Cerebellar GABA and executive function among adult female carriers of the fragile X messenger ribonucleoprotein 1 premutation: a pilot study to examine neural underpinnings of the clinical phenotype.

The FMR1 premutation is associated with a complex clinical phenotype, with increased risk for outcomes across the domains of psychological disorders, motor functioning, and reproductive health. A key gap is understanding intermediate processing that may help to explain how the FMR1 premutation alters brain functioning to confer increased risk across these domains. The current study begins to address this gap by focusing on two candidate, interrelated processes: cerebellar GABA and executive function. Data were collected from a cohort of 15 adult female FMR1 premutation carriers and a comparison group of 15 age-matched unaffected controls. Cerebellar GABA concentration was measured using edited magnetic resonance spectroscopy (MEGA-sLASER) at 3 T. Executive function was measured across two units of analysis: the error-related negativity, an EEG marker of automatic error detection, as well as performance-based measures from validated neuropsychological tests. Premutation carriers exhibited an atypical scalp topography of the error-related negativity. In controls but not in premutation carriers, error-related brain activity was associated with cerebellar GABA concentration and performance-based executive function. This pattern of preliminary findings suggests that the FMR1 premutation may alter the neural network involved in error monitoring. If these findings are confirmed in larger cohorts, they have potential implications for understanding the emergence of the broader clinical phenotype in adult FMR1 premutation carriers.