Early neural shift detection using functional magnetic resonance imaging: a pilot study with Parkinson’s disease patients undergoing istradefylline and hybrid assistive limb interventions

Background: Parkinson's disease (PD) presents with not only motor symptoms but also non-motor features, including cognitive impairment. Although conventional assessments usually require extended observation periods to detect functional changes, more sensitive measures may enable the detection of changes over shorter intervals. Istradefylline, an adenosine A2A receptor antagonist, and the Hybrid Assistive Limb (HAL) device are emerging therapeutic options for PD. However, their short-term functional effects remain unclear, especially when assessed using traditional clinical and neuropsychological tools. Methods: We enrolled six PD patients (Hoehn and Yahr stages II-III) in our prospective, single-center study. Three patients received istradefylline for 1 month in addition to stable antiparkinsonian medication, and three underwent a 2-week HAL-assisted rehabilitation program while continuing their usual medication. Functional magnetic resonance imaging (fMRI) scans and a battery of clinical, cognitive, mood, sleep, and quality of life assessments were conducted at baseline and follow-up (2 weeks for the HAL-assisted rehabilitation group and 1 month for the istradefylline group). We compared the changes in task-related fMRI activation and traditional clinical endpoints. Results: All six patients completed the study without serious adverse events. After 1 month of istradefylline treatment, fMRI findings showed increased activation in multiple brain regions associated with motor and cognitive control. In contrast, clinical outcome measures (including cognitive, motor, mood, sleep, and quality-of-life scores) showed no significant improvement at follow-up in either the istradefylline group or the HAL-assisted rehabilitation group. Conclusion: Short-term istradefylline administration elicited measurable changes in brain activation patterns without corresponding clinical or cognitive gains, which suggests that fMRI may serve as a more sensitive biomarker of early, subthreshold neural adaptations than conventional assessments. However, these findings must be interpreted with caution due to the small sample size and exploratory nature of the study.