Periodic Reporting for period 4 - SIMULTAN (Aging-related changes in brain activation and deactivation during cognition: novel insights into the physiology of the human mind from simultaneous PET-fMRI imaging)
Reporting period: 2021-01-01 to 2022-12-31
Functional magnetic resonance imaging (fMRI) is an imaging method that is sensitive to transient increases in neural activity during cognitive operations. There is no doubt that fMRI has led to a breakthrough in our ability to measure how the complexities of the mind are rooted in biology. However, fMRI measurements are only an indirect measure of neural activity and reflect a complex interplay between hemodynamic and metabolic demands. Indeed, there are highly reliable patterns of fMRI activation that have had a large impact on the study of the human mind but that cannot be readily linked to concomitant changes in neural activity. Figure 1 illustrates the novel approach of the SIMULTAN project in which "traditional" fMRI images from thinking tasks are supplementd with simultaneously acquired images of glucose consumption, a more direct measure of neural activity. With this method we were able to provide new insights into the bran basis of learning and memory and help re-interpret common patterns of fMRI activation. For example, a consistent finding from fMRI of externally focused cognitive control is negative signal change in the brain’s default mode network (DMN), but the neural underpinnings of negative signals have long been unknown. The results we obtained support an explanation of DMN deactivations as a reflection of an active, energy-demanding suppression of task-irrelevant activity. The results open up avenues for understanding abnormal fMRI activity patterns in DMN in aging and psychiatric disease. Next, we set out to explore the intriguing observation that older adults (65+) often display higher levels and more widespread fMRI activation of the prefrontal cortex during performance of a cognitive task.To this end, we collected hybrid PET-fMRI data in healthy older adults and compared the patterns of task-related activity from both imaging modalities to younger adults (work package 2) and to themselves over time (work package 3). We showed that changes in the fMRI signal and synaptic activity as measured by glucose metabolism generally converge but overactivations observed with fMRI in older adults are not coupled with increased synaptic activity. These findings suggest that what is often interpreted to be compensatory activity in older adults is in fact not neuronal in origin. Knowing that differences in fMRI activity between young and older adults reflects altered blood flow properties or neurovascular coupling in an aging brain could inform interventions that target the vascular system.
The project used a novel imaging technique that combines traditional fMRI with a simultaneous measurement of glucose consumption using a PET scan. Our assumption throughout the project was that signal changes in fMRI reflect neural activity if they are paralleled in space and time by transient changes in glucose metabolism. If they are not, they are likely to reflect altered neuro-vascular coupling, either through different mediating mechanisms or through cardiovascular events. For WP1, SIMULTAN collected data from 30 healthy young adults. Confirming our hypothesis and providing proof of concept for the novel hybrid imaging technique, we found good agreement between fMRI signal increases and increased glucose metabolism in frontal-parietal areas that are active during cognitive control compared to rest. Interestingly, we found that task-induced fMRI deactivations, which have been difficult to fully understand, are not paralleled by overlapping task-induced changes in glucose metabolism. This showed that task-induced deactivations are not antagonistic to fMRI activations and highlight a special role for deactivated areas (also known as default mode areas). The results have been presented in oral presentations at two different international conferences (OHBM 2019 in Rome and The Conference for Neuroreceptor Mapping in London 2018) and are published in PNAS in 2021.
For WP2 we collected data from 40 healthy older adults. The finding that cognitively healthy older adults often show widespread fMRI activity during task performance has been interpreted as neural compensation. We tested this hypothesis using a modern human imaging technique in which the fMRI data were again simultaneously complemented with measures of glucose consumption as a proxy for synaptic activity. It was found that patterns of additional fMRI activity in older adults that were not detectable in young controls were not accompanied by synaptic activity. The main results are published in the Journal of Neuroscience in 2023.
WP 3 supplements WP2 with a longitudinal component which means that the 40 older adults were invited back toward the end of the project for a second scan. Here, the aim was to compare fMRI and glucose metabolims in older adults to themselves over a period of 3 years. The longitudinal analysis of cognitive and physical health from the project's own data collection was complemented by data from large publicly available data sources (the PPMI, results published in Andersson et al. 2021 Frontiers in Psychology, and ongoing work with data from the Survey of Health and Retirement in Europe SHARE). Preliminary results confirm our results from WP2 that trajectories of cognitive stability over time are not accompanied by compensatory neural activity but rather reflect a maintained healthy brain.
For WP2 we collected data from 40 healthy older adults. The finding that cognitively healthy older adults often show widespread fMRI activity during task performance has been interpreted as neural compensation. We tested this hypothesis using a modern human imaging technique in which the fMRI data were again simultaneously complemented with measures of glucose consumption as a proxy for synaptic activity. It was found that patterns of additional fMRI activity in older adults that were not detectable in young controls were not accompanied by synaptic activity. The main results are published in the Journal of Neuroscience in 2023.
WP 3 supplements WP2 with a longitudinal component which means that the 40 older adults were invited back toward the end of the project for a second scan. Here, the aim was to compare fMRI and glucose metabolims in older adults to themselves over a period of 3 years. The longitudinal analysis of cognitive and physical health from the project's own data collection was complemented by data from large publicly available data sources (the PPMI, results published in Andersson et al. 2021 Frontiers in Psychology, and ongoing work with data from the Survey of Health and Retirement in Europe SHARE). Preliminary results confirm our results from WP2 that trajectories of cognitive stability over time are not accompanied by compensatory neural activity but rather reflect a maintained healthy brain.
State of the art cognitive neuroscience has put forward the idea that cortical networks are better understood in terms of a gradient-like organization with the default mode network at its apex. Our results align well with these emerging ideas and go beyond the state of the art by providing empirical evidence for a new understanding of default mode deactivations during cognitive control. In support of our work opening up new frontiers of research, our publication in PNAS was accompanied by a commentary concluding: "... an enticing discovery that may help to reveal the complexities of intrinsic brain activity. More studies like these are now needed where multiple modalities are performed simultaneously to help us understand the complexities of how neuronal and synaptic activity, blood flow and metabolism interrelate, and how they together contribute to brain function." (Goyal and Snyder 2021, PNAS). The second major endeavour of the project was to tackle one of the most intriguing questions of the cognitive neurosciences of aging, namely why some older individuals show little or no cognitive decline even into very old age. In this project, we went beyond the state of the art by directly examining synaptic activity of older adults during task performance through functional glucose PET imaging. Using this technique in combination with fMRI, we found no evidence for increased synaptic activity in older adults. The results speak against a compensatory account and in favour of alternative explanation, e.g. aging-related changes in neurovascular coupling. The results were published in The Journal of Neuroscience and selected by the editors as particularly "noteworthy for the scientific community".