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

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. This work investigates the alterations in frontoparietal effective connectivity in regions with atypical activation during working memory performance, with particular attention to self-connections (intrinsic inhibitory influences each region exerts on itself). Forty-three adolescents with NF1 and 26 age-matched neurotypical controls completed functional magnetic resonance imaging scans during a verbal working memory task. Dynamic causal models (DCMs) were estimated for the 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 intrinsic (self-) connections. Leave-one-out cross-validation (LOO-CV) was performed to test the generalisability of group differences. NF1 participants demonstrated greater endogenous self-connectivity of left dlPFC and IPG. The DCM that best explained the effects of working memory showed that the NF1 group has increased intrinsic connectivity of left vlPFC but weaker intrinsic connectivity of left dlPFC, left SPG and right IPG. The parameters of these connections showed a modest but positive predictive correlation coefficient of 0.34 (p = 0.002) with diagnosis status, suggesting a predictive value. Overall, increased endogenous self-connectivity of left dlPFC and IPG 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, left SPG and right IPG and more inhibitory intrinsic connectivity of left vlPFC in NF1. This discrepancy between endogenous 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.