Effect of Alzheimer's Pathology on Task-Related Brain Network Reconfiguration in Aging.

Large-scale brain networks undergo widespread changes with older age and in neurodegenerative diseases such as Alzheimer's disease (AD). Research in young adults (YA) suggest that the underlying functional architecture of brain networks remains relatively consistent between rest and task states. However, it remains unclear whether the same is true in aging and to what extent any changes may be related to accumulation of AD pathology such as ß-amyloid (Aß) and tau. Here, we examined age-related differences in functional connectivity (FC) between rest and an object-scene mnemonic discrimination task using fMRI in young and older adults (OA; both females and males). We used an a priori episodic memory network (EMN) parcellation scheme associated with object and scene processing, that included anterior-temporal regions and posterior-medial regions. We also used positron emission topography to measure Aß and tau in older adults. The correlation between rest and task FC (i.e., FC similarity) was reduced in older compared with younger adults. Older adults with lower FC similarity in EMN had higher levels of tau in the same EMN regions and performed worse during object, but not scene, trials during the fMRI task. These findings link AD pathology, particularly tau, to a less stable functional architecture in memory networks. They also suggest that smaller changes in FC organization between rest and task states may facilitate better performance in older age. Interpretations are limited by methodological factors related to different acquisition directions and durations between rest and task scans.SIGNIFICANCE STATEMENT The brain's large-scale network organization is relatively consistent between rest and task states in young adults (YA). We found that memory networks in older adults (OA) were less correlated between rest and (memory) task states compared with young adults. Older adults with less correlated brain networks also had higher levels of Alzheimer's disease (AD) pathology in the same regions, suggesting that a less stable network architecture may reflect the early evolution of AD. Older adults with less correlated brain networks also performed worse during the memory task suggesting that more similar network organization between rest and task states may facilitate better performance in older age.

Regional Tau Effects on Prospective Cognitive Change in Cognitively Normal Older Adults.

Studies suggest that tau deposition starts in the anterolateral entorhinal cortex (EC) with normal aging, and that the presence of ß-amyloid (Aß) facilitates its spread to neocortex, which may reflect the beginning of Alzheimer's disease (AD). Functional connectivity between the anterolateral EC and the anterior-temporal (AT) memory network appears to drive higher tau deposition in AT than in the posterior-medial (PM) memory network. Here, we investigated whether this differential vulnerability to tau deposition may predict different cognitive consequences of EC, AT, and PM tau. Using 18F-flortaucipir (FTP) and 11C-Pittsburgh compound-B (PiB) positron emission tomography (PET) imaging, we measured tau and Aß in 124 cognitively normal human older adults (74 females, 50 males) followed for an average of 2.8 years for prospective cognition. We found that higher FTP in all three regions was individually related to faster memory decline, and that the effects of AT and PM FTP, but not EC, were driven by Aß+ individuals. Moreover, when we included all three FTP measures competitively in the same model, only AT FTP significantly predicted memory decline. Our data support a model whereby tau, facilitated by Aß, transits from EC to cortical regions that are most closely associated with the anterolateral EC, which specifically affects memory in the initial stage of AD. Memory also appears to be affected by EC tau in the absence of Aß, which may be less clinically consequential. These findings may provide clarification of differences between normal aging and AD, and elucidate the transition between the two stages.SIGNIFICANCE STATEMENT Tau and ß-amyloid (Aß) are hallmarks of Alzheimer's disease (AD) but are also found in cognitively normal people. It is unclear whether, and how, this early deposition of tau and Aß may affect cognition in normal aging and the asymptomatic stage of AD. We show that tau deposition in the entorhinal cortex (EC), which is common in advanced age, predicts memory decline in older adults independent of Aß, likely reflecting normal, age-related memory loss. In contrast, tau in anterior-temporal (AT) regions is most predictive of memory decline in Aß+ individuals. These data support the idea that tau preferentially spreads to specific cortical regions, likely through functional connections, which plays a primary role in memory decline in the early stage of AD.

Alzheimer's Pathology Is Associated with Dedifferentiation of Intrinsic Functional Memory Networks in Aging.

In presymptomatic Alzheimer's disease (AD), beta-amyloid plaques (Aß) and tau tangles accumulate in distinct spatiotemporal patterns within the brain, tracking closely with episodic memory decline. Here, we tested whether age-related changes in the segregation of the brain's intrinsic functional episodic memory networks-anterior-temporal (AT) and posterior-medial (PM) networks-are associated with the accumulation of Aß, tau, and memory decline using fMRI and PET. We found that AT and PM networks were less segregated in older than that in younger adults and this reduced specialization was associated with more tau and Aß in the same regions. The effect of network dedifferentiation on memory depended on the amount of Aß and tau, with low segregation and pathology associated with better performance at baseline and low segregation and high pathology related to worse performance over time. This pattern suggests a compensation phase followed by a degenerative phase in the early, preclinical phase of AD.

