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Brain aging even in healthy older adults is characterized by a decline in cognitive functions including memory, learning and attention. Among others, memory is one of the major cognitive functions affected by aging. Understanding the mechanisms underlying age-related memory decline may help pave the road for novel treatment strategies. Here, we tried to elucidate the neural correlates associated with memory decline using structural and functional neuroimaging and neuromodulation with transcranial direct current stimulation (tDCS).
Over the course of three studies, we investigated 1) the influence of white matter integrity and grey matter volume on memory performance in healthy older adults, 2) the role of functional coupling within the memory network in predicting memory performance and the impact of tDCS in modulating retrieval performance in healthy older adults, 3) the effect of tDCS over the sensorimotor cortex on cognitive performance in young adults.
MRI was used to study associations of cognitive performance with white matter integrity and grey matter volume, and examine their causal relationship in the course of aging. White matter integrity was assessed by acquiring diffusion tensor imaging (DTI) and performing deterministic tractography based on constrained spherical deconvolution. Grey matter volume was estimated using fully automated segmentation. Both white matter integrity and grey matter volume were correlated with behavioral data of a verbal episodic memory task. Percentage of correct answers at retrieval was used to measure memory performance (Manuscript 1). In addition, anodal tDCS (atDCS) (1 mA, 20 min) was applied over CP5 (left temporoparietal cortex) to modulate memory formation in healthy older adults. Participants underwent resting-state fMRI before the stimulation. Functional connectivity analysis was performed to determine whether functional coupling within the memory network predicted initial memory performance, and to examine its association to tDCS-induced enhancement effect (Manuscript 2). Finally, atDCS (1 mA, 20 min) was applied over C3 (left sensorimotor cortex) to explore the effect of tDCS over the sensorimotor cortex on cognitive performance in young adults. During the stimulation, participants performed three tasks; gestural task, attentional load task and simple reaction time task (Manuscript 3).
Results showed that volumes of the left dentate gyrus (DG) and tractography-based fractional anisotropy (FA) of individual fornix pathways were positively related to memory retrieval in older adults. Brain-behavior associations were observed for correct rejections rather than hits of memory performance, indicating specificity of memory network functioning for detecting false associations. Thus, the data suggested a particular role of neural integrity that promotes successful memory retrieval in older adults. Subsequent mediation analysis showed that left DG volume mediated the effect of fornix FA on memory performance (48%), corrected for age, revealing a crucial role of hippocampal pathway microstructure in modulating memory performance in older adults (Manuscript 1). tDCS results showed that atDCS led to better retrieval performance and increasing learning curves, indicating that brain stimulation can induce plasticity of episodic memory processes in older adults. Combining tDCS and fMRI, hippocampo-temporoparietal functional connectivity was positively associated with initial memory performance in healthy older adults and was positively correlated with the magnitude of individual tDCS-induced enhancement, suggesting that individual tDCS responsiveness may be determined by intrinsic network coupling (Manuscript 2). Finally, our findings suggested that atDCS over left sensorimotor cortex reduced reaction times in the gestural-verbal integration task, specifically for incongruent pairs of gestures and verbal expressions, indicating the role of sensorimotor cortex in gestural-verbal integration in young adults (Manuscript 3).
The results of all three studies may help to elucidate age-related structural deterioration and functional coupling network underlying cognitive processes in healthy adults. Furthermore, these studies emphasized the importance of interventions like tDCS in modulating cognitive performance, specifically episodic verbal memory and gestural-verbal integration. By unveiling the specific role of brain structures and functional network coupling as well as the role of tDCS in modulating cognitive performance, our results contribute to a better understanding of brain-behavior associations, and may help to develop clinical interventional approaches, tailored for specific cognitive functions in aging.
Age-related deterioration in white and gray matter is linked to cognitive deficits. Reduced microstructure of the fornix, the major efferent pathway of the hippocampus, and volume of the dentate gyrus (DG), may cause age-associated memory decline. However, the linkage between these anatomical determinants and memory retrieval in healthy aging are poorly understood. In 30 older adults, we acquired diffusion tensor and T1-weighted images for individual deterministic tractography and volume estimation. A memory task, administered outside of the scanner to assess retrieval of learned associations, required discrimination of previously acquired picture-word pairs. The results showed that fornix fractional anisotropy (FA) and left DG volumes were related to successful retrieval. These brain-behavior associations were observed for correct rejections, but not hits, indicating specificity of memory network functioning for detecting false associations. Mediation analyses showed that left DG volume mediated the effect of fornix FA on memory (48%), but not vice versa. These findings suggest that reduced microstructure induces volume loss and thus negatively affects retrieval of learned associations, complementing evidence of a pivotal role of the fornix in healthy aging. Our study offers a neurobehavioral model to explain variability in memory retrieval in older adults, an important prerequisite for the development of interventions to counteract cognitive decline.
Action comprehension that is related to language or gestural integration has been shown to engage the motor system in the brain, thus providing preliminary evidence for the gestural-verbal embodiment concept. Based on the involvement of the sensorimotor cortex (M1) in language processing, we aimed to further explore its role in the cognitive embodiment necessary for gestural-verbal integration. As such, we applied anodal (excitatory) and sham transcranial direct current stimulation (tDCS) over the left M1 (with reference electrode over the contralateral supraorbital region) during a gestural-verbal integration task where subjects had to make a decision about the semantic congruency of the gesture (prime) and the word (target). We used a cross-over within-subject design in young subjects. Attentional load and simple reaction time (RT) tasks served as control conditions, applied during stimulation (order of three tasks was counterbalanced). Our results showed that anodal (atDCS) compared to sham tDCS (stDCS) reduced RTs in the gestural-verbal integration task, specifically for incongruent pairs of gestures and verbal expressions, with no effect on control task performance. Our findings provide evidence for the involvement of the sensorimotor system in gestural-verbal integration performance. Further, our results suggest that functional modulation induced by sensorimotor tDCS may be specific to gestural-verbal integration. Future studies should now evaluate the modulatory effect of tDCS on semantic congruency by using tDCS over additional brain regions and include assessments of neural connectivity.