Disrupted Frontoparietal Dynamics in Neurofibromatosis Type 1: Reduced Sensitivity and Atypical Modulation During Working Memory

Abstract Neurofibromatosis Type 1 (NF1) is a rare, single-gene neurodevelopmental disorder. Atypical brain activation patterns have been linked to working memory difficulties in individuals with NF1. The present work investigates if NF1 has increased inhibitory activity in the frontoparietal network during working memory tasks compared to neurotypical controls. Forty-three adolescents with NF1 and twenty-six age-matched neurotypical controls completed functional magnetic resonance imaging scans during a verbal working memory task. Dynamic causal models (DCMs) were estimated for bilateral frontoparietal network (dorsolateral and ventrolateral prefrontal cortices (dlPFC and vlPFC), superior and inferior parietal gyri (SPG and IPG)). The 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. NF1 participants demonstrated greater average intrinsic connectivity of left dlPFC, IPG, SPG and bilateral vlPFC. The DCM that best explained effects of working memory showed that NF1 group has increased intrinsic connectivity of left vlPFC, but weaker intrinsic connectivity of right vlPFC and left dlPFC. The parameters of these connections showed a modest but positive predictive correlation of r = 0.19 (p = 0.055) with diagnosis status, suggesting a trend toward predictive value. Overall, increased average intrinsic connectivity of left dlPFC, IPG, SPG and bilateral vlPFC in NF1, suggests reduced 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 less inhibitory self-connectivity of left dlPFC and left vlPFC, and more inhibitory intrinsic connectivity of right vlPFC in NF1. 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. Competing Interest Statement The authors have declared no competing interest. Footnotes ↵* Joint senior authors Data/code availability: The NF1 group’s data have been deposited on the Sage Bionetworks data repository https://www.synapse.org/. Approved researchers can request to obtain the data which are subject to data sharing agreements. Codes for data processing and analysis are available at https://github.com/MCLit/NF1-DCM-WM. Ethics statement: Ethics approval for the study was obtained from the North West-Greater Manchester South Research Ethics Committee (reference: 18/NW/0762). Written informed consent was obtained from the parents and older adolescent participants and assent was obtained from the younger participants. Conflict of Interests: None of the authors have a conflict of interest to disclose Refining figures and results and interpretation.