Risky Decision Making in Neurofibromatosis Type 1: An Exploratory Study

Abstract

Background: Neurofibromatosis type 1 (NF1) is a monogenic disorder affecting cognitive function. About one third of children with NF1 have attentional disorders, and the cognitive phenotype is characterized by impairment in prefrontally-mediated functions. Mouse models of NF1 show irregularities in GABA release and striatal dopamine metabolism. We hypothesized that youth with NF1 would show abnormal behavior and neural activity on a task of risk-taking reliant on prefrontal-striatal circuits.

Methods: Youth with NF1 (N=29) and demographically comparable healthy controls (N=22), ages 8-19, were administered a developmentally sensitive gambling task, in which they chose between low-risk gambles with a high probability of obtaining a small reward, and high-risk gambles with a low probability of obtaining a large reward. We used functional magnetic resonance imaging (fMRI) to investigate neural activity associated with risky decision making, as well as age-associated changes in these behavioral and neural processes.

Results: Behaviorally, youth with NF1 tended to make fewer risky decisions than controls. Neuroimaging analyses revealed significantly reduced neural activity across multiple brain regions involved in higher-order semantic processing and motivation (i.e., anterior cingulate, paracingulate, supramarginal, and angular gyri) in patients with NF1 relative to controls during the task. We also observed atypical age-associated changes in neural activity in patients with NF1, such that during risk taking, neural activity tended to decrease with age in controls, whereas it tended to increase with age in patients with NF1.

Conclusions: Findings suggest that developmental trajectories of neural activity during risky decision-making may be disrupted in youth with NF1.

Keywords: Decision-Making; Development; Functional MRI; Neurofibromatosis Type I; Phenotype-Genotype; Psychiatric Disorders.

Figure 1

The Cake Gambling Task. Participants are asked to choose between low-risk gambles with a high probability of obtaining a small reward (2 coins), versus high-risk gambles with a smaller probability of obtaining a higher reward (4-16 coins). In total, there were 84 trials, with 21 trials per condition. The trials were presented in an event-related fashion, and the order was consistent among subjects.

Figure 2

Behavioral results on the Cake Gambling Task. A. Overall Performance. Patients with NF1 showed reduced risky decision-making relative to controls in the 12 coin condition (p=0.030), and a trend towards reduced risky decision-making in the 16 coin condition (p=0.081). Both groups showed an increased tendency to make risky decisions with higher reward (p=0.004 in controls; p=0.014 in NF1 patients). B. Post Feedback Behavior. After receiving positive feedback (win), patients with NF1 were more likely than controls to make a safe decision (p=0.050). The groups did not differ on their responses after a loss.

Figure 3

fMRI results for neural activity during risky and safe decision making. Clusters represent regions where controls show significantly increased activity as compared to patients with NF1. Graphs represent percent signal change. A. Risky choice. We found significantly increased activity in the paracingulate cortex (p=6.56e-07) and anterior cingulate cortex (p=9.67e-05) in controls relative to NF1 patients. B. Safe choice. Controls showed significantly increased activity in the supramarginal gyrus (p-5.32E-11) and angular gyrus (p=4.83E-06) relative to NF1 patients.

Figure 4

fMRI results for neural activity during risky vs. safe decision making, and relationship with age. Clusters represent regions that showed a significant group by age interaction effect for risky vs. safe decisions. We found a significant interaction in the middle frontal gyrus and frontal pole, such that controls showed a negative relationship between neural activity and age, whereas patients with NF1 showed increasing neural activity with increasing age. Graphs represent percent signal change. Pearson correlation values: frontal pole: NF1: r=0.60, p=0.01; Controls: r=−0.49, p=0.04; angular gyrus: NF1: r=0.34, p=0.18; Controls: r=−0.76, p<0.01.

Figure 5

fMRI results for neural activity during risky vs. safe decision making, and relationship with individual propensity to make risky decisions. Clusters represent regions that showed a significant group interaction .Specifically, we found a significant interaction in the posterior cingulate cortex and frontal pole, such that controls showed a negative relationship between neural activity and risky decision-making, whereas patients with NF1 showed a positive relationship between neural activity and risky decision-making. Graphs represent percent signal change. Pearson correlation values: posterior cingulate: NF1: r=0.64, p<0.01; Controls: r=−0.57, p=0.02; frontal pole: NF1: r=0.41, p=0.10; Controls: r=−0.47, p=0.06.