Neuropsychological and neurobehavioral outcomes of responsive neurostimulation in epilepsy: A systematic review and meta‐analysis

OBJECTIVE: The Responsive Neurostimulation System (RNS) is a US Food and Drug Administration-approved closed-loop brain neurostimulation device for patients with drug-resistant epilepsy. Given the cognitive/neurobehavioral impact of epilepsy and the putative neuroplasticity with neuromodulation, we aimed to understand the effect of RNS on cognition. METHODS: We systematically searched four databases, PubMed/Medline, EMBASE, Web of Science, and Cochrane, from inception until April 2025. Primary outcomes were neuropsychological tests in global intellectual functioning and across five cognitive domains: language, memory, executive functioning, visuospatial functioning, and attention/processing speed. We also included measures evaluating depression and anxiety symptoms and quality of life in epilepsy. A random-effects meta-analysis was performed when at least two measures were available across studies, calculating the standardized mean difference (SMD) and 95% confidence interval (CI) between baseline and postoperative testing at or over 12 months. RESULTS: Of 2227 articles identified, we included 10 studies in our qualitative systematic review and five nonduplicated studies (373 patients) in our meta-analysis. Intellectual functioning, cognitive functioning, depression, anxiety, and quality of life either improved or remained stable across the included studies. Meta-analysis revealed nonsignificant changes in intellectual functioning (SMD = -.03, 95% CI = -.49 to .42) and two of the five cognitive domains: language (Boston Naming Test: SMD = .12, 95% CI = -.10 to .33; Verbal Comprehension Index: SMD = -.16, 95% CI = -.58 to .26) and visuospatial functioning (Perceptual Reasoning Index: SMD = .07, 95% CI = -.36 to .49). The remaining domains could not be evaluated given the limited number of studies. For mood, meta-analysis revealed a nonsignificant decrease in depression score (Beck Depression Inventory-II: SMD = -.14, 95% CI = -.33 to .06). GRADE (Grading of Recommendations Assessment, Development, and Evaluation) certainty of evidence was moderate for intellectual and visuospatial functioning and high for language and depression measures. SIGNIFICANCE: Our systematic review and meta-analysis suggest that RNS does not impact neuropsychological and neurobehavioral outcomes at a group level, at least for the measures examined. We review putative mechanisms by which RNS may impact cognition and offer suggestions for future research in this domain.