Objective: Frontotemporal Dementia (FTD) is a neurodegenerative disorder that results in disinhibition and difficulty with flexible responding when provided feedback. Inflexible responding is observed early in the course of the illness and contributes to the financial and social morbidities of FTD. Reversal learning is an established cognitive paradigm that indexes flexible responding in the face of feedback signaling a change in reinforcement contingencies, with components of reversal learning associated with specific neurotransmitter systems. The objective of the study was to evaluate the neural mechanisms underlying impaired flexible behavioural responding in FTD using a reversal learning paradigm combined with fMRI.

Methods: Twenty-two patients meeting the diagnostic criteria for FTD and twenty-one healthy controls completed the study. Participants completed an fMRI-adapted reversal learning task that indexes behavioural flexibility when provided positive and negative feedback.

Results: Patients with FTD demonstrated poorer behavioural flexibility relative to controls and abnormal BOLD responses within the left ventrolateral prefrontal cortex to incorrect responses made during the learning phase, and during correct responses when reward contingencies were reversed. As well, patients showed decreased activity within the left dorsal lateral prefrontal cortex to incorrect responses compared to controls.

Conclusions: These findings suggest that reversal learning impairments in patients with FTD, in particular those with frontal predominant atrophy, may be related to impaired flexible motor responding when selecting among several choices and deficient attention to relevant stimuli during instances of conflict (i.e. receiving negative feedback). These results and the associated neurotransmitter systems mediating these regions may provide targets for future pharmacological or behavioural interventions mediating these cognitive deficits.