Brain-behavior relationships in healthy aging : a multimodal approach

Aging is a multifactorial process including physical, psychological and social changes. With the development of high-technology medicine life expectancy has increased tremendously, leading to a shift in focus in medicine and research from physical problems to cognitive alterations. Given an increase in the proportion of older adults in the population, age-related cognitive decline is now considered a major health issue in the current century. Therefore, facilitation of healthy aging emerges as a leading research priority. Next to cognitive alterations (e.g., processing speed, executive functions and memory) (Buckner, 2004; Salthouse, 1996, 2003, 2009), deficits in motor performance (e.g., slowing of movement, gait and balance difficulties and coordination of multi-joint movement; for a review: Seidler et al., 2010) are also apparent in older adults. Because age-related deteriorations in cognitive and motor abilities have far-reaching consequences such as decline in life satisfaction and quality of life (Abrahamson, Clark, Perkins, & Arling, 2012; St John & Montgomery, 2010), as well as difficulties in activities of daily living, identifying underlying mechanisms is crucial. However, the neuroanatomical and neurofunctional underpinnings of cognitive and motor behavior are still not precisely understood. Based on a multimodal analysis approach of magnetic resonance imaging (MRI) sequences, which is considered as a cutting-edge technique in neuroimaging research, the present thesis aims to gain further insight in the relationship between brain and behavior. Both studies in this dissertation are based on a large, well-educated and healthy sample from the “Longitudinal Healthy Aging Brain” (LHAB) database project conducted at the International Normal Aging and Plasticity Imaging Center (INAPIC). By the use of joint analysis of two MRI modalities, the first study aimed to gain more insight into the white matter tissue class of the brain. In addition to macrostructural measures, such as volumes for white matter hyperintensities (WMH) and normal appearing white matter (NAWM; white matter in the cerebrum outside WMH), white matter microstructural integrity within WMH and NAWM was evaluated in this study. In a second step, white matter properties were related to several clearly defined measures of executive functioning and processing speed. The results emphasize the importance to distinguish and analyze white matter integrity within and outside WMH separately since white matter integrity within WMH is not only significantly lower, but also differently associated with cognitive abilities than white matter integrity within NAWM. The second study investigated the relationship between the structural and functional connectivity of the cingulum bundle, a white matter pathway connecting two major hubs of the default mode network, and their relationship with cognitive and motor performance within the context of healthy aging. The overarching aim of the study was to examine if functional connectivity explains unique variance, in addition to the amount explained by structural connectivity in cognitive and motor performance, using hierarchical regressions. The results show neither a relationship between structural and functional connectivity of the cingulum bundle nor an association between functional connectivity strength and age. Nonetheless, a relation between white matter integrity of the cingulum bundle and age is apparent. Further, functional connectivity strength is a predictor for individual differences in cognitive and motor behavior tests with a strong speed component, whereas no additive effect is found including structural and functional connectivity measures in the same hierarchical regression model. Nevertheless, the findings indicate that maintained functional connectivity strength may be of great importance for healthy cognitive aging despite white matter integrity loss. Altern ist ein von vielen verschiedenen Faktoren beeinflusster und interindividuell sehr unterschiedlich verlaufender Prozess, der auch von physischen, psychischen und kognitiven Veränderungen geprägt ist. Mit der stetig ansteigenden Lebenserwartung steigt auch der Anteil älterer Menschen