Neural Dedifferentiation across the Lifespan in the Motor and Somatosensory Systems.

Age-related declines in sensorimotor performance have been linked to dedifferentiation of neural representations (i.e., more widespread activity during task performance in older versus younger adults). However, it remains unclear whether changes in neural representations across the adult lifespan are related between the motor and somatosensory systems, and whether alterations in these representations are associated with age declines in motor and somatosensory performance. To investigate these issues, we collected functional magnetic resonance imaging and behavioral data while participants aged 19-76 years performed a visuomotor tapping task or received vibrotactile stimulation. Despite one finding indicative of compensatory mechanisms with older age, we generally observed that 1) older age was associated with greater activity and stronger positive connectivity within sensorimotor and LOC regions during both visuomotor and vibrotactile tasks; 2) increased activation and stronger positive connectivity were associated with worse performance; and 3) age differences in connectivity in the motor system correlated with those in the somatosensory system. Notwithstanding the difficulty of disentangling the relationships between age, brain, and behavioral measures, these results provide novel evidence for neural dedifferentiation across the adult lifespan in both motor and somatosensory systems and suggest that dedifferentiation in these two systems is related.

Network segregation varies with neural distinctiveness in sensorimotor cortex.

Normal aging is associated with declines in sensorimotor function. Previous studies have linked age-related behavioral declines to decreases in neural differentiation (i.e., dedifferentiation), including decreases in the distinctiveness of neural activation patterns and in the segregation of large-scale neural networks at rest. However, no studies to date have explored the relationship between these two neural measures and whether they explain the same aspects of behavior. To investigate these issues, we collected a battery of sensorimotor behavioral measures in older and younger adults and estimated (a) the distinctiveness of neural representations in sensorimotor cortex and (b) sensorimotor network segregation in the same participants. Consistent with prior findings, sensorimotor representations were less distinct and sensorimotor resting state networks were less segregated in older compared to younger adults. We also found that participants with the most distinct sensorimotor representations exhibited the most segregated sensorimotor networks. However, only sensorimotor network segregation was associated with individual differences in sensorimotor performance, particularly in older adults. These novel findings link network segregation to neural distinctiveness, but also suggest that network segregation may play a larger role in maintaining sensorimotor performance with age.

Neural distinctiveness declines with age in auditory cortex and is associated with auditory GABA levels.

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. In this study, we investigated whether neural dedifferentiation extends to the auditory cortex. Inspired by previous animal work, we also investigated 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 music and foreign speech. 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) were associated with individual differences in neural distinctiveness in the auditory cortex in the older adults. These results demonstrate that age-related neural dedifferentiation extends to the auditory cortex and suggest that declining GABA levels may play a role in neural dedifferentiation in older adults.

Sensorimotor network segregation declines with age and is linked to GABA and to sensorimotor performance.

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.

Michigan Neural Distinctiveness (MiND) study protocol: investigating the scope, causes, and consequences of age-related neural dedifferentiation.

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 .

Neural predictors of sensorimotor adaptation rate and savings.

In this study, we investigate whether individual variability in the rate of visuomotor adaptation and multiday savings is associated with differences in regional gray matter volume and resting-state functional connectivity. Thirty-four participants performed a manual adaptation task during two separate test sessions, on average 9 days apart. Functional connectivity strength between sensorimotor, dorsal cingulate, and temporoparietal regions of the brain was found to predict the rate of learning during the early phase of the adaptation task. In contrast, default mode network connectivity strength was found to predict both the rate of learning during the late adaptation phase and savings. As for structural predictors, greater gray matter volume in temporoparietal and occipital regions predicted faster early learning, whereas greater gray matter volume in superior posterior regions of the cerebellum predicted faster late learning. These findings suggest that the offline neural predictors of early adaptation may facilitate the cognitive aspects of sensorimotor adaptation, supported by the involvement of temporoparietal and cingulate networks. The offline neural predictors of late adaptation and savings, including the default mode network and the cerebellum, likely support the storage and modification of newly acquired sensorimotor representations.

Effects of a spaceflight analog environment on brain connectivity and behavior.

