“Braking” Down Tremor: Reassessment of Tremor Pathomechanisms Considering Striatal Cholinergic Interneurons

Abstract

The essential PD motor symptoms= are classically attributed to nigrostriatal dopaminergic degeneration. However, tremor presents a distinct profile which can predominate, precede other motor features, display heterogeneous response to dopaminergic therapies, and sometimes persist despite dopaminergic optimization. More recently cholinergic systems—striatal and extrastriatal—have been highlighted as active modulators of tremor. Zhang et al recently addressed a central question in striatal physiology: whether activation of cholinergic interneurons (ChIs) promotes or suppresses dopamine (DA) release.1 Utilizing ex-vivo fast-scan cyclic voltammetry, dual optogenetics, in vivo fiber photometry, and computational modeling—they demonstrate that ChI activation via β2-containing nicotinic acetylcholine receptors (nAChRs) transiently suppresses, rather than facilitates, subsequent DA release. This suppression is temporally constrained and attributed to a refractory-like state in dopaminergic axons (rather than vesicular depletion) and is abolished by nAChR antagonism. This suppression is more pronounced in the dorsolateral striatum than the nucleus accumbens, indicating regional differentiation. The critical determinant of suppression is the temporal interval between ChI activation and dopaminergic stimulation, indicating that cholinergic signaling acts as a dynamic, inverse amplitude modulator of DA release. These findings highlight ChIs not as simple facilitators or frequency filters but as regulators imposing transient inhibitory control over dopaminergic signaling through nAChR-mediated axonal mechanisms in an intricate interaction characterized by regional specificity, temporal dynamics, and receptor-subtype selectivity. The identification of this axonal “brake” revises fundamental assumptions about striatal microcircuitry and neuromodulation in PD. Cholinergic involvement in tremor was first suggested in 1950, when anticholinergics suppressing tremor in animals mirrored clinical efficacy in PD patients.2 Later studies highlighted the importance of M4 receptors on direct-pathway striatal medium spiny neurons.3 M4 antagonists like tropicamide were more effective and better tolerated than non-selective agents (e.g., atropine), supporting selective cholinergic modulation over broad antimuscarinic strategies.4 Vesicular acetylcholine transporter imaging also links tremor to cholinergic deficits in the putamen and cerebellar vermis, while bradykinesia and postural instability are linked to changes the pallidum and thalamus—supporting a distributed cholinergic network model.5 Furthermore, cholinergic, rather than dopaminergic, connectivity, better predicts levodopa response in tremor-dominant PD. Clinically, these mechanistic insights refine the therapeutic approach to tremor. ChI-mediated suppression of striatal DA release provides a physiological basis for variable levodopa responsiveness, suggesting that tremor persistence may reflect dynamic cholinergic gating rather than inadequate dopaminergic replacement. This supports reconsidering selective anticholinergic strategies (including M4-focused agents or α4β2-nAChR modulators) as rational adjuncts for patients whose tremor remains refractory despite dopaminergic optimization. By targeting ChI-driven inhibitory control, such agents may enhance phasic DA availability in tremor-relevant circuits. These findings also inform non-pharmacological interventions: individual differences in cholinergic tone may influence DBS- or MRgFUS-responsiveness, underscoring the value of circuit-specific profiling when selecting therapies. Zhang et al suggest that ChIs exert temporally-precise suppression on DA release, introducing a symptom-specific dynamic modulation of striatal signaling.1 Tremor appears particularly susceptible to this cholinergic modulation, as evidenced by limited responsiveness to dopaminergic therapy, antimuscarinic efficacy, and cholinergic deficits in tremor-linked regions. Several knowledge gaps remain. The precise temporospatial integration of striatal/brainstem cholinergic circuits in tremor remains unclear and the role of ChI-mediated DA suppression in generating rhythmic tremor patterns warrants further study. (1) Research project: A. Conception, B. Organization, C. Execution; (2) Statistical Analysis: A. Design, B. Execution, C. Review and Critique; (3) Manuscript: A. Writing of the first draft, B. Review and Critique. O.P.K.: 1A, 1B, 1C, 3A C.F.: 1A, 1B, 1C, 3B Ethical Compliance Statement: No Ethics Committee was required for this study, No specific guidelines were followed for this opinion/hot topic/review article. Informed Patient Consent was not necessary for this work. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines. Financial Disclosures and Conflicts of Interest: All authors declare no relevant conflicts of interest. All authors declare that there are no relevant financial disclosures. No funding was sourced for this manuscript. Author disclosures are available in the Supporting Information. Data S1. Coi_disclosure. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.