Impulse control disorder is linked to dyskinesia development through a cortical network in Parkinson’s disease

Impulse control disorder (ICD) constitutes a neuropsychiatric complication with consequences for quality of life, social functioning, and decision-making. In Parkinson’s disease (PD), ICD has been linked to dopaminergic dysfunction and impaired inhibitory control within frontostriatal circuits. Given that levodopa-induced dyskinesia (LID) is also associated with dopamine therapy and overlapping frontostriatal dysfunction, these conditions may share a neural mechanism whose cortical substrate remains unclear.

We investigated the longitudinal relationship between baseline ICD and subsequent LID development in 464 patients with PD from the Parkinson’s Progression Markers Initiative followed for more than 4 years and categorized according to ICD status. Survival analysis showed that baseline ICD was associated with an increased LID risk independent of putaminal dopamine transporter availability after adjustment for age and sex (hazard ratio=1.3375, p = 0.0238). Threshold-free network-based statistics identified an ICD-related subnetwork with reduced morphological similarity connectivity in patients with ICD, with hub regions in the bilateral paracentral lobules and left caudal anterior cingulate cortex.

Causal mediation analysis indicated that the within-module z-score of the left paracentral lobule mediated the association between ICD-related network disruption and LID development (average causal mediation effect=0.0136, 95% confidence interval = [0.0028,0.0328]), whereas no such mediation was observed for putaminal dopamine transporter availability. These findings suggest that ICD is linked to altered cortical network organization, with downstream topological vulnerability of the left paracentral lobule that may contribute to LID development. They highlight the clinical importance of incorporating ICD history into treatment planning for LID management in PD.

PPMI, a public-private partnership, is funded by the Michael J. Fox Foundation for Parkinson’s Research and funding partners, including 4D Pharma, Abbvie, AcureX, Allergan, Amathus Therapeutics, Aligning Science Across Parkinson’s, AskBio, Avid Radiopharmaceuticals, BIAL, BioArctic, Biogen, Biohaven, BioLegend, BlueRock Therapeutics, Bristol-Myers Squibb, Calico Labs, Capsida Biotherapeutics, Celgene, Cerevel Therapeutics, Coave Therapeutics, DaCapo Brainscience, Denali, Edmond J. Safra Foundation, Eli Lilly, Gain Therapeutics, GE HealthCare, Genentech, GSK, Golub Capital, Handl Therapeutics, Insitro, Jazz Pharmaceuticals, Johnson & Johnson Innovative Medicine, Lundbeck, Merck, Meso Scale Discovery, Mission Therapeutics, Neurocrine Biosciences, Neuron23, Neuropore, Pfizer, Piramal, Prevail Therapeutics, Roche, Sanofi, Servier, Sun Pharma Advanced Research Company, Takeda, Teva, UCB, Vanqua Bio, Verily, Voyager Therapeutics, the Weston Family Foundation, and Yumanity Therapeutics.

This study was supported by a National Research Foundation (NRF) grant provided by the Korea government (RS-2022-NR072160) to M.S. Baek, and an NRF grant provided by the Korea government (RS-2024-00358576) to S.W. These authors contributed equally: Min Seok Baek, Mincheol Park.

Department of Neurology, Wonju Severance Christian Hospital, Yonsei University Wonju College of Medicine, Wonju, 26426, Republic of Korea Research Institute of Metabolism and Inflammation, Yonsei University Wonju College of Medicine, Wonju, 26426, Republic of Korea Department of Biomedical Sciences, Cancer Research Institute, Seoul National University Medical Research Center, Seoul, 03080, Republic of Korea Department of Neurology, Korea University College of Medicine, Anam Hospital, Seoul, 02855, Republic of Korea Department of Neurology, Chung-Ang University College of Medicine, Seoul, 14353, Republic of Korea Department of Neurology, Yonsei University College of Medicine, Seoul, 03722, Republic of Korea Correspondence to Min Seok Baek or Mincheol Park. The authors declare no competing interests. This study is a secondary analysis of de-identified data obtained from the Parkinson’s Progression Markers Initiative (PPMI) database (www.ppmi-info.org/access-data-specimens/download-data), a publicly available resource; no new data were collected from human participants for this analysis.