Lifespan Neuromodulation of Cognition (LINE)
In this project, we use imaging to examine how neuronal changes in older adulthood are associated with neurodegenerative diseases involving cognitive decline. Our particular focus is on certain neurotransmitters, so-called neuromodulators.
Neuromodulatory systems play a central role in how the brain supports attention, learning, and memory throughout life. Neuromodulators such as noradrenaline and dopamine are neurochemicals that are produced in small clusters of cells (nuclei) deep within the brain and released across widespread cortical and subcortical networks, where they regulate the efficiency of neural communication. Neuromodulatory systems are particularly vulnerable to age-related degeneration, and are thought to play a key role in cognitive decline during normal human aging and in neurodegenerative pathologies such as Alzheimer's disease.
The Lifespan Neuromodulation of Cognition (LINE) project investigates how age-related changes in neuromodulatory systems contribute to differences in cognitive functioning across adulthood and old age. Both empirically and conceptually, this line of research extends the Institute’s longstanding interest in neuromodulation and aging. Our work focuses on the blue spot (locus coeruleus), the brain's primary source of noradrenaline, as well as dopaminergic nuclei in the midbrain. These small subcortical structures influence large-scale brain networks involved in attention, learning and memory, as well as adaptive behavior, and are among the earliest regions affected by Alzheimer's-related pathology.
To understand how neuromodulation shapes cognitive aging, we combine multiple complementary approaches. We use advanced multimodal Magnetic Resonance Imaging (MRI) to quantify the structural integrity of neuromodulatory nuclei; functional MRI to examine their interactions with large-scale brain networks; pupillometry as a moment-to-moment indicator of neuromodulatory activity; and comprehensive cognitive assessments to characterize attention, learning, and memory. By following participants longitudinally, we investigate how changes in neuromodulatory systems relate to cognitive changes over time and how these processes differ between healthy and pathological aging.
A major goal of the LINE project is to identify the distinct contributions of noradrenergic and dopaminergic systems to different aspects of aging cognition. Our research has shown that the integrity of the locus coeruleus is closely linked to episodic memory, whereas dopaminergic midbrain nuclei are more strongly associated with working memory. Importantly, we also have found that changes in the noradrenergic system predict future episodic memory performance. We further investigate how neuromodulatory activity supports flexible behavior by combining functional neuroimaging, pupillometry, and behavioral paradigms that probe learning under changing environmental conditions.
Beyond understanding healthy aging, LINE seeks to uncover the mechanisms linking neuromodulatory decline to Alzheimer's disease. In collaboration with clinical and international partners, ongoing projects combine longitudinal brain imaging with blood-based biomarkers of Alzheimer's pathology to investigate how early pathological processes interact with changes in neuromodulatory brain systems and cognition. These studies aim to improve our understanding of preclinical disease development and identify potential biomarkers of cognitive decline.
Our most recent work goes beyond observational approaches by experimentally modulating neuromodulatory activity using non-invasive vagus nerve stimulation while simultaneously measuring brain activity, pupil responses, and physiological signals. Together, these multimodal studies provide new insights into how neuromodulatory systems shape cognition across the lifespan and how their dysfunction contributes to age-related cognitive decline.