Examining the cognitive phenotype in Neurofibromatosis 1: a systematic review of functional imaging studies

Neurofibromatosis 1 (NF1) is a rare genetic condition, frequently associated with learning difficulties. Functional neuroimaging techniques have been used to investigate brain mechanisms underlying learning difficulties in NF1, but these remain poorly understood. We conducted a systematic review of functional neuroimaging studies in NF1 from 2000-2024 aiming to develop a neurobiological framework for understanding the NF1 cognitive phenotype. A total of 44 studies were identified as relevant across functional magnetic resonance imaging (fMRI), electroencephalography (EEG), magnetic resonance spectroscopy (MRS), positron emission topography (PET), transcranial magnetic stimulation (TMS) and arterial spin labelling (ASL) techniques. Findings suggest mechanisms underlying learning in NF1 may be characterised as excitation/ inhibition imbalance, dysconnectivity between brain regions and perturbations in neural activation patterns. We suggest, disruptions in GABAergic signalling, beginning in early development, may alter the whole brain function, explaining the differential patterns of brain activity, connectivity, and brain chemistry. As most of the reviewed studies were cross-sectional in nature, future research should focus on longitudinal designs to better understand developmental changes in brain mechanisms and how these processes evolve over time. Finally, it is essential to explore environmental modifiers in shaping the cognitive phenotypes associated with NF1.