Diminished preparatory physiological responses in frontotemporal lobar degeneration syndromes

Abstract

Abstract Researchers typically study physiological responses either after stimulus onset or when the emotional valence of an upcoming stimulus is revealed. Yet, participants may also respond when they are told that an emotional stimulus is about to be presented even without knowing its valence. Increased physiological responding during this time may reflect a ‘preparation for action’. The generation of such physiological responses may be supported by frontotemporal regions of the brain that are vulnerable to damage in frontotemporal lobar degeneration. We examined preparatory physiological responses and their structural and functional neural correlate in five frontotemporal lobar degeneration clinical subtypes (behavioural variant frontotemporal dementia, n = 67; semantic variant primary progressive aphasia, n = 35; non-fluent variant primary progressive aphasia, n = 30; corticobasal syndrome, n = 32; progressive supranuclear palsy, n = 30). Comparison groups included patients with Alzheimer’s disease (n = 56) and healthy controls (n = 35). Preparatory responses were quantified as cardiac interbeat interval decreases (i.e. heart rate increases) from baseline to an ‘instruction period’, during which participants were told to watch the upcoming emotional film but not provided the film’s valence. Patients’ behavioural symptoms (apathy and disinhibition) were also evaluated via a caregiver-reported measure. Compared to healthy controls and Alzheimer’s disease, the frontotemporal lobar degeneration group showed significantly smaller preparatory responses. When comparing each frontotemporal lobar degeneration clinical subtype with healthy controls and Alzheimer’s disease, significant group differences emerged for behavioural variant frontotemporal dementia and progressive supranuclear palsy. Behavioural analyses revealed that frontotemporal lobar degeneration patients showed greater disinhibition and apathy compared to Alzheimer’s disease patients. Further, these group differences in disinhibition (but not apathy) were mediated by patients’ smaller preparatory responses. Voxel-based morphometry and resting-state functional MRI analyses revealed that across patients and healthy controls, smaller preparatory responses were associated with smaller volume and lower functional connectivity in a circuit that included the ventromedial prefrontal cortex and cortical and subcortical regions of the salience network. Diminished preparatory physiological responding in frontotemporal lobar degeneration may reflect a lack of preparation for actions that are appropriate for an upcoming situation, such as approaching or withdrawing from emotional stimuli. The ventromedial prefrontal cortex and salience network are critical for evaluating stimuli, thinking about the future, triggering peripheral physiological responses, and processing and interpreting interoceptive signals. Damage to these circuits in frontotemporal lobar degeneration may impair preparatory responses and help explain often-observed clinical symptoms such as disinhibition in these patients.