Byeongwook Lee

Parkinson’s disease (PD) is primarily diagnosed through its characteristic motor deficits, yet it also encompasses progressive cognitive impairments that profoundly affect quality of life. While dopaminergic medications are routinely prescribed to manage motor symptoms in PD, their influence extends to cognitive functions as well. Here we investigate how dopaminergic medication influences aberrant brain circuit dynamics associated with encoding, maintenance and retrieval working memory (WM) task-phases processes. PD participants, both on and off dopaminergic medication, and healthy controls, performed a Sternberg WM task during fMRI scanning. We employ a Bayesian state-space computational model to delineate brain state dynamics related to different task phases. Importantly, a within-subject design allows us to examine individual differences in the effects of dopaminergic medication on brain circuit dynamics and task performance. We find that dopaminergic medication alters connectivity within prefrontal-basal ganglia-thalamic circuits, with changes correlating with enhanced task performance. Dopaminergic medication also restores engagement of task-phase-specific brain states, enhancing task performance. Critically, we identify an “inverted-U-shaped” relationship between medication dosage, brain state dynamics, and task performance. Our study provides valuable insights into the dynamic neural mechanisms underlying individual differences in dopamine treatment response in PD, paving the way for more personalized therapeutic strategies.

Background: Alzheimer’s disease (AD) is a progressive and severely debilitating disease that negatively affects cognitive and memory function and is linked to increased disability in everyday functioning and risk of mortality. Neurodegeneration of focal brain areas in AD progressively impacts large‐scale brain circuits, leading to significant cognitive impairments. However, little is known regarding aberrant context‐dependent dynamic causal interactions between distributed brain regions, and their links to cognitive impairments and neuropathology, across AD clinical stages.Method: We addressed critical gaps in our knowledge of functional circuit mechanisms underlying cognitive dysfunction in AD by leveraging innovative computational tools and state‐of‐the‐art clinical, phenotypic, cognitive, experimental, fMRI data from AD Human Connectome Project database.Result: To this end, we identified that (1) dynamic causal interaction patterns between DMN‐MTL‐FPN‐SN nodes distinguish between clinical stages of AD in working memory task, (2) dynamic causal interactions between DMN‐MTL‐FPN‐SN nodes become progressively weaker along clinical AD disease stages in both memory tasks, and (3) dynamic causal interaction patterns between DMN‐MTL‐FPN‐SN nodes are significantly associated with task performance.Conclusion: These findings will identify aberrant dynamic causal circuits associated with episodic and working memory deficits across AD clinical stages.

The default mode network (DMN) is critical for self-referential mental processes, and its dysfunction is implicated in many neuropsychiatric disorders. However, the neurophysiological properties and task-based functional organization of the rodent DMN are poorly understood, limiting its translational utility. Here, we combine fiber photometry with functional magnetic resonance imaging (fMRI) and computational modeling to characterize dynamics of putative rat DMN nodes and their interactions with the anterior insular cortex (AI) of the salience network. Our analysis revealed neuronal activity changes in AI and DMN nodes preceding fMRI-derived DMN activations and cyclical transitions between brain network states. Furthermore, we demonstrate that salient oddball stimuli suppress the DMN and enhance AI neuronal activity and that the AI causally inhibits the retrosplenial cortex, a prominent DMN node. These findings elucidate the neurophysiological foundations of the rodent DMN, its spatiotemporal dynamical properties, and modulation by salient stimuli, paving the way for future translational studies.