Disrupted avoidance learning in functional neurological disorder: Implications for harm avoidance theories

Abstract

Background: Functional neurological disorder (FND) is an elusive disorder characterized by unexplained neurological symptoms alongside aberrant cognitive processing and negative affect, often associated with amygdala reactivity.

Methods: We examined the effect of negative conditioning on cognitive function and amygdala reactivity in 25 FND patients and 20 healthy volunteers (HV). Participants were first conditioned to stimuli paired with negative affective or neutral (CS +/CS -) information. During functional MRI, subjects then performed an instrumental associative learning task to avoid monetary losses in the context of the previously conditioned stimuli. We expected that FND patients would be better at learning to avoid losses when faced with negatively conditioned stimuli (increased harm avoidance). Multi-echo resting state fMRI was also collected from the same subjects and a robust denoising method was employed, important for removing motion and physiological artifacts.

Results: FND subjects were more sensitive to the negative CS + compared to HV, demonstrated by a reinforcement learning model. Contrary to expectation, FND patients were generally more impaired at learning to avoid losses under both contexts (CS +/CS -), persisting to choose the option that resulted in a negative outcome demonstrated by both behavioural and computational analyses. FND patients showed enhanced amygdala but reduced dorsolateral prefrontal cortex responses when they received negative feedback. Patients also had increased resting state functional connectivity between these two regions.

Conclusions: FND patients had impaired instrumental avoidance learning, findings that parallel previous observations of impaired action-outcome binding. FND patients further show enhanced behavioural and neural sensitivity to negative information. However, this did not translate to improved avoidance learning. Put together, our findings do not support the theory of harm avoidance in FND. We highlight a potential mechanism by which negative contexts interfere with adaptive behaviours in this under-explored disorder.

Keywords: Amygdala; Avoidance learning; Conversion disorder; Functional neurological disorder.

Fig. 1

Task schematic. 1. Conditioning phase outside the scanner: One of four abstract shapes were paired with either a negative outcome (aversive sound and image) or a neutral outcome (neutral tone and image) for a total of 120 trials. Participants were separately shown a third shape with no outcome to control for familiarity. 2. Avoidance learning task during functional MRI: Following the conditioning phase, participants underwent functional MRI scanning while performing an instrumental aversion learning task with feedback. Participants chose between two stimuli (previously conditioned or familiar versus novel). The previously conditioned and familiar stimuli (CS + or CS −) was more likely to be associated with a monetary loss outcome (66/33% contingency). Subjects needed to learn to avoid the stimulus associated with loss.

Fig. 2

Avoidance learning captured by Q-learning reinforcement learning model. Top: Functional neurological disorder (FND) patients showed impaired avoidance learning in the presence of a negative CS +, a neutral CS − and an unconditioned familiar stimulus (group effects: accuracy, p = 0.019; trials to acquisition, p = 0.038) compared to healthy volunteers (HV). Bottom: The learning rate, alpha, was significantly lower across conditions in the FND group (p = 0.037). The temperature parameter, beta, was elevated in FND (p = 0.025), with a group × condition interaction (p = 0.03) and significant group difference in the CS + condition (p < 0.001), but not for CS − or familiar (p > 0.05). The initial value estimate, gamma, was also lower in FND compared to HV (p = 0.036).

Fig. 3

Patients with functional neurological disorder (FND) showed decreased left dorsolateral prefrontal cortex (dlpfc) and increased bilateral amygdala responses to monetary loss outcomes during a probabilistic avoidance learning task, compared to healthy volunteers (HV). Parameter estimates (PE) are plotted and peak difference clusters are displayed on a standard MNI template.

Fig. 4

Patients with functional neurological disorder (FND) have increased resting state functional connectivity between bilateral amygdala and right dorsolateral prefrontal cortex (dlpfc, yellow cluster displayed). In the FND group, there was a trend towards negative relationship between amygdala and dlpfc connectivity with goal-directed avoidance learning accuracy in the context of a neutral CS − (t = − 2.03, p = 0.059).

Supplementary Fig. 1

Amygdala reactivity and anxiety. Parameter estimates for amygdala responses to loss showed a significant group interaction with anxiety score (state and trait anxiety inventory, STAI), in which patients with functional neurological disorder (FND) showed a negative relationship between amygdala reactivity and anxiety but healthy volunteers (HV) showed a positive relationship.