Sensorimotor functioning is adaptively altered following long-duration spaceflight. The question of whether microgravity affects other central nervous system functions such as brain network organization and its relationship with behavior is largely unknown, but of importance to the health and performance of astronauts both during and post-flight. In the present study, we investigate the effects of prolonged exposure to an established spaceflight analog on resting state brain functional connectivity and its association with behavioral changes in 17 male participants. These bed rest participants remained in bed with their heads tilted down six degrees below their feet for 70 consecutive days. Resting state functional magnetic resonance imaging (rs-fMRI) and behavioral data were obtained at seven time points averaging around: 12 and 8days prior to bed rest; 7, 50, and 70days during bed rest; and 8 and 12days after bed rest. To assess potential confounding effects due to scanning interval or task practice, we also acquired rs-fMRI and behavioral measurements from 14 control participants at four time points. 70days of head-down tilt (HDT) bed rest resulted in significant changes in the functional connectivity of motor, somatosensory, and vestibular areas of the brain. Moreover, several of these network alterations were significantly associated with changes in sensorimotor and spatial working memory performance, which suggests that neuroplasticity mechanisms may facilitate adaptation to the microgravity analog environment. The findings from this study provide novel insights into the underlying neural mechanisms and operational risks of spaceflight analog-related changes in sensorimotor performance.

Metacognition, cortical thickness, and tauopathy in aging.

We investigated self-rating of cognitive task performance (self-appraisal) and the difference between self-rating and actual task performance (appraisal discrepancy) in cognitively healthy older adults and their relationship with cortical thickness and Alzheimer's disease (AD) biomarkers, amyloid and tau. All participants (N = 151) underwent neuropsychological testing and 1.5T structural magnetic resonance imaging. A subset (N = 66) received amyloid-PET with [11C] PiB and tau-PET with [18F] Flortaucipir. We found that worse performers had lower self-appraisal ratings, but still overestimated their performance, consistent with the Dunning-Kruger effect. Self-appraisal rating and appraisal discrepancy revealed distinct relationships with cortical thickness and AD pathology. Greater appraisal discrepancy, indicating overestimation, was related to thinning of inferior-lateral temporal, fusiform, and rostral anterior cingulate cortices. Lower self-appraisal was associated with higher entorhinal and inferior temporal tau. These results suggest that overestimation could implicate structural atrophy beyond AD pathology, while lower self-appraisal could indicate early behavioral alteration due to AD pathology, supporting the notion of subjective cognitive decline prior to objective deficits.

GABA levels in ventral visual cortex decline with age and are associated with neural distinctiveness.

Age-related neural dedifferentiation-a decline in the 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 nonhuman primates and more recent work in humans, we hypothesized that the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) declines with age and is associated with neural dedifferentiation in older adults. 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 positively predicted individual differences in neural distinctiveness. 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.

Age-Related Reductions in Tactile and Motor Inhibitory Function Start Early but Are Independent.

Aging is associated with declines in motor and somatosensory function. Some of these motor declines have been linked to age-related reductions in inhibitory function. Here we examined whether tactile surround inhibition also changes with age and whether these changes are associated with those in the motor domain. We tested a group of 56 participants spanning a wide age range (18-76 years old), allowing us to examine when age differences emerge across the lifespan. Participants performed tactile and motor tasks that have previously been linked to inter- and intra-hemispheric inhibition in the somatosensory and motor systems. The results showed that aging is associated with reductions in inhibitory function in both the tactile and motor systems starting around 40 years of age; however, age effects in the two systems were not correlated. The independent effects of age on tactile and motor inhibitory function suggest that distinct mechanisms may underlie age-related reductions in inhibition in the somatosensory and motor systems.

Exercise effects on bed rest-induced brain changes.

PURPOSE: Spaceflight negatively affects sensorimotor behavior; exercise mitigates some of these effects. Head down tilt bed rest (HDBR) induces body unloading and fluid shifts, and is often used to investigate spaceflight effects. Here, we examined whether exercise mitigates effects of 70 days HDBR on the brain and if fitness and brain changes with HDBR are related. METHODS: HDBR subjects were randomized to no-exercise (n = 5) or traditional aerobic and resistance exercise (n = 5). Additionally, a flywheel exercise group was included (n = 8). Exercise protocols for exercise groups were similar in intensity, therefore these groups were pooled in statistical analyses. Pre and post-HDBR MRI (structure and structural/functional connectivity) and physical fitness measures (lower body strength, muscle cross sectional area, VO2 max, body composition) were collected. Voxel-wise permutation analyses were used to test group differences in brain changes, and their associations with fitness changes. RESULTS: Comparisons of exercisers to controls revealed that exercise led to smaller fitness deterioration with HDBR but did not affect brain volume or connectivity. Group comparisons showed that exercise modulated post-HDBR recovery of brain connectivity in somatosensory regions. Posthoc analysis showed that this was related to functional connectivity decrease with HDBR in non-exercisers but not in exercisers. Correlational analyses between fitness and brain changes showed that fitness decreases were associated with functional connectivity and volumetric increases (all r >.74), potentially reflecting compensation. Modest brain changes or even decreases in connectivity and volume were observed in subjects who maintained or showed small fitness gains. These results did not survive Bonferroni correction, but can be considered meaningful because of the large effect sizes. CONCLUSION: Exercise performed during HDBR mitigates declines in fitness and strength. Associations between fitness and brain connectivity and volume changes, although unadjusted for multiple comparisons in this small sample, suggest that supine exercise reduces compensatory HDBR-induced brain changes.

