CNS*2026 Halifax

Jeeyune Jung^*1,3,   Adam Newton^1,3,  Donald Doherty^1,3,  Hong-Yuan Chu^2,3,  Samuel Neymotin⁴ , William Lytton^1,3
1. Department of Physiology and Pharmacology, SUNY Downstate Health Sciences University, Brooklyn, NY, USA 
^2. Department of Pharmacology and Physiology, Georgetown University Medical Center, Washington, DC, USA 
^3. Aligning Science Across Parkinson’s (ASAP) Collaborative Research Network, Chevy Chase, MD, USA
⁴ Center for Biomedical Imaging & Neuromodulation, Nathan Kline Institute, Orangeburg, NY, USA

^*Email: [email protected]


Introduction
Parkinson’s disease (PD) involves not only basal ganglia dopamine loss but also cortical dysfunction, including excessive beta synchronization, abnormal beta–gamma coupling, altered bursting, and impaired corticospinal recruitment. Early locus coeruleus degeneration may reduce cortical norepinephrine (NE), disrupting cell-type-specific gain control in pyramidal tract (PT) and intratelencephalic (IT) neurons. We tested whether experimentally constrained NE modulation restores cortical excitability and network dynamics in an advanced MitoPark motor cortex model and whether NE-sensitive cortical biomarkers support severity mapping and prediction of dopamine-therapy response.




Methods
Whole-cell patch-clamp recordings from Layer 5 PT and IT neurons quantified NE (10 µM)-induced changes in firing–current relationships. Conductance-based single-cell models were fit to baseline and NE responses and embedded in a biophysically detailed laminar M1 network model in NEURON/NetPyNE. Parkinsonian simulations incorporated reduced PT5B intrinsic excitability and reduced thalamocortical drive, with disease-stage-dependent NE scaling from PK/PD modeling. From the resulting simulations, we extracted cortical biomarkers including PT5B firing, IT5B beta-synchronized bursting, IT/PT imbalance, beta power, beta-burst duration, beta–high gamma phase-amplitude coupling, and avalanche slope, which were then used for severity mapping. 

Results
NE exerted opposite intrinsic effects across Layer 5 pyramidal subtypes: PT firing increased, whereas IT repetitive firing decreased. In the Parkinsonian network, NE-dependent conductance changes partially rescued pathological dynamics: PT5B firing increased by ~60–70%, IT5B bursting declined, the IT/PT activity ratio shifted toward control-like values, and pathological beta–high gamma phase-amplitude coupling decreased by ~40%. Across the biomarker set, NE shifted cortical dynamics toward the control regime. In the machine-learning framework, greater deviation from control tracked greater disease severity and predicted progressively shorter and weaker levodopa benefit as NE support declined.
Discussion
These findings identify NE-sensitive intrinsic gain control as a mechanistic bridge between single-cell excitability and pathological cortical state in PD. Loss of noradrenergic modulation may directly contribute to corticospinal under-recruitment, hypersynchronous beta activity, and broader cortical biomarker abnormalities, whereas restoring NE-dependent PT/IT balance may complement dopamine-based therapy. This multiscale framework links cellular mechanisms, network dysfunction, severity mapping, and predicted treatment response, positioning noradrenergic modulation as a promising strategy for advanced PD.

References
1. Dura-Bernal, S., et al. (2023). Multiscale model of primary motor cortex circuits predicts in vivo cell-type-specific, behavioral state-dependent dynamics. Cell Reports.
2. Chu, H. Y., et al. (2024). Dysfunction of motor cortices in Parkinson’s disease. Cerebral Cortex.
3. Doherty, D. W., et al. (2025). Enhanced beta power emerges from simulated parkinsonian primary motor cortex. npj Parkinson’s Disease.

Acknowledgments
This work was supported by the Aligning Science Across Parkinson’s (ASAP) Collaborative Research Network. We thank colleagues for providing experimental data used to constrain the model. Computational resources were provided by SUNY Downstate Health Sciences University.