Modulating the cholinergic system—Novel targets for deep brain stimulation in Parkinson's disease

Journal of Neurochemistry, vol. 169, pp. e16264

Abstract

Parkinson's disease (PD) is the second-fastest growing neurodegenerative disease in the world. The major clinical symptoms rigor, tremor, and bradykinesia derive from the degeneration of the nigrostriatal pathway. However, PD is a multi-system disease, and neurodegeneration extends beyond the degradation of the dopaminergic pathway. Symptoms such as postural instability, freezing of gait, falls, and cognitive decline are predominantly caused by alterations of transmitter systems outside the classical dopaminergic axis. While levodopa and deep brain stimulation (DBS) of the subthalamic nucleus or globus pallidus internus effectively address PD primary motor symptoms, they often fall short in mitigating axial symptoms and cognitive impairment. Along these lines, the cholinergic system is increasingly recognized to play a crucial role in governing locomotion, postural stability, and cognitive function. Thus, there is a growing interest in bolstering the cholinergic tone by DBS of cholinergic targets such as the pedunculopontine nucleus (PPN) and nucleus basalis of Meynert (NBM), aiming to alleviate these debilitating symptoms resistant to traditional treatment strategies targeting the dopaminergic network. This review offers a comprehensive overview of the role of cholinergic dysfunction in PD. We discuss the impact of PPN and NBM DBS on the management of symptoms not readily accessible to established DBS targets and pharmacotherapy in PD and seek to provide guidance on patient selection, surgical approach, and stimulation paradigms.

Authors 5

1. Victoria Sofie Witzig corresponding Aachen Department of Neurology

   RWTH Aachen University

   Affiliation as printed

   Department of Neurology RWTH Aachen University Aachen Germany

   Department of Neurology, RWTH Aachen University, Aachen, Germany

2. Rastislav Pjontek Aachen Department of Neurosurgery

   University Hospital Cologne · RWTH Aachen University

   Affiliation as printed

   Department of Neurosurgery RWTH Aachen University Aachen Germany

   Department of Stereotactic and Functional Neurosurgery University Hospital Cologne Cologne Germany

   Department of Neurosurgery, RWTH Aachen University, Aachen, Germany

   Department of Stereotactic and Functional Neurosurgery, University Hospital Cologne, Cologne, Germany

3. Sonny K. H. Tan

   University of Antwerp · Antwerp University Hospital

   Affiliation as printed

   Department of Neurosurgery Antwerp University Hospital Edegem Belgium

   Translational Neurosciences, Faculty of Medicine and Health Sciences University of Antwerp Antwerp Belgium

   Department of Neurosurgery, Antwerp University Hospital, Edegem, Belgium

   Translational Neurosciences, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium

4. Jörg Bernhard Schulz Aachen Department of Neurology

   Jülich Aachen Research Alliance · RWTH Aachen University

   Affiliation as printed

   Department of Neurology RWTH Aachen University Aachen Germany

   JARA‐BRAIN Institute Molecular Neuroscience and Neuroimaging Jülich Research Center GmbH and RWTH Aachen University Aachen Germany

   Department of Neurology, RWTH Aachen University, Aachen, Germany

5. Florian Holtbernd Aachen Department of Neurology

   Forschungszentrum Jülich · Jülich Aachen Research Alliance · RWTH Aachen University

   Affiliation as printed

   Department of Neurology RWTH Aachen University Aachen Germany

   JARA‐BRAIN Institute Molecular Neuroscience and Neuroimaging Jülich Research Center GmbH and RWTH Aachen University Aachen Germany

   Jülich Research Center, Institutes of Neuroscience and Medicine (INM‐4, INM‐11) Jülich Germany

   Department of Neurology, RWTH Aachen University, Aachen, Germany