Fronto-parietal effective connectivity during working memory in Neurofibromatosis Type 1 adolescents and neurotypical controls

Background Neurofibromatosis Type 1 (NF1) is a rare, a single-gene neurodevelopmental disorder. Atypical brain activation patterns have been linked to working memory difficulties in NF1 patients. The present work investigated if greater inhibitory activity underlies in interactions between neuronal populations in NF1 patients, as estimated with effective connectivity during working memory ask. Methods Forty-three adolescent patients with NF1 and twenty-six age-matched neurotypical controls completed functional magnetic resonance imaging scans during a verbal working memory task. Dynamic causal models were estimated for bilateral fronto-parietal network (dorsolateral and ventrolateral prefrontal cortices (dlPFC and vlPFC), superior and inferior parietal gyri (SPG and IPG)). Parametric empirical Bayes approach with Bayesian model reduction was used to test the hypothesis that NF1 diagnosis would be characterised by greater inhibitory self-connections (intrinsic connectivity). Leave-one-out cross-validation (LOO-CV) was performed to test the generalisability of group differences. Results NF1 participants have greater average connectivity of left dlPFC, IPG, SPG and bilateral vlPFC. The winning model of Bayesian model reduction investigating effects of working memory showed that NF1 patients have stronger intrinsic connectivity of left vlPFC, but weaker connectivity of right vlPFC and left dlPFC. The parameters of these connections were weakly predictive of NF1 diagnosis; correlation coefficient between true and predicted scores was 0.19 (p = 0.055) Conclusions Increased average connectivity of left dlPFC, IPG, SPG and bilateral vlPFC in NF1, suggests greater overall sensitivity of these regions to inputs. Working memory evoked different patterns of input processing in NF1, that cannot be characterised by increased inhibition alone. Instead, modulatory connectivity related to working memory showed more inhibitory self-connectivity of left dlPFC and left vlPFC, and less inhibitory intrinsic connectivity of right vlPFC in NF1. Importantly, this discrepancy between average and modulatory connectivity suggests that overall NF1 participants are responsive to cognitive task-related inputs but may show atypical adaptation to the task demands of working memory.