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

Abstract 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 .https://deepblue.lib.umich.edu/bitstream/2027.42/148569/1/12883_2019_Article_1294.pd

The Effects of Age-Related Hearing Loss on the Brain and Cognitive Function

Age-related hearing loss is a common problem for older adults, leading to communication difficulties, isolation, and cognitive decline. Recently, hearing loss has been identified as potentially the most modifiable risk factor for dementia. Listening in challenging situations, or when the auditory system is damaged, strains cortical resources, which may change how the brain responds to cognitively demanding situations more generally. Here, we review the effects of age-related hearing loss on brain areas involved in speech perception, from the auditory cortex, through attentional networks, to the motor system. We explore current perspectives on the possible causal relation between hearing loss, neural reorganisation, and cognitive impairment. Through this synthesis we aim to inspire innovative research and novel interventions for ameliorating hearing loss and cognitive decline

Causes and Consequences of Dedifferentiation in the Aging Brain.

Cognitive performance declines across the adult lifespan. According to the dedifferentiation hypothesis of cognitive aging, age-related cognitive impairments reflect reductions in the fidelity of neural representations. However, behavioral tests of this hypothesis have yielded mixed results. Thus, the present research sought to explore age-related dedifferentiation using pattern classification of neural activity, which may yield a more direct measure of representational fidelity. Three studies examined age differences in the fidelity of the neural representations of visual stimuli, motor actions, and cognitive task sets, respectively. Study 1 showed that multi-voxel activation patterns evoked by presentation of face and house stimuli were less distinctive in older adults than in young adults. No regions showed greater distinctiveness in older adults than in young adults, and the spatial pattern of category information was similar across age groups, suggesting that older adults do not compensate for low- fidelity representations in visual cortex by forming higher-fidelity representations elsewhere in the brain. Study 2 extended these results to the domain of motor control, using multi-voxel pattern analysis to distinguish between left- and right-hand finger movements. Older adults showed reduced distinctiveness throughout a network of regions related to motor representation and control; again, no regions showed greater distinctiveness in older adults. Study 3 further investigated age differences in neural representations in the context of verbal and spatial working memory tasks. Results from memory encoding and retrieval were consistent with Studies 1 and 2, with reduced discrimination of verbal versus spatial information in older adults. In contrast, results from working memory maintenance showed that representational fidelity was decreased in older adults at high levels of task demand but increased in older adults at low levels of demand. Overall, results from perceptual and motor tasks were consistent with the dedifferentiation hypothesis, while results from memory maintenance were more consistent with compensation-related accounts of cognitive aging. These results suggest that both dedifferentiation- and compensation-based accounts can explain some phenomena, but that neither theory can offer a comprehensive account of age differences in neural representation. Future research should investigate the generalizability of the present results across analysis methods, cognitive tasks, and participant populations.PhDPsychologyUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/107180/1/jmcarp_1.pd

Effects of Aging on Paired-Pulse Behavior of Rat Somatosensory Cortical Neurons

Aging affects all levels of neural processing including changes of intracortical inhibition and cortical excitability. The paired-pulse stimulation protocol, the application of 2 stimuli in close succession, is used to investigate cortical excitability. The paired-pulse behavior is characterized by the fact that the second response is significantly suppressed at short interstimulus intervals (ISIs) but approaches the first response with increasing ISIs. However, there are controversial reports about the influence of age on paired-pulse behavior. We therefore used pairs of tactile stimuli (ISIs from tens to hundreds of milliseconds) to record extracellular responses of somatosensory cortical neurons of young and aged rats. Paired-pulse behavior was quantified as the ratio of the amplitude of the second response divided by the first. For all ISIs, we found significantly higher ratios in the old animals indicating reduced paired-pulse suppression (PPS). Evaluation of the single response components revealed a significant reduction of the response to the first stimulus for old animals but no age-dependent decrement to the second. Changes in PPS are usually mediated by modulating the second response characteristics. Thus, our data demonstrate reduced PPS due to an overall reduction of the first response as a form of modified PPS developing at old age

Age Effects on Neural Discriminability and Monitoring Process During Memory Retrieval for Auditory Words

After hearing a list of words (e.g., dream, awake, and bed), older adults tended to have more difficulty than younger adults in distinguishing targets (e.g., dream) from lures (e.g., sleep) and foils (e.g., pen) in a visual recognition test. Age-related reduction in neural discriminability in the visual cortex has been linked to deficits in memory discriminability of pictures. However, no study has examined age differences in auditory discrimination and prefrontal monitoring during true and false memory retrieval after hearing words. The current study used a visual recognition test following an auditory study of words and showed that older adults had lower true recognition and higher propensity for high-confidence false recognition compared to young adults. Using classification-based multivariate pattern analysis for functional neuroimaging data during memory retrieval, we found that neural activation patterns in the primary auditory cortex could be used to distinguish between auditorily-studied targets and unstudied lures in young adults, but not in older adults. Moreover, prefrontal monitoring for lures was weaker in older adults as compared to young adults. Individual differences analysis showed that neural discriminability in the primary auditory cortex was positively related to true recognition, whereas prefrontal activation for lures was negatively related to the propensity for high-confidence false recognition in young adults but not in older adults. Together, age differences in true and false memories following auditory study are associated with reduced neural discriminability in the primary auditory cortex and reduced prefrontal monitoring during retrieval

