Decoding expectation and surprise in dementia: the paradigm of music

Abstract

Making predictions about the world and responding appropriately to unexpected events are essential functions of the healthy brain. In neurodegenerative disorders, such as frontotemporal dementia and Alzheimer's disease, impaired processing of 'surprise' may underpin a diverse array of symptoms, particularly abnormalities of social and emotional behaviour, but is challenging to characterize. Here, we addressed this issue using a novel paradigm: music. We studied 62 patients (24 female; aged 53-88) representing major syndromes of frontotemporal dementia (behavioural variant, semantic variant primary progressive aphasia, non-fluent-agrammatic variant primary progressive aphasia) and typical amnestic Alzheimer's disease, in relation to 33 healthy controls (18 female; aged 54-78). Participants heard famous melodies containing no deviants or one of three types of deviant note-acoustic (white-noise burst), syntactic (key-violating pitch change) or semantic (key-preserving pitch change). Using a regression model that took elementary perceptual, executive and musical competence into account, we assessed accuracy detecting melodic deviants and simultaneously recorded pupillary responses and related these to deviant surprise value (information-content) and carrier melody predictability (entropy), calculated using an unsupervised machine learning model of music. Neuroanatomical associations of deviant detection accuracy and coupling of detection to deviant surprise value were assessed using voxel-based morphometry of patients' brain MRI. Whereas Alzheimer's disease was associated with normal deviant detection accuracy, behavioural and semantic variant frontotemporal dementia syndromes were associated with strikingly similar profiles of impaired syntactic and semantic deviant detection accuracy and impaired behavioural and autonomic sensitivity to deviant information-content (all P < 0.05). On the other hand, non-fluent-agrammatic primary progressive aphasia was associated with generalized impairment of deviant discriminability (P < 0.05) due to excessive false-alarms, despite retained behavioural and autonomic sensitivity to deviant information-content and melody predictability. Across the patient cohort, grey matter correlates of acoustic deviant detection accuracy were identified in precuneus, mid and mesial temporal regions; correlates of syntactic deviant detection accuracy and information-content processing, in inferior frontal and anterior temporal cortices, putamen and nucleus accumbens; and a common correlate of musical salience coding in supplementary motor area (all P < 0.05, corrected for multiple comparisons in pre-specified regions of interest). Our findings suggest that major dementias have distinct profiles of sensory 'surprise' processing, as instantiated in music. Music may be a useful and informative paradigm for probing the predictive decoding of complex sensory environments in neurodegenerative proteinopathies, with implications for understanding and measuring the core pathophysiology of these diseases.

Keywords: frontotemporal dementia; music; pupillometry; surprise; voxel-based morphometry.

Graphical Abstract

Figure 1

Performance of detection of different types of deviants in melodies, for all participant groups. For each panel (deviant condition), d-prime value is plotted for individuals within each participant group (see also Table 2). Each dot corresponds to an individual data point; boxes code the interquartile range, whiskers represent the ranges for the bottom 25% and the top 25% of the data values (excluding outliers) and the horizontal line in each box represents the median d-prime value. AD, patient group with Alzheimer’s disease; bvFTD, patient group with behavioural variant frontotemporal dementia; Control, healthy control group; nfvPPA, patient group with non-fluent-agrammatic variant primary progressive aphasia; svPPA, patient group with semantic variant primary progressive aphasia.

Figure 2

Time course of pupil dilatation responses to melodic deviants in each of the experimental conditions, for all participant groups. Onset of the deviant note is at time 0 (indicated by vertical grey line on each panel). To generate these pupil time series, trial-by-trial pupil time series from individual participants were first filtered, smoothed, converted to z-scores based on the signal mean and standard deviation for that participant’s dataset and baseline-corrected by subtracting the pre-deviant baseline (details in Supplementary material); the plots show the mean normalized pupil time series flanked by error envelopes representing the standard deviation of the group pupillary response, for each experimental condition (coded at lower left). AD, patient group with Alzheimer’s disease; bvFTD, patient group with behavioural variant frontotemporal dementia; Controls, healthy control group; nfvPPA, patient group with non-fluent-agrammatic variant primary progressive aphasia; svPPA, patient group with semantic variant primary progressive aphasia.

Figure 3

Neuroanatomical correlates of accurate detection of melodic deviants and coupling between detection and musical surprise value in the combined patient cohort. Statistical parametric maps (SPMs) show regional grey matter volume positively associated with acoustic (top panels) and syntactic (middle panels) deviant detection accuracy and coupling between deviant detection accuracy and deviant note IC (bottom panels) in familiar melodies, based on voxel-based morphometry of patients’ brain MR images. SPMs are thresholded for display purposes at P < 0.001 uncorrected over the whole brain; however, local maxima of areas shown were each significant at P < 0.05 after family-wise error correction for multiple voxel-wise comparisons within pre-specified anatomical regions of interest (see Table 3 and Supplementary Fig. 2); T-scores are coded on the colour bar. SPMs are overlaid on sections of the normalized study-specific T1-weighted mean brain MR image; the MNI coordinate (mm) of the plane of each section is indicated, and the right hemisphere is shown on the right in coronal sections.