und Hochbetagten an der Gesamtbevölkerung. Als Folge dieser demographischen Entwicklung ist der Unterschied zwischen gesundem versus pathologischem Altern vermehrt in den Fokus der Forschung gerückt. Nicht nur wird gerade das Nachlassen der kognitiven Fähigkeiten im Alter von den Betroffenen als besonders einschneidend für deren Lebensqualität und –zufriedenheit erlebt, sondern stellt auch die Gesamtgesellschaft vor grosse Herausforderungen im Gesundheitsbereich und steht darum besonders im Zentrum der Aufmerksamkeit der Forschung. Somit ist die Erforschung der zugrundeliegenden Mechanismen der kognitiven Beeinträchtigung von grösster Wichtigkeit. Über die Zusammenhänge zwischen dem Ausmass des kognitiven Abbaus und den Veränderungen der Gehirnanatomie im Kontext gesunden Alterns ist jedoch wenig bekannt. Das Ziel dieser Dissertation besteht darin, durch die Kombination verschiedener magnetresonanztomographischer (MRT) Aufnahmen der Komplexität des Gehirns besser Rechnung tragen zu können und damit einen tieferen Einblick in den Zusammenhang zwischen Verhalten und Gehirn zu erhalten. Beide Studien im Rahmen dieser Dissertation basieren auf Daten des ersten Messzeitpunktes des Longitudinal Healthy Aging Brain (LHAB) Datenbank-Projektes, welches am Kompetenzzentrum für Plastizität im Alter an der Universität Zürich durchgeführt wird. Die in dieser Datenbank erfasste, zahlenmässig grosse Stichprobe zeichnet sich durch eine überdurchschnittlich gute Bildung und Gesundheit für ihre Altersklasse aus. Das Ziel der ersten Studie war es, die Integrität der normal erscheinenden weissen Substanz und der krankhaft veränderten weissen Substanz, welche auch als Läsion bezeichnet wird und im MRT-Signal heller bzw. hyperintens erscheint, detaillierter zu erforschen und den Zusammenhang zwischen diesen Charakteristika und psychometrischen kognitiven Tests (Exekutivfunktionen und Wahrnehmungsgeschwindigkeit) zu untersuchen. Dabei wurde die Integrität der weissen Substanz im normal erscheinenden sowie hyperintensem Gewebe quantifiziert und zu den erzielten Leistungen in den kognitiven Tests in Bezug gesetzt. Die Resultate zeigen, dass Integritätswerte der weissen Substanz innerhalb der Läsionen signifikant tiefer sind als in der normal erscheinenden weissen Substanz. Weiter waren die Integritätswerte innerhalb und ausserhalb der Läsionen unterschiedlich mit den kognitiven Leistungen assoziiert. Beide Resultate weisen darauf hin, dass es nicht ausreicht, nur das Volumen der weissen Substanz zu untersuchen. Eher sollte die weisse Substanz zuerst bezüglich ihrer Integrität klassifiziert werden. Weiter zeigen unsere Resultate, dass der Grad der Intaktheit in den Läsionen positiv mit Verhaltensdaten korreliert, wohingegen kein Zusammenhang zwischen der Grösse der Läsion und der kognitiven Leistungsfähigkeit gefunden wurde. Diese Ergebnisse legen die Schlussfolgerung nahe, dass weniger die Grösse der Läsion, sondern eher der Grad der Beschädigung einen Prädiktor für den Erhalt der Leistungsfähigkeit im Alter darstellt. Die zweite Studie untersuchte die Beschaffenheit der strukturellen und funktionellen Verbindungen zwischen zwei spezifischen Hirnarealen des „Default Mode Networks“ und beabsichtigte die strukturellen und funktionellen Marker mit kognitiven und motorischen Fähigkeiten in Verbindung zu bringen. Weiter wurde untersucht, ob die Kombination der strukturellen und funktionellen Daten mehr Varianz hinsichtlich des beobachteten Verhaltens aufklärt als beide Marker getrennt. Die Datenanalyse zeigte jedoch keine additiven Effekte, d.h. die Kombination struktureller und funktioneller Verbindungsparameter trägt in unserem Datensatz nicht zu einer grösseren Varianzerklärung kognitiver und motorischer Fähigkeiten bei. Die Stärke der funktionellen Verbindung zwischen den beiden Arealen scheint jedoch ein Prädiktor für die kognitive Leistungsfähigkeit zu sein, insbesondere für diejenigen Fähigkeiten, die stark durch die Wahrnehmungsgeschwindigkeit beeinflusst sind. Da nur strukturelle Verbindungen einen Zusammenhang mit dem Alter aufwiesen, darf angenommen werden, dass die Aufrechterhaltung funktioneller Verbindungen trotz der Beeinträchtigung struktureller Integrität möglich ist und für das gesunde Altern von grosser Wichtigkeit zu sein scheint

