Uncovering the prevalence and neural substrates of anhedonia in frontotemporal dementia

Abstract

Much of human behaviour is motivated by the drive to experience pleasure. The capacity to envisage pleasurable outcomes and to engage in goal-directed behaviour to secure these outcomes depends upon the integrity of frontostriatal circuits in the brain. Anhedonia refers to the diminished ability to experience, and to pursue, pleasurable outcomes, and represents a prominent motivational disturbance in neuropsychiatric disorders. Despite increasing evidence of motivational disturbances in frontotemporal dementia (FTD), no study to date has explored the hedonic experience in these syndromes. Here, we present the first study to document the prevalence and neural correlates of anhedonia in FTD in comparison with Alzheimer’s disease, and its potential overlap with related motivational symptoms including apathy and depression. A total of 172 participants were recruited, including 87 FTD, 34 Alzheimer’s disease, and 51 healthy older control participants. Within the FTD group, 55 cases were diagnosed with clinically probable behavioural variant FTD, 24 presented with semantic dementia, and eight cases had progressive non-fluent aphasia (PNFA). Premorbid and current anhedonia was measured using the Snaith-Hamilton Pleasure Scale, while apathy was assessed using the Dimensional Apathy Scale, and depression was indexed via the Depression, Anxiety and Stress Scale. Whole-brain voxel-based morphometry analysis was used to examine associations between grey matter atrophy and levels of anhedonia, apathy, and depression in patients. Relative to controls, behavioural variant FTD and semantic dementia, but not PNFA or Alzheimer’s disease, patients showed clinically significant anhedonia, representing a clear departure from pre-morbid levels. Voxel-based morphometry analyses revealed that anhedonia was associated with atrophy in an extended frontostriatal network including orbitofrontal and medial prefrontal, paracingulate and insular cortices, as well as the putamen. Although correlated on the behavioural level, the neural correlates of anhedonia were largely dissociable from that of apathy, with only a small region of overlap detected in the right orbitofrontal cortices whilst no overlapping regions were found between anhedonia and depression. This is the first study, to our knowledge, to demonstrate profound anhedonia in FTD syndromes, reflecting atrophy of predominantly frontostriatal brain regions specialized for hedonic tone. Our findings point to the importance of considering anhedonia as a primary presenting feature of behavioural variant FTD and semantic dementia, with distinct neural drivers to that of apathy or depression. Future studies will be essential to address the impact of anhedonia on everyday activities, and to inform the development of targeted interventions to improve quality of life in patients and their families.

Anhedonia in Semantic Dementia—Exploring Right Hemispheric Contributions to the Loss of Pleasure

“…Abnormal hedonic processing of sounds has been documented in a mixed sample of FTLD, including SD patients, correlating with grey matter atrophy in a right-lateralised network including the anteromedial temporal lobe, insula, anterior cingulate, and nucleus accumbens [39]. These regions map remarkably well onto those reported in a recent study of anhedonia in an independent mixed FTLD sample, comprising SD patients [22], suggesting a modulating role for right-sided brain regions in the genesis of anhedonia in SD.…”

“…Scores range from 14 to 56, with lower scores indicating a lower level of hedonic tone, i.e., a higher level of anhedonia. Given the well-documented lack of insight in many dementia disorders [49], we modified the SHAPS to probe carer ratings of anhedonia in the patient across two time points: (i) before symptom onset and (ii) current time [22]. These two measures formed the main scores of interest for subsequent analyses.…”

“…Whole-brain voxel-based morphometry (VBM) analyses were employed to investigate voxel-by-voxel changes in grey matter intensity between groups, using FSL (FMRIB Software Library: https://fsl.fmrib.ox.ac.uk/fsl/fslwiki (accessed on 27 July 2021)). A standard pre-processing pipeline was implemented as per previous studies [22,51]. Briefly, this included brain extraction [52], tissue segmentation [53], and alignment of brain-extracted images to the Montreal Neurological Institute (MNI) standard space using a non-linear approach [54,55].…”

“…An alternate proposal is that the excessive reward-seeking behaviours emerging in the context of right-hemisphere atrophy described by Perry and colleagues stem from a blunted sensitivity to rewarding stimuli [21]. A recent study demonstrated a marked attenuation in the capacity to experience pleasure in FTD, attributable to dysregulation of an extended frontostriatal network typically implicated in reward processing [22]. Importantly, the neuroanatomical signature of anhedonia in FTD was found to be predominantly right-lateralised converging on orbitofrontal, paracingulate, and insular cortices, as well as the right putamen [22].…”

“…A recent study demonstrated a marked attenuation in the capacity to experience pleasure in FTD, attributable to dysregulation of an extended frontostriatal network typically implicated in reward processing [22]. Importantly, the neuroanatomical signature of anhedonia in FTD was found to be predominantly right-lateralised converging on orbitofrontal, paracingulate, and insular cortices, as well as the right putamen [22]. These insights resonate with reports of right-sided frontoinsular involvement in canonical features of reward insensitivity in bvFTD, such as overeating and sweet food cravings [23][24][25][26].…”