Non-invasive brain stimulation for treating cognitive and neuropsychiatric non-motor symptoms in Parkinson's disease and atypical parkinsonism: a systematic review and meta-analysis of randomized controlled trials

Cognitive and neuropsychiatric non-motor symptoms (NMS) are common in Parkinson’s disease (PD) and atypical parkinsonism (AP), yet their management is difficult. Non-invasive brain stimulation (NIBS) may offer a therapeutic option. To provide a joint and comprehensive overview of studies on NIBS to treat cognitive and neuropsychiatric NMS in PD and AP. We searched for randomized, sham-controlled trials on repeated NIBS sessions for treating cognitive and neuropsychiatric NMS in PD and AP. Studies were categorised by NIBS technique/protocol, NMS, and stimulation target. We found 27 studies on repetitive transcranial stimulation (rTMS; N = 1309 patients, range 18–106) and 7 studies on transcranial direct current stimulation (tDCS; N = 221, 10–77). Cognition was assessed in 17 rTMS and 6 tDCS studies, depression by 24 rTMS and 4 tDCS studies, anxiety by 11 rTMS and 1 tDCS studies, apathy by 4 rTMS and 1 tDCS studies, psychosis by 1 tDCS study. Variability in NIBS targets and parameters, outcome measures, treatment duration and follow-up raised some concerns (N = 26) or high risk of bias (N = 8). The meta-analysis on PD suggested that, despite high heterogeneity and low-to-moderate certainty of evidence, excitatory rTMS of the left dorsolateral prefrontal cortex (DLPFC) and the primary motor cortex, and inhibitory rTMS of the right DLPFC may be effective for depression and anxiety. Methodological heterogeneity impeded robust conclusions on the efficacy of NIBS for cognitive and neuropsychiatric NMS in PD and AP. We propose a roadmap for the design of future studies.