The integration of size and weight cues for perception and action: evidence for a weight-size illusion

Humans routinely estimate the size and weight of objects. Yet, when lifting two objects of equal weight but different size, they often perceive the smaller object as being heavier. This size-weight illusion (SWI) is known to have a lesser effect on motor control of object lifting. How the nervous system combines "weight” and "size” cues with prior experience and whether these cues are differentially integrated for perception and sensorimotor action is still not fully understood. Therefore, we assessed not only whether the experience of size biases weight perception, but also if experience of weight biases the size perception of objects. Further, to investigate differences between perceptual and motor systems for cue-experience integration, participants haptically explored the weight of an object with one hand and then shaped the aperture of their other hand to indicate its perceived size. Results—First, next to a SWI, healthy adults (N=21) perceived lighter objects as being smaller and heavier objects as being larger, demonstrating a weight-size illusion (WSI). Second, participants were more susceptible to either the SWI or WSI. Third, aperture of the non-exploring hand was scaled to perceived weight and not to physical size. Hand openings were consistently smaller than physical size, with SWI-sensitive participants being significantly more affected than WSI-sensitive subjects. We conclude: first, both size and weight perceptions are biased by prior experience. Weight perception is biased by expectations of size, while size perception is influenced by the expectancy of weight. Second, humans have the tendency to use one cue predominantly for both types of perception. Third, combining perceived weight with expected size influenced hand motor control, while online haptic feedback was largely ignored. Finally, we present a processing model underlying the size-weight cue integration for the perceptual and motor syste

Improving sleep and cognition by hypnotic suggestion in the elderly

Sleep quality markedly declines across the human lifespan. Particularly the amount of slow-wave sleep (SWS) decreases with age and this decrease is paralleled by a loss of cognitive functioning in the elderly. Here we show in healthy elderly females that the amount of SWS can be extended by a hypnotic suggestion "to sleep deeper" before sleep. In a placebo-controlled cross-over design, participants listened to hypnotic suggestions or a control tape before a midday nap while high density electroencephalography was recorded. After the hypnotic suggestion, we observed a 57% increase in SWS in females suggestible to hypnosis as compared to the control condition. Furthermore, left frontal slow-wave activity (SWA), characteristic for SWS, was significantly increased, followed by a significant improvement in prefrontal cognitive functioning after sleep. Our results suggest that hypnotic suggestions might be a successful alternative for widely-used sleep-enhancing medication to extend SWS and improve cognition in the elderly

Bridging the brain structure – brain function gap in prosodic speech processing in older adults

Age-related decline in speech perception may result in difficulties partaking in spoken conversation and potentially lead to social isolation and cognitive decline in older adults. It is therefore important to better understand how age-related differences in neurostructural factors such as cortical thickness (CT) and surface area (CSA) are related to neurophysiological sensitivity to speech cues in younger and older adults. Age-related differences in CT and CSA of bilateral auditory-related areas were extracted using FreeSurfer in younger and older adults with normal peripheral hearing. Behavioral and neurophysiological sensitivity to prosodic speech cues (word stress and fundamental frequency of oscillation) were evaluated using discrimination tasks and a passive oddball paradigm, while EEG was recorded, to quantify mismatch negativity (MMN) responses

Cerebellar gray and white matter volume and their relation with age and manual motor performance in healthy older adults