Exercise as potential countermeasure for the effects of 70 days of bed rest on cognitive and sensorimotor performance.

BACKGROUND: Spaceflight has been associated with changes in gait and balance; it is unclear whether it affects cognition. Head down tilt bed rest (HDBR) is a microgravity analog that mimics cephalad fluid shifts and body unloading. In consideration of astronaut's health and mission success, we investigated the effects of HDBR on cognition and sensorimotor function. Furthermore, we investigated if exercise mitigates any cognitive and sensorimotor sequelae of spaceflight. METHOD: We conducted a 70-day six-degree HDBR study in 10 male subjects who were randomly assigned to a HDBR supine exercise or a HDBR control group. Cognitive measures (i.e., processing speed, manual dexterity, psychomotor speed, visual dependency, and 2D and 3D mental rotation) and sensorimotor performance (functional mobility (FMT) and balance performance) were collected at 12 and 8 days pre-HDBR, at 7, 50, and 70 days in HDBR, and at 8 and 12 days post-HDBR. Exercise comprised resistance training, and continuous and high-intensity interval aerobic exercise. We also repeatedly assessed an outside-of-bed rest control group to examine metric stability. RESULTS: Small practice effects were observed in the control group for some tasks; these were taken into account when analyzing effects of HDBR. No significant effects of HDBR on cognition were observed, although visual dependency during HDBR remained stable in HDBR controls whereas it decreased in HDBR exercise subjects. Furthermore, HDBR was associated with loss of FMT and standing balance performance, which were almost fully recovered 12 days post-HDBR. Aerobic and resistance exercise partially mitigated the effects of HDBR on FMT and accelerated the recovery time course post-HDBR. DISCUSSION: HDBR did not significantly affect cognitive performance but did adversely affect FMT and standing balance performance. Exercise had some protective effects on the deterioration and recovery of FMT.

The impact of mind-body awareness training on the early learning of a brain-computer interface.

Brain-computer interface (BCI) systems allow users to interact with their environment by bypassing muscular control to tap directly into the users' thoughts. In the present study, we investigate the role of prior experience with yoga and meditation, examples of formalized mind-body awareness training (MBAT), in learning to use a one-dimensional sensorimotor rhythm based BCI. Thirty-six human subjects volunteered to participate in two different cohorts based on past experience with MBAT - experienced MBAT practitioners and controls. All subjects participated in three BCI experiments to achieve competency in controlling the BCI system. The MBAT cohort achieved BCI competency significantly faster than the control cohort. In addition, the MBAT cohort demonstrated enhanced ability to control the system on various measures of BCI performance and improved significantly more over time when compared to control. Our work provides insight into valuable strategies for reducing barriers to BCI fluency that limit the more widespread use of these systems.

Quadcopter control in three-dimensional space using a noninvasive motor imagery-based brain-computer interface.

OBJECTIVE: At the balanced intersection of human and machine adaptation is found the optimally functioning brain-computer interface (BCI). In this study, we report a novel experiment of BCI controlling a robotic quadcopter in three-dimensional (3D) physical space using noninvasive scalp electroencephalogram (EEG) in human subjects. We then quantify the performance of this system using metrics suitable for asynchronous BCI. Lastly, we examine the impact that the operation of a real world device has on subjects' control in comparison to a 2D virtual cursor task. APPROACH: Five human subjects were trained to modulate their sensorimotor rhythms to control an AR Drone navigating a 3D physical space. Visual feedback was provided via a forward facing camera on the hull of the drone. MAIN RESULTS: Individual subjects were able to accurately acquire up to 90.5% of all valid targets presented while travelling at an average straight-line speed of 0.69 m s(-1). SIGNIFICANCE: Freely exploring and interacting with the world around us is a crucial element of autonomy that is lost in the context of neurodegenerative disease. Brain-computer interfaces are systems that aim to restore or enhance a user's ability to interact with the environment via a computer and through the use of only thought. We demonstrate for the first time the ability to control a flying robot in 3D physical space using noninvasive scalp recorded EEG in humans. Our work indicates the potential of noninvasive EEG-based BCI systems for accomplish complex control in 3D physical space. The present study may serve as a framework for the investigation of multidimensional noninvasive BCI control in a physical environment using telepresence robotics.