Excessive GABAergic activity in striatal and frontal cortical regions more than dopaminergic functions are related to daytime sleepiness in Parkinson’s disease: An exploratory 11C-flumazenil PET study

Abstract

Aims: Increased gamma-aminobutyric acid type A (GABA_A) receptor activity has been identified in hypersomnolence syndromes, but its role and regional cerebral topography of receptor occupancy in excessive daytime sleepiness (EDS) in Parkinson’s disease (PD) is unknown. Dopaminergic functions or medications may contribute to EDS. Neuroimaging shows evidence of increased brain GABAergic activity in PD. We investigated the relationship between EDS, GABA_A receptor binding, striatal dopamine and dopaminergic medication use in PD.

Methods: Six PD patients underwent [¹¹C]flumazenil GABA_A receptor and [¹¹C]dihydrotetrabenazine (DTBZ) dopaminergic positron emission tomography (PET), clinical and Epworth Sleepiness Scale (ESS) assessments.

Results: Mean ESS score was 12.7 ± 4.5. Mean levodopa equivalent dose (LED) was 1,170 ± 616 mg. There was no significant correlation between nigrostriatal [¹¹C]DTBZ PET (R = 0.138, p = 0.792) or disease duration (R = 0.209, p = 0.902) and ESS scores. In contrast, there was a significant inverse relationship between striatal GABA_A receptor activity and ESS scores (β = -0.942, p = 0.024), more prominent in the caudate head (β = -0.949, p = 0.011). Therefore, frontal cortex binding was explored. A significant inverse relationship between frontal cortical GABA_A receptor activity and ESS (R = -0.884, p = 0.042) was found. A trend toward positive association between LED and ESS (R = 0.773, p = 0.053), was weakened (β = -0.128, p = 0.738) by the addition of caudate head GABA_A receptor activity into the model (β = -1.066, p = 0.055), suggesting that the association between LED and ESS may be mediated by GABAergic changes in the striatum.

Conclusion: Increased striatal and frontal cortical GABAergic activity is a more significant determinant of daytime somnolence than dopaminergic functions in PD. Findings may augur novel inverse GABA_A receptor agonist drug therapy for EDS in PD.

Keywords

GABA_A receptor / Parkinson’s disease / excessive daytime sleepiness / positron emission tomography / flumazenil

Acknowledgements

The authors thank all patients for their time commitment. We further thank research assistants, especially Christine Minderovic and Cyrus Sarosh, as well as PET technologists, cyclotron operators, and chemists, for their assistance with this study.

The published article incorporates and extends on material that was previously presented in 2016 Neurologyconference abstract (https://www.neurology.org/doi/abs/10.1212/WNL.86.16_supplement.S13.008). More detailed analyses are presented and discussed in the manuscript.

Authors contribution

Bohnen NI, Beaulieu ML: Conceptualization, methodology, formal analysis.

Vangel R, Reddy M, Van Hout A: Writing-original draft.

Carli G: Writing-review & editing.

Roytman S, Kanel P, Scott PJH: Visualization, data curation.

Conflicts of interest

The authors declare no conflicts of interest.

Ethical approval

This study was conducted in accordance with the Declaration of Helsinki and approved by the Institutional Review Boards of the Ann Arbor Department of Veterans Affairs Medical Center and the University of Michigan (HUM00130361).

Consent to participate

Consent to participate was obtained from all participants or their legal representatives, ensuring that participants were fully informed about the study’s purpose, procedures, risks, and benefits before consenting to participate.

Consent for publication

Not applicable.

Availability of data and materials

The data and materials could be obtained from the corresponding author.

Funding

This research was supported by the National Institutes of Health (Grant Nos. R01 NS099535, P01 NS015655, and RO1 NS070856), and the Department of Veterans Affairs (Grant No. I01 RX000317).

Copyright

© The Author(s) 2026.

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