) that should increase GABA activity. Discussion By collecting multimodal imaging measures along with extensive behavioral measures from the same subjects, we are linking individual differences in neurochemistry, neural representation, and behavioral performance, rather than focusing solely on group differences between young and old participants. Our findings have the potential to inform new interventions for age-related declines. Trial registration This study was retrospectively registered with the ISRCTN registry on March 4, 2019. The registration number is ISRCTN17266136 .

Age-related neural dedifferentiationreduced distinctiveness of neural representations in the aging brain-has been associated with age-related declines in cognitive abilities. But why does neural distinctiveness decline with age? Based on prior work in non-human primates, we hypothesized that the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) declines with age and is associated with neural dedifferentiation. To test this hypothesis, we used magnetic resonance spectroscopy (MRS) to measure GABA and functional MRI (fMRI) to measure neural distinctiveness in the ventral visual cortex in a set of older and younger participants. Relative to younger adults, older adults exhibited lower GABA levels and less distinct activation patterns for faces and houses in the ventral visual cortex. Furthermore, individual differences in GABA within older adults predicted individual differences in neural distinctiveness even after controlling for gray matter volume and age. These results provide novel support for the view that age-related reductions of GABA contribute to age-related reductions in neural distinctiveness (i.e., neural dedifferentiation) in the human ventral visual cortex. Significance StatementNeural representations in the ventral visual cortex are less distinguishable in older compared to younger humans, and this neural dedifferentiation is associated with age-related cognitive deficits. Animal models suggest that reductions in the inhibitory neurotransmitter gamma aminobutyric acid (GABA) may play a role. To investigate this hypothesis, we combined functional magnetic resonance imaging (fMRI) and magnetic resonance spectroscopy (MRS) in a study of the human ventral visual cortex. We observed reduced distinctiveness of neural patterns and reduced GABA levels in older compared to younger adults. Furthermore, older adults with higher GABA levels tended to have more distinctive neural representations. These findings suggest that reduced GABA levels contribute to age-related declines in neural distinctiveness in the human ventral visual cortex.

1 Background: Aging is often associated with behavioral impairments, but some people age more 2 gracefully than others. Why? One factor that may play a role is individual differences in the 3 distinctiveness of neural representations. Previous research has found that neural activation 4 patterns in visual cortex in response to different visual stimuli are often more similar (i.e., less 5 distinctive) in older vs. young participants, a phenomenon referred to as age-related neural 6 dedifferentiation. Furthermore, older people whose neural representations are less distinctive 7 tend to perform worse on a wide range of behavioral tasks. The Michigan Neural Distinctiveness 8 (MiND) project aims to investigate the scope of neural dedifferentiation (e.g., does it also occur 9 in auditory, motor, and somatosensory cortex?), one potential cause (age-related reductions in 10 the inhibitory neurotransmitter gamma-aminobutyric acid (GABA)), and the behavioral 11 consequences of neural dedifferentiation. This protocol paper describes the study rationale and 12 methods being used in complete detail, but not the results (data collection is currently underway). 13Methods/Design: The MiND project consists of two studies: the main study and a drug study. In 14 the main study, we are recruiting 60 young and 100 older adults to perform behavioral tasks that 15 measure sensory and cognitive function. They also participate in functional MRI (fMRI), MR 16 spectroscopy (MRS), and diffusion weighted imaging (DWI) sessions, providing data on neural 17 distinctiveness and GABA concentrations. In the drug study, we are recruiting 25 young and 25 18 older adults to compare neural distinctiveness, measured with fMRI, after participants take (1) a 19 benzodiazepine (lorazepam) that should increase GABA activity or (2) a placebo. 20 Discussion: By collecting multimodal imaging measures (fMRI, MRS, DWI) along with 21 extensive behavioral measures from the same subjects, we are linking individual differences in 22 neurochemistry, neural representation, and behavioral performance, rather than focusing solely 23 3 on group differences between young and old participants. Our findings have the potential to 24 inform new interventions for age-related declines. 25 Background 29Normal aging is associated with pervasive declines in cognitive, motor, and sensory 30 function, even in the absence of significant disease. Further, both the number of older adults and 31 the proportion of older adults in the population are growing at alarming rates. Consequently, tens 32 of millions of healthy people are already experiencing age-related behavioral impairments, and 33 that number is only going to grow. Nevertheless, there are substantial individual differences in 34 age-related behavioral impairments. Some otherwise healthy people experience significant age-35 related declines, while others do not. What distinguishes those who age gracefully from those 36 who experience significant impairments? The answer to that question could transform efforts to 37 reduce, o...

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The medial temporal lobe (MTL) is critical to associative memory success. Yet not all types of associations may be processed in a similar manner within MTL subregions. In particular, work suggests that intra- and inter-item associations not only exhibit differences in overall rates of recollection, but also recruit different MTL subregions. Whereas intra-item associations, akin to unitization, take advantage of associations between within-item features, inter-item associations form links across discrete items. The current work aimed to examine the neural differences between these two types of associations using multivariate neural analyses. Specifically, the current study examined differences across face-occupation as a function of whether the pairing was viewed as a person performing the given job (intra-item binding) or a person saying that they knew someone who had a particular job (inter-item binding). The results show that at encoding, successfully recollected intra- and inter- item associations are discriminable from one another in the hippocampus, parahippocampal cortex, and perirhinal cortex. Additionally, the two trial types are reinstated distinctly such that inter-item trials have higher neural reinstatement from encoding to retrieval compared to intra-item trials in the hippocampus. We conclude that intra- and inter- associative pairs may utilize similar neural regions that represent patterns of activation differentially at encoding. However, in order to reinstate information to the same degree (i.e., subsequently successfully recollected) inter-item associations may act in a compensatory manner, while it is not necessary for intra-item associations to be reinstated to the same degree. This may indicate that intra-item associations promote more efficient reinstatement.