VBM signatures of abnormal eating behaviours in frontotemporal lobar degeneration

Abstract

The brain bases of specific human behaviours in health and disease are not well established. In this voxel-based morphometric (VBM) study we demonstrate neuroanatomical signatures of different abnormalities of eating behaviour (pathological sweet tooth and increased food consumption, or hyperphagia) in individuals with frontotemporal lobar degeneration (FTLD). Sixteen male patients with FTLD were assessed using the Manchester and Oxford Universities Scale for the Psychopathological Assessment of Dementia and classified according to the presence or absence of abnormal eating behaviours. Volumetric brain magnetic resonance imaging was performed in all patients and in a group of nine healthy age-matched male controls and grey matter changes were assessed using an optimised VBM protocol. Compared with healthy controls, the FTLD group had a typical pattern of extensive bilateral grey matter loss predominantly involving the frontal and temporal lobes. Within the FTLD group, grey matter changes associated with different abnormal behaviours were assessed independently using a covariate-only model. The development of pathological sweet tooth was associated with grey matter loss in a distributed brain network including bilateral posterolateral orbitofrontal cortex (Brodmann areas 12/47) and right anterior insula. Hyperphagia was associated with more focal grey matter loss in anterolateral OFC bilaterally (Brodmann area 11). In accord with emerging evidence in humans and other species, our findings implicate distinct components of a multi-component brain network in the control of specific aspects of eating behaviour.

Introduction

The brain bases of specific human behaviours in health and disease have attracted much recent interest (Regard and Landis, 1997, Bechara et al., 2000, Benjamin et al., 2000, Blair and Cipolotti, 2000, London et al., 2000, Small et al., 2001b, Small et al., 2005, Brody et al., 2002, O'Doherty et al., 2002, Volle et al., 2002, Tataranni and DelParigi, 2003, Arana et al., 2003, De Araujo et al., 2003a, De Araujo et al., 2003b, Gottfried et al., 2003, Levine et al., 2003, Thompson et al., 2003, Kringelbach and Rolls, 2004, Gorno-Tempini et al., 2004b, Hinton et al., 2004, Pelchat et al., 2004, Wang et al., 2004, Uher and Treasure, 2005, Rosen et al., 2005, Williams et al., 2005) but remain incompletely understood. Behavioural abnormalities are a cardinal diagnostic feature and an important clinical issue in frontotemporal lobar degeneration (FTLD): a group of neurodegenerative diseases characterised by progressive focal frontal and temporal lobe atrophy which together constitute a common cause of dementia in younger age groups (McKhann et al., 2001, Chan et al., 2001, Ikeda et al., 2002, Thompson et al., 2003, Gorno-Tempini et al., 2004a, Gorno-Tempini et al., 2004b, Rosen et al., 2005, Whitwell et al., 2005, Williams et al., 2005). FTLD is both clinically and pathologically heterogeneous, however three main syndromic variants are recognised: frontotemporal dementia (FTD), presenting with predominant behavioural problems, semantic dementia (SD) presenting as an impairment of semantic memory, and progressive non-fluent aphasia (PNFA) presenting with predominant speech production difficulties (McKhann et al., 2001, Chan et al., 2001, Ikeda et al., 2002, Thompson et al., 2003, Gorno-Tempini et al., 2004a, Gorno-Tempini et al., 2004b, Rosen et al., 2005, Williams et al., 2005). These clinical phenotypes are associated with characteristic patterns of brain atrophy on magnetic resonance imaging (MRI): typically, FTD is associated with bilateral frontal atrophy; SD is associated with predominantly left anterior temporal lobe atrophy; and PNFA is associated with left peri-Sylvian atrophy. Although the clinical picture is variable, behavioural disturbances can occur in all FTLD syndromes and are often striking early in the course of FTD and SD. Disturbances of eating behaviour are common, and may include increased food consumption (hyperphagia), compulsive food seeking, food fads, and craving of sweet foods or pathological ‘sweet tooth’ (Ikeda et al., 2002, Thompson et al., 2003, Gorno-Tempini et al., 2004b, Rosen et al., 2005, Williams et al., 2005). Of the plethora of behavioural abnormalities described in FTLD, abnormal eating behaviour is a particularly attractive target for neuroanatomical correlation, as a priori anatomical hypotheses concerning the likely brain substrates are available. Moreover, human eating behaviour is of great neurobiological interest, as it links basic homeostatic drives and sensory processes with complex cognition.

While functional imaging studies in the healthy brain allow distributed functional networks to be delineated, the study of diseased brains is necessary in order to identify critical areas within a distributed network. In contrast to many patients with focal brain lesions, where function is lost as a result of brain damage, patients with FTLD also illustrate the effects of brain damage in ‘releasing’ abnormal behaviour that is often complex and may be goal-directed. These individuals therefore present a unique opportunity to identify brain regions that are likely to be essential for specific human behaviours in both health and disease (Rosen et al., 2005, Williams et al., 2005). Despite much recent interest in establishing brain substrates for behavioural change in FTLD (Thompson et al., 2003, Gorno-Tempini et al., 2004b, Rosen et al., 2005, Williams et al., 2005), few correlations have so far been established between specific behaviours and volume loss in particular brain regions. This is a difficult issue for at least two reasons: degenerative diseases tend to produce diffuse pathological and anatomical changes, even where (as in FTLD) the process is relatively focal; and abnormal behaviours may be correlated with one another and with the overall stage and severity of disease.

In this study, we used the automated and unbiased technique of voxel-based morphometry (VBM) in order to assess grey matter changes associated with specific abnormalities of eating behaviour (pathological sweet tooth, increased food consumption and increased speed of eating) that are commonly prominent in patients with FTLD. Evidence emerging from functional imaging, electrophysiological and focal lesion studies in humans and other species suggests that food seeking and consumption are mediated by a distributed network of brain areas. The most consistently implicated areas across studies are primary and non-primary gustatory and limbic cortices in the insula and anterior temporal lobe (especially the right) and orbitofrontal cortex (OFC) bilaterally (Small et al., 1997, Small et al., 2001a, Small et al., 2001b, Small et al., 2003, Small et al., 2004, O'Doherty et al., 2001, De Araujo et al., 2003a, De Araujo et al., 2003b, Killgore et al., 2003, Hinton et al., 2004, Kringelbach et al., 2003, Kringelbach et al., 2004, Wang et al., 2004, Kadohisa et al., 2005, Rolls, 2005, Small, 2006). This network is involved in the regulation of biological drives and the interface with complex goal-directed behaviour (Bechara et al., 2000, O'Doherty et al., 2002, Arana et al., 2003, Gottfried et al., 2003, Small et al., 2003, Kringelbach and Rolls, 2004, Rolls, 2005). Alterations in the function of the network have been implicated in the pathogenesis of a wide range of disease states, including eating disorders (Regard and Landis, 1997, Levine et al., 2003, Tataranni and DelParigi, 2003, Pelchat et al., 2004, Uher and Treasure, 2005) and drug addiction (London et al., 2000, Brody et al., 2002), which have certain behavioural features similar to those exhibited by individuals with FTLD. In the present study, we hypothesised that this brain network (bilateral OFC, right insula and anterior temporal lobes) is damaged in individuals with FTLD who exhibit abnormalities of eating behaviour, and further, that specific areas of brain volume reduction in FTLD are associated with particular abnormalities of eating behaviour.