Age related hearing loss and cognitive impairment - a current perspective

Age related hearing loss (ARHL) is one of the commonest health conditions of the elderly people which have an important relation with the cognition. Long standing hearing deprivation leads to decline of the cognitive performance. This has impact on quality of communication and result in social isolation, depression and enhances the dementia. Cognitive decline may be misdiagnosed or over-diagnosed when the sensory abilities of the patients are not properly evaluated. Adequate intervention by use of hearing aid or cochlear implant improves the communication, cognitive function, social, emotion function and positively impact on the quality of life. With rise of the elderly population and concomitant increase of ARHL with associated cognitive impairment, it is imperative to discuss this morbid clinical entity in present scenario. Cognitive decline in elderly age have a profound impact on the affected person, on caregivers and society. The financial costs for cognitive impairment in ARHL are also major source of concern for the society. In this review article, we focus on the epidemiology, pathophysiology, hypotheses of etiological mechanisms between the ARHL and cognitive decline or impairment, impact of cognitive impairment on quality of life and prevention

Age Differences in Interhemispheric Interactions: Callosal Structure, Physiological Function, and Behavior

There is a fundamental gap in understanding how brain structural and functional network connectivity are interrelated, how they change with age, and how such changes contribute to older adults’ sensorimotor deficits. Recent neuroimaging approaches including resting state functional connectivity MRI (fcMRI) and diffusion tensor imaging (DTI) have been used to assess brain functional (fcMRI) and structural (DTI) network connectivity, allowing for more integrative assessments of distributed neural systems than in the past. Declines in corpus callosum size and microstructure with advancing age have been well documented, but their contributions to age deficits in unimanual and bimanual function are not well defined. Our recent work implicates age-related declines in callosal size and integrity as a key contributor to unimanual and bimanual control deficits. Moreover, our data provide evidence for a fundamental shift in the balance of excitatory and inhibitory interhemispheric processes that occurs with age, resulting in age differences in the relationship between functional and structural network connectivity. Training studies suggest that the balance of interhemispheric interactions can be shifted with experience, making this a viable target for future interventions

