Aging is typically associated with declines in sensorimotor performance. Previous studies have linked some age-related behavioral declines to reductions in network segregation. For example, compared to young adults, older adults typically exhibit weaker functional connectivity within the same functional network but stronger functional connectivity between different networks. Based on previous animal studies, we hypothesized that such reductions of network segregation are linked to age-related reductions in the brain's major inhibitory transmitter, gamma aminobutyric acid (GABA). To investigate this hypothesis, we conducted graph theoretical analyses of resting state functional MRI data to measure sensorimotor network segregation in both young and old adults. We also used magnetic resonance spectroscopy to measure GABA levels in the sensorimotor cortex and collected a battery of sensorimotor behavioral measures. We report four main findings. First, relative to young adults, old adults exhibit both less segregated sensorimotor brain networks and reduced sensorimotor GABA levels. Second, less segregated networks are associated with lower GABA levels. Third, less segregated networks and lower GABA levels are associated with worse sensorimotor performance. Fourth, network segregation mediates the relationship between GABA and performance. These findings link age-related differences in network segregation to age-related differences in GABA levels and sensorimotor performance. More broadly, they suggest a neurochemical substrate of age-related dedifferentiation at the level of large-scale brain networks.

Neural activation patterns in the ventral visual cortex in response to different categories of visual stimuli (e.g., faces vs. houses) are less selective, or distinctive, in older adults than in younger adults, a phenomenon known as age-related neural dedifferentiation. Previous work in animals suggests that age-related reductions of the inhibitory neurotransmitter, gamma aminobutyric acid (GABA), may play a role in this age-related decline in neural distinctiveness.In this study, we investigated whether neural dedifferentiation extends to auditory cortex and whether individual differences in GABA are associated with individual differences in neural distinctiveness in humans. 20 healthy young adults (ages 18-29) and 23 healthy older adults (over 65) completed a functional magnetic resonance imaging (fMRI) scan, during which neural activity was estimated while they listened to foreign speech and music. GABA levels in the auditory, ventrovisual and sensorimotor cortex were estimated in the same individuals in a separate magnetic resonance spectroscopy (MRS) scan. Relative to the younger adults, the older adults exhibited both (1) less distinct activation patterns for music vs. speech stimuli and (2) lower GABA levels in the auditory cortex. Also, individual differences in auditory GABA levels (but not ventrovisual or sensorimotor GABA levels) predicted individual differences in neural distinctiveness in the auditory cortex in the older adults. These results demonstrate that agerelated neural dedifferentiation extends to the auditory cortex and suggest that declining GABA levels may play a role in neural dedifferentiation in older adults. Significance StatementPrior work has revealed age-related neural dedifferentiation in the visual cortex. GABA levels also decline with age in several parts of the human cortex. Here, we report that these two agerelated changes are linked; neural dedifferentiation is associated with lower GABA levels in older adults. We also show that age-related neural dedifferentiation extends to auditory cortex, suggesting that it may be a general feature of the aging brain. These findings provide novel insights into the neurochemical basis of age-related neural dedifferentiation in humans and also offer a potential new avenue for investigating age-related declines in central auditory processing.

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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 .

Measures of perceived affordances—judgments of action capabilities—are an objective way to assess whether users perceive mediated environments similarly to the real world. Previous studies suggest that judgments of stepping over a virtual gap using augmented reality (AR) are underestimated relative to judgments of real-world gaps, which are generally overestimated. Across three experiments, we investigated whether two factors associated with AR devices contributed to the observed underestimation: weight and field of view (FOV). In the first experiment, observers judged whether they could step over virtual gaps while wearing the HoloLens (virtual gaps) or not (real-world gaps). The second experiment tested whether weight contributes to underestimation of perceived affordances by having participants wear the HoloLens during judgments of both virtual and real gaps. We replicated the effect of underestimation of step capabilities in AR as compared to the real world in both Experiments 1 and 2. The third experiment tested whether FOV influenced judgments by simulating a narrow (similar to the HoloLens) FOV in virtual reality (VR). Judgments made with a reduced FOV were compared to judgments made with the wider FOV of the HTC Vive Pro. The results showed relative underestimation of judgments of stepping over gaps in narrow vs. wide FOV VR. Taken together, the results suggest that there is little influence of weight of the HoloLens on perceived affordances for stepping, but that the reduced FOV of the HoloLens may contribute to the underestimation of stepping affordances observed in AR.

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.