Saniyenin altındaki ve çoklu saniye düzeyindeki dopamin dinamikleri, insan zaman algısındaki değişkenliğe aracılık eder

Özet (abstract)

Aberrant interval timing in the millisecond-to-second range is a consistent feature of neurological and neuropsychiatric disorders involving striatal dysfunction, yet its neurochemical substrates in the human brain remain poorly characterised. Striatal dopamine has long been implicated in temporal processing, but evidence from animal models and human pharmacological studies has proved difficult to reconcile, in part because endogenous dopamine dynamics in humans have been inaccessible at relevant timescales. Patients with Parkinson's disease (N=5, 62-73 years; two women) completed a temporal bisection task (300 trials), judging whether visual stimulus intervals (500-1100 ms) were closer to a learned short (500 ms) or long (1100 ms) reference. Dopamine and serotonin concentrations were measured in the caudate nucleus during awake deep brain stimulation surgery using fast-scan cyclic voltammetry. Elastic net machine-learning models trained on in vitro voltammetry data were applied to human recordings to derive dopamine and serotonin time series at 10 Hz. We used cluster-based permutation analysis to identify stimulus-aligned time windows in which dopamine or serotonin differed between short and long judgements, and entered mean concentrations from these windows as predictors of temporal performance in trial-level hierarchical mixed-effects models. Slower, steady-state dopaminergic and serotonergic tone, quantified as the mean concentration within successive multi-minute periods, was also assessed as a predictor of temporal behaviour. Finally, behavioural performance was compared with a healthy control cohort (N=17, 50-66 years; seven women). Elevated phasic dopamine (625-670 ms after stimulus onset) increased the likelihood of short judgements and was associated with reduced temporal overestimation bias. This association was independent of objective clock time, with the identical analysis yielding non-significant results for the short versus the long stimulus intervals. By contrast, tonic dopamine levels covaried with sensitivity in discriminating stimulus intervals (temporal precision). Lower tonic dopamine was associated with poorer temporal precision both within patients over the experimental session and in patients relative to healthy controls. No corresponding effects were observed for serotonin, indicating dopamine specificity across phasic and tonic timescales. By resolving endogenous striatal dopamine with sub-second precision during conscious human behaviour, this study links temporally distinct dopaminergic dynamics to dissociable aspects of timing behaviour in Parkinson's disease. This challenges accounts of dopamine as a single modulatory influence and situates these findings within the literature on dissociable effects of phasic and tonic dopaminergic signalling, reconciling discrepancies between human and animal evidence and advancing understanding of the neurochemical basis of human time perception.

Yazarların özeti; kaynağından alınmıştır. Brain, 2026 · DOI ↗