OBJECTIVES: Functional neuroimaging and voxel-based morphometry studies have confirmed the important role of the cerebellum in motor behavior. However, little is known about the relationship between cerebellar gray (GMv) and white matter (WMv) volume and manual motor performance in aging individuals. This study aims to quantify the relationship between cerebellar tissue volume and manual motor performance. EXPERIMENTAL DESIGN: To gain more insight into cerebellar function and how it relates to the role of the primary motor cortex (M1), we related cerebellar GMv, WMv, and M1v to manual motor performance in 217 healthy older individuals. Left and right cerebellar GMv and WMv, and M1v were obtained using FreeSurfer. The following motor measures were obtained: grip force, tapping speed, bimanual visuomotor coordination, and manual dexterity. PRINCIPAL OBSERVATIONS: Significant positive relationships were observed between cerebellar GMv and WMv and grip strength, right cerebellar WMv and right-hand tapping speed, right cerebellar WMv and dexterity, M1v and grip strength, and right M1v and left-hand dexterity, though effect sizes were small. CONCLUSIONS: Our results show that cerebellar GMv and WMv are differently associated with manual motor performance. These associations partly overlap with the brain-behavior associations between M1 and manual motor performance. Not all observed associations were lateralized (i.e., ipsilateral cerebellar and contralateral M1v associations with motor performance), which could point to age-related neural dedifferentiation. The current study provides new insights in the role of the cerebellum in manual motor performance. In consideration of the small effect sizes replication studies are needed to validate these results. Hum Brain Mapp, 2015. © 2015 Wiley Periodicals, Inc

Executive Functions in Healthy Older Adults Are Differentially Related to Macro- and Microstructural White Matter Characteristics of the Cerebral Lobes

Aging is associated with microstructural white matter (WM) changes. WM microstructural characteristics, measured with diffusion tensor imaging (DTI), are different in normal appearing white matter (NAWM) and WM hyperintensities (WMH). It is largely unknown how the microstructural properties of WMH are associated with cognition and if there are regional effects for specific cognitive domains. We therefore examined within 200 healthy older participants (a) differences in microstructural characteristics of NAWM and WMH per cerebral lobe; and (b) the association of macrostructural (WMH volume) and microstructural characteristics (within NAWM and WMH separately) of each lobe with measures of executive function and processing speed. Multi-modal imaging (i.e., T1, DTI, and FLAIR) was used to assess WM properties. The Stroop and the Trail Making Test were used to measure inhibition, task-switching (both components of executive function), and processing speed. We observed that age was associated with deterioration of white matter microstructure of the NAWM, most notably in the frontal lobe. Older participants had larger WMH volumes and lowest fractional anisotropy values within WMH were found in the frontal lobe. Task-switching was associated with cerebral NAWM volume and NAWM volume of all lobes. Processing speed was associated with total NAWM volume, and microstructural properties of parietal NAWM, the parietal WMH, and the temporal NAWM. Task-switching was related to microstructural properties of WMH of the frontal lobe and WMH volume of the parietal lobe. Our results confirm that executive functioning and processing speed are uniquely associated with macro- and microstructural properties of NAWM and WMH. We further demonstrate for the first time that these relationships differ by lobar region. This warrants the consideration of these distinct WM indices when investigating cognitive function

Associations between age, motor function, and resting state sensorimotor network connectivity in healthy older adults

Aging is associated with impaired motor performance across a range of tasks. Both primary neural representations of movement and potential compensatory cognitive mechanisms appear to be disrupted in older age. Here we determined how age is associated with resting state sensorimotor functional connectivity, and whether connectivity strength is associated with motor performance. We investigated the association between age and resting state functional connectivity of several sensorimotor networks in 191 healthy older, right-handed individuals. Regions of interest were defined in the left motor cortex, left putamen, and right cerebellar lobules V and VIII. Analyses were adjusted for head motion, gray matter volume, diastolic blood pressure, and smoker status; we then evaluated whether connectivity is associated with participants' manual motor performance. We found both increased and decreased connectivity within portions of the motor cortical and cerebellar networks after adjusting for covariates. We observed that connectivity increased with age for the motor cortex and cerebellar lobule VIII with the putamen, providing evidence of greater interactivity across networks with age. Higher tapping frequency and greater grip force were associated with stronger connectivity between the motor cortex during resting state, putamen, cerebellar lobule VIII and the insular cortex, suggesting that greater network interactivity may protect against age declines in performance

Reliability and statistical power analysis of cortical and subcortical FreeSurfer metrics in a large sample of healthy elderly

