An ecological approach to identify distinct neural correlates of disinhibition in frontotemporal dementia

Abstract

Disinhibition is a core symptom of many neurodegenerative diseases, particularly frontotemporal dementia, and is a major cause of stress for caregivers. While a distinction between behavioural and cognitive disinhibition is common, an operational definition of behavioural disinhibition is still missing. Furthermore, conventional assessment of behavioural disinhibition, based on questionnaires completed by the caregivers, often lacks ecological validity. Therefore, their neuroanatomical correlates are non-univocal. In the present work, we used an original behavioural approach in a semi-ecological situation to assess two specific dimensions of behavioural disinhibition: compulsivity and social disinhibition. First, we investigated disinhibition profile in patients compared to controls. Then, to validate our approach, compulsivity and social disinhibition scores were correlated with classic cognitive tests measuring disinhibition (Hayling Test) and social cognition (mini-Social cognition & Emotional Assessment). Finally, we disentangled the anatomical networks underlying these two subtypes of behavioural disinhibition, taking in account the grey (voxel-based morphometry) and white matter (diffusion tensor imaging tractography). We included 17 behavioural variant frontotemporal dementia patients and 18 healthy controls. We identified patients as more compulsive and socially disinhibited than controls. We found that behavioural metrics in the semi-ecological task were related to cognitive performance: compulsivity correlated with the Hayling test and both compulsivity and social disinhibition were associated with the emotion recognition test. Based on voxel-based morphometry and tractography, compulsivity correlated with atrophy in the bilateral orbitofrontal cortex, the right temporal region and subcortical structures, as well as with alterations of the bilateral cingulum and uncinate fasciculus, the right inferior longitudinal fasciculus and the right arcuate fasciculus. Thus, the network of regions related to compulsivity matched the "semantic appraisal" network. Social disinhibition was associated with bilateral frontal atrophy and impairments in the forceps minor, the bilateral cingulum and the left uncinate fasciculus, regions corresponding to the frontal component of the "salience" network. Summarizing, this study validates our semi-ecological approach, through the identification of two subtypes of behavioural disinhibition, and highlights different neural networks underlying compulsivity and social disinhibition. Taken together, these findings are promising for clinical practice by providing a better characterisation of inhibition disorders, promoting their detection and consequently a more adapted management of patients.

Keywords: Compulsivity; Diffusion tensor imaging; Semi-ecological situation; Social disinhibition; Voxel-based morphometry.

Fig. 1

Illustrative reconstruction of the tracts of interest in a sagittal (left) and a coronal (right) view. The cingulum (light blue), the forceps minor (yellow), the uncinate fasciculus (neon green), the inferior longitudinal fasciculus (light green) and the arcuate fasciculus (dark blue) are displayed. These data are from a behavioural variant frontotemporal dementia patient (64 years old, male): the tracts of interest are derived from 3D Slicer and overlaid on the T1-weighted image associated to the fractional anisotropy map.

Fig. 2

Significant correlations between the Hayling time B-A and compulsivity (a) and between the emotion recognition score and compulsivity (b) and social disinhibition (c). r: Spearman’s correlation coefficient, p: p-value derived from the Spearman’s correlation.

Fig. 3

Regions of significant grey matter atrophy associated with compulsivity (a,b) and social disinhibition (c,d) in behavioural variant frontotemporal dementia patients and healthy controls (A) and in behavioural variant frontotemporal dementia patients only (B). Results are displayed in neurological convention on the 3-dimensional brain template and on axial and sagittal slices of the MNI standard brain (P < 0.001 uncorrected). L: left; R: right. (C) Partial regression plots of residual grey matter volume associated with residual compulsivity (a,c) and residual social disinhibition (b,d) influenced by the covariates age, sex and total intracranial volume in behavioural variant frontotemporal dementia patients (a,d) and healthy controls (c,d). Grey matter volumes were extracted from all clusters of significant grey matter atrophy associated with compulsivity and social disinhibition. (D) Scatter plots with marked subjects related to the global maxima of atrophy associated with compulsivity (a) and social disinhibition (b) in behavioural variant frontotemporal dementia patients and healthy controls. The 17 first scans are bvFTD patients, the 18 lasts scans are HC.

Fig. 4

Behavioural disinhibition and fractional anisotropy of white matter tracts. Linear regression model and scatter plots of compulsivity and social disinhibition scores and fractional anisotropy in the left cingulum (a), the forceps minor (b) and the left uncinate fasciculus (c) in behavioural variant frontotemporal dementia patients. Equations and p-values are derived from the linear regression model.

Fig. 5

Schematic representation of the cortical regions and white matter tracts involved in compulsivity (a) and social disinhibition (b). Each white matter bundle associated with a deficit is displayed in a specific colour as in Fig. 1. Non-significant bundles are shown in grey. See also Supplementary Table 4 for statistical significance. Abbreviations = ILF: Inferior longitudinal fasciculus; L: Left; OFC; Orbitofrontal cortex; R: Right.