Cerebrospinal fluid metabolomic remodeling following repeated anodal transcranial direct current stimulation in Parkinson’s disease: an exploratory paired study

Background Transcranial direct current stimulation (tDCS) has been explored as a non-invasive adjunctive intervention for Parkinson’s disease (PD), but its biochemical consequences within the human central nervous system remain poorly defined. We investigated whether repeated anodal tDCS administered over a five-day treatment interval was accompanied by changes in the cerebrospinal fluid (CSF) metabolome in a paired pre-post exploratory design. Methods Fourteen patients with PD underwent five consecutive daily sessions of anodal tDCS over the primary motor cortex. Paired CSF samples were collected before and after the stimulation course under fasting conditions. Untargeted metabolomic profiling of polar and non-polar fractions was performed using ultra-performance liquid chromatography coupled with trapped ion mobility quadrupole time-of-flight mass spectrometry. Pre- and post-interval clinical scores and metabolite abundances were compared using paired statistical analyses, and multivariate, pathway-level, and molecular mapping analyses were used to support biological interpretation. Results Over the treatment interval, group-level motor, cognitive, and non-motor clinical scores changed significantly, including Unified Parkinson’s Disease Rating Scale Part III, Korean Montreal Cognitive Assessment, and Korean Non-Motor Symptoms Scale scores (all p < 0.01). After curation and duplicate removal, 389 metabolites were retained for downstream interpretation. Pre-post differences were observed in both polar and non-polar fractions, with more evident multivariate displacement in the non-polar dataset. Under the prespecified exploratory screening criteria, representative altered metabolites included increased inosine, hypoxanthine, xanthine, xanthosine, L-tyrosine, and 3-O-methyl-L-DOPA, together with decreased palmitic acid, stearic acid, and docosahexaenoic acid. Altered non-polar metabolites were concentrated in phosphatidylcholine-, glycerophosphocholine-, and sphingomyelin-associated species. Integrated molecular mapping further suggested that these pre-post differences clustered within biochemical domains related to purine-related metabolism, aromatic amino acid metabolism, fatty acid-related metabolism, and membrane-associated lipid metabolism. Conclusions In this exploratory paired study, repeated anodal tDCS was accompanied by measurable pre-post shifts in the CSF metabolome in patients with PD. The dominant signals involved purine-related metabolites, tyrosine/L-DOPA-related metabolites, fatty acid-associated metabolites, and membrane lipid classes. Because the study was small, lacked a sham-control group, and relied on putative untargeted annotations, these findings should be regarded as hypothesis-generating rather than causal evidence of metabolic mechanisms. Nonetheless, they support the feasibility of using CSF metabolomics to characterize molecular correlates observed during neuromodulation in PD.