How aging shapes neural representations of continuous spaces

The human brain undergoes remarkable changes over the lifespan, including its structural as well as functional characteristics. One functional change that has been identified in the brain of older adults is the phenomenon of neural dedifferentiation. This describes a process in which neural responses lose specificity over the course of aging, rendering neural representations of, for instance, distinct visual categories increasingly similar to each other. Findings in non-human animals have shown that tuning profiles of neural populations over a continuous stimulus space (e.g. an object’s rotation) become broader with age, effectively widening the spectrum of stimuli that a single neuron responds to. Although research in humans has drawn on this finding as a potential mechanism for age-related dedifferentiation, it has not yet tested whether this process occurs for neural representations of continuous space. This presents a disconnect between the work on neural dedifferentiation in humans on the one hand, and animal work on its mechanisms on the other. The main goal of this dissertation was to address this disconnect and to further understand how aging shapes representations of continuous spaces. To achieve this, the three research articles that form the main body of this dissertation focus on the cognitive domains of spatial navigation and reinforcement learning. Article I analyzes functional magnetic resonance imaging (fMRI) data collected during virtual spatial navigation of older and younger adults and presents evidence that the phenomenon of age-related neural dedifferentiation in humans extends to representations of a continuous variable, namely walking direction. The results are based on a newly introduced analysis approach that allows the field to assess the similarity of neural responses towards stimuli stemming from the same continuous space. Article II combines a double-blind cross-over drug intervention with a design similar to article I and investigates the mechanistic role of the transmitter dopamine in age-related neural dedifferentiation. The study replicates the findings of article I and confirms the causal role of neuromodulation on the specificity of neural representations suggested by computational models. In particular, results show that the administration of L-DOPA, a dopamine precursor, enhances the specificity with which different walking directions are represented in the brain of younger and older adults. Finally, article III moves towards more abstract continuous space and uses a reinforcement learning paradigm to assess how a younger and older age group learn from surprising events. More specifically, it investigates if prediction errors, a continuous quantity reflecting the difference between an expected and obtained outcome of an action, are represented differently in learning and behavior of younger and older individuals. Behavioral results indicate that older adults showed heightened sensitivity to surprise compared to younger adults, overrepresenting the extreme end of the continuous space of prediction errors in their decisions. In summary, this thesis has made a number of contributions towards our understanding of how aging influences representations of continuous space. For one, it provides the first evidence of age-related neural dedifferentiation of a continuous variable in humans, based on a newly developed analysis approach. In doing so, it closes an important gap between related research in humans and non-human animals. It furthermore accounts for a key mechanism of dedifferentiation, confirming the causal influence of dopamine on the specificity of neural representations, as predicted by computational models. Finally, the thesis shows that diverging representations of continuous space in older adults also extend to the more abstract domain of outcome-based learning.Das menschliche Gehirn unterliegt im Laufe des Lebens bemerkenswerten Veränderungen, die sowohl strukturelle als auch funktionelle Eigenschaften betreffen. Eine funktionelle Veränderung, die insbesondere im Gehirn älteren Erwachsenen festgestellt wurde, ist das Phänomen der neuronalen Dedifferenzierung. Dies beschreibt einen Prozess, bei dem die nervlichen Reaktionen im Laufe des Alterns an Spezifität verlieren, so dass die neuronalen Repräsentationen z.B. verschiedener visueller Kategorien einander immer ähnlicher werden. Untersuchungen an Tieren haben gezeigt, dass die Reaktionsprofile neuronaler Populationen über einen kontinuierlichen Reizraum (z.B. die Drehung eines Objekts) mit zunehmendem Alter breiter werden, wodurch sich das Spektrum der Reize, auf die ein einzelnes Neuron reagiert, effektiv erweitert. Obwohl die Forschung am Menschen auf diesen Befund als einen der möglichen zugrundeliegenden Mechanismen hingewiesen hat, konnte eine altersbedingte Dedifferenzierung bisher nicht für neuronale Repräsentationen eines kontinuierlichen Raums nachgewiesen werden. Dies stellt eine Diskrepanz zwischen den Arbeiten zur neuronalen Dedifferenzierung beim Menschen einerseits und den Arbeiten zu den zugehörigen Mechanismen bei Tieren andererseits dar. Das Hauptziel dieser Dissertation war es, diese Diskrepanz zu beseitigen und besser zu verstehen, wie das Altern die Repräsentation von kontinuierlichen Räumen formt. Um dies zu erreichen, konzentrieren sich die drei Forschungsartikel, die den Hauptteil dieser Dissertation bilden, auf die kognitiven Bereiche der räumlichen Navigation und des Verstärkungslernens. In Artikel I analysiere ich Daten der funktionellen Magnetresonanztomographie (fMRI), die während der virtuellen räumlichen Navigation älterer und jüngerer Erwachsener erhoben wurden. Ich präsentiere Belege dafür, dass das Phänomen der altersbedingten neuronalen Dedifferenzierung beim Menschen auch Repräsentation einer kontinuierlichen Variable, nämlich der Laufrichtung, betrifft. Die Ergebnisse basieren auf einem neu eingeführten Analyseansatz, der es erlaubt, die Ähnlichkeit der neuronalen Reaktionen auf Reize zu bewerten, die aus dem- selben kontinuierlichen Raum stammen. Artikel II kombiniert eine doppelblinde Cross-over-Medikamentenintervention mit einem ähnlichen Design wie Artikel I und untersucht die mechanistische Rolle des Transmitters Dopamin bei altersbedingter neuronaler Dedifferenzierung. Die Studie repliziert die Ergebnisse von Artikel I und bestätigt die kausale Rolle der Neuromodulation auf die Spezifität der neuronalen Repräsentationen, wie sie von Computermodellen vorhergesagt wurde. Insbesondere zeigen die Ergebnisse, dass die Verabreichung von L-DOPA, einer Dopaminvorstufe, die Spezifität mit der verschiedene Laufrichtungen im Gehirn von jüngeren und älteren Erwachsenen repräsentiert werden erhöht. Artikel III schließlich befasst sich mit einem abstrakteren kontinuierlichen Raum und verwendet ein Paradigma des Verstärkungslernens, um zu untersuchen, wie sich jüngere und ältere Menschen beim Lernen von überraschenden Ereignissen unterscheiden. Genauer gesagt wird untersucht, ob Vorhersagefehler, eine kontinuierliche Größe, die die Differenz zwischen der erwarteten und der erhaltenen Belohnung einer Handlung widerspiegelt, im Lernen und Verhalten von jüngeren und älteren Personen unterschiedlichen Einfluss nehmen. Die Ergebnisse zeigen, dass ältere Erwachsene im Vergleich zu jüngeren Erwachsenen eine erhöhte Empfindlichkeit gegenüber überraschenden Belohnungen zeigen und, dass das extreme Ende des Kontinuums der Vorhersagefehler in ihren Entscheidungen größeren Einfluss nimmt. Zusammenfassend lässt sich sagen, dass diese Arbeit eine Reihe von Beiträgen zu unserem Verständnis darüber geleistet hat, wie das Altern die Repräsentationen des kontinuierlichen Raums beeinflusst. Zum einen liefert sie auf der Grundlage eines neu entwickelten Analyseansatzes den ersten Nachweis für altersbedingte neuronale Dedifferenzierung im Kontext einer kontinuierlichen Variable. Damit schließt sie eine wichtige Lücke zwischen verwandten Arbeiten in Menschen und nicht-menschlichen Tieren. Bezüglich der Mechanismen der neuronalen Dedifferenzierung bestätigt sie darüber hinaus den kausalen Einfluss von Dopamin auf die Spezifität neuronaler Repräsentationen, wie von Computermodellen vorhergesagt. Schließlich zeigt die Arbeit, dass divergierende Repräsentationen des kontinuierlichen Raums bei älteren Erwachsenen auch im abstrakteren Bereich des ergebnisbasierten Lernens präsent sind