FreeSurfer is a tool to quantify cortical and subcortical brain anatomy automatically and noninvasively. Previous studies have reported reliability and statistical power analyses in relatively small samples or only selected one aspect of brain anatomy. Here, we investigated reliability and statistical power of cortical thickness, surface area, volume, and the volume of subcortical structures in a large sample (N=189) of healthy elderly subjects (64+ years). Reliability (intraclass correlation coefficient) of cortical and subcortical parameters is generally high (cortical: ICCs>0.87, subcortical: ICCs>0.95). Surface-based smoothing increases reliability of cortical thickness maps, while it decreases reliability of cortical surface areas and volumes. Nevertheless, statistical power of all measures benefits from smoothing. When aiming to detect a 10% difference between groups, the number of subjects required to test effects with sufficient power over the entire cortex varies between cortical measures (cortical thickness: N=39, surface area: N=21, volume: N=81; 10mm smoothing, power=0.8, α=0.05). For subcortical regions this number is between 16 and 76 subjects, depending on the region. We also demonstrate the advantage of within-subject designs over between-subject designs. Furthermore, we publicly provide a tool that allows researchers to perform a priori power analysis and sensitivity analysis to help evaluate previously published studies and to design future studies with sufficient statistical power

Regional cerebellar volumetric correlates of manual motor and cognitive function

Cerebellar volume declines with aging. Few studies have investigated age differences in regional cerebellar volume (RCV) and their association with motor and cognitive function. In 213 healthy older adults, we investigated the association of age with motor skills, cognition and RCV. Subsequently, we studied the association of RCV with motor skills and cognition. RCVs were derived from T1-weighted MRI scans using the automated SUIT segmentation method and clustered using principal component analysis (PCA). Motor skill (manual dexterity, tapping speed, bimanual visuomotor coordination, grip force) and cognition (mental rotation, verbal memory, inhibition, mental flexibility) were assessed. Behavioral measures were clustered into compounds using PCA: left hand motor skill, right hand motor skill, verbal memory and mental flexibility, and mental rotation & inhibition. Volume of the rostral middle frontal gyri (rMFG) and premotor areas (PMA) were related to performance for reference. Analyses were adjusted for age, sex, and education. Volume of the cerebellar anterior lobe and top of the superior posterior lobe were positively associated with motor skill. Volume of the bottom part of the posterior superior lobe and the inferior posterior lobe was positively associated with cognition. PMA volume was associated with cognition and motor skill and rMFG volume with motor skill. Although these results did not survive FDR correction, their effect sizes suggest that regional cerebellar volume selectively contributes to cognitive and motor skill. Effect sizes of cerebellar associations with performance were similar to those of rMFG/PMA and performance suggesting parallel contributions to performance

Structural and functional connectivity in healthy aging: Associations for cognition and motor behavior

Age-related behavioral declines may be the result of deterioration of white matter tracts, affecting brain structural (SC) and functional connectivity (FC) during resting state. To date, it is not clear if the combination of SC and FC data could better predict cognitive/motor performance than each measure separately. We probed these relationships in the cingulum bundle, a major white matter pathway of the default mode network. We aimed to attain deeper knowledge about: (a) the relationship between age and the cingulum's SC and FC strength, (b) the association between SC and FC, and particularly (c) how the cingulum's SC and FC are related to cognitive/motor performance separately and combined. We examined these associations in a healthy and well-educated sample of 165 older participants (aged 64-85). SC and FC were acquired using probabilistic tractography to derive measures to capture white matter integrity within the cingulum bundle (fractional anisotropy, mean, axial and radial diffusivity) and a seed-based resting-state functional MRI correlation approach, respectively. Participants performed cognitive tests measuring processing speed, memory and executive functions, and motor tests measuring motor speed and grip force. Our data revealed that only SC but not resting state FC was significantly associated with age. Further, the cingulum's SC and FC showed no relation. Different relationships between cognitive/motor performance and SC/FC separately were found, but no additive effect of the combined analysis of cingulum's SC and FC for predicting cognitive/motor performance was apparent. Hum Brain Mapp, 2015. © 2015 Wiley Periodicals, Inc