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Right frontoinsula (FI) dysconnectivity and von Economo neuron (VEN) loss correlate with the behavioral variant of frontotemporal dementia (bvFTD) functional severity. Two recent studies sought the neuroanatomical correlates of bvFTD disease severity, as measured using the Clinical Dementia Rating (CDR) scale, sum of boxes score. (A) Intrinsic connectivity mapping in vivo revealed that disease severity correlated with right FI connectivity to the rest of the salience network. (B) Postmortem quantitative neuropathological analysis of bilateral FI, performed on a nonoverlapping group of patients, revealed a convergent finding, with right-sided VEN loss correlating best with bvFTD clinical severity.
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The behavioral variant of frontotemporal dementia (bvFTD) slowly undermines emotion, social behavior, personal conduct, and decision making. These deficits occur in concert with focal neurodegeneration that can be quantified with modern structural and functional imaging and neuropathological methods. As a result, studies of bvFTD have helped to cla...
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... atrophy, as seen when death occurs prematurely due to comorbid motor neuron disease, showed selective VEN and fork cells losses ( Figure 5), and depletion of these cells correlated with atrophy sever- ity. Parallel to the findings from intrinsic connectivity mapping in vivo, right (but not left) FI VEN loss corre- lated with clinical severity (Fig. 6B). Furthermore, right (but not left) FI VEN and fork cell loss predicted greater disinhibition and overall behavioral symptom ...
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Background:
von Economo neurones (VEN) are bipolar neurones located in the anterior cingulate cortex (ACC) and the frontoinsular cortex (FI), areas affected early in behavioural variant frontotemporal dementia (bvFTD), in which VEN may constitute a selectively vulnerable cellular population.
Aim:
A previous study has shown a selective loss of VE...
Citations
... BvFTD-associated atrophy maps the salience network, an intrinsic connectivity network that functions to represent the emotional significance of internal and external stimuli in order to guide behavioural responses. [48][49][50] The medial pulvinar is highly connected with salience network nodes such as the anterior insula and ACC, 51 and damage to the pulvinar has been shown to disrupt functional connectivity in the salience network in bvFTD patients. 52 Atrophy to the medial pulvinar and ACC may thus increase impulsive decisionmaking by causing dysfunctions of the salience network, thereby reducing the positive salience of larger later rewards. ...
Behavioural variant frontotemporal dementia (bvFTD) is a neurodegenerative disorder characterized by behavioural changes and atrophy in brain regions important for decision-making. Computations such as trading off between larger later (LL) and smaller sooner (SS) rewards, called delay discounting in behavioural economics, might be heavily impaired by bvFTD. In this cross-sectional study, our objectives were to investigate (1) whether bvFTD patients show higher delay discounting than healthy controls, (2) whether this maladaptive discounting correlates with impulsivity-related bvFTD symptoms, and (3) in which brain regions atrophy is related to bvFTD's steeper discounting. BvFTD patients (N=24) and matched controls (N=18) performed two delay discounting tasks: one with monetary rewards and one with food rewards. We compared discount rates (log(k)) in bvFTD patients and controls and tested their correlations with symptoms. We used participants' structural MRI data and applied whole-brain mediation analyses to investigate brain structures mediating the effect of bvFTD on delay discounting. For both monetary and food rewards, delay discounting was significantly higher in bvFTD patients than in healthy controls. BvFTD patients' higher discounting of both money and food was associated with their greater disinhibition and eating behaviour changes. Whole-brain mediation analyses revealed that (1) several brain regions (left thalamic pulvinar, left parahippocampal cortex, right temporal lobe) were predictive of steeper discounting of both money and food and (2) grey matter density in these brain regions, including most prominently the medial pulvinar, mediated the effect of bvFTD on discounting. The impulsive preference for sooner rewards captured by delay discounting might constitute a common mechanism of the behavioural symptoms of inhibition deficit and eating behaviour changes in bvFTD. Future studies could further investigate the potential role of medial pulvinar structural modifications as a transdiagnostic marker and a therapeutic target of impulsivity troubles.
... Over time, atrophy spreads into adjacent orbital and dorsolateral frontal regions and eventually into the parietal lobe. The progressive involvement of these brain regions is thought to interrupt the adequate functioning of the salience (Olojugba et al., 2007) (Tartaglia et al., 2008) (Omar et al., 2009) network and its interactions with the default mode and executive networks, leading to the emergence of typical social cognition deficits such as the inability to solve social dilemmas, making moral judgments, recognizing facial emotions and experiencing empathy in social situations (Antonioni et al., 2023;Seeley et al., 2012). Although genetic bvFTD may give rise to distinct atrophy patterns, including temporal and frontotemporal subtypes for MAPT-related FTD (Young et al., 2021), social cognition deficits early in the symptomatic period of the disease have been described in all three primary genetic mutations (GRN, MAPT, and C9orf72) (Russell et al., 2020). ...
Erotomania (de Clérambault's syndrome) refers to the delusional belief that another person, usually socially unreachable, is in love with the holder of the delusion. The occurrence of erotomania in Frontotemporal Dementia has rarely been reported. We present the unique case of a 59-year-old woman with a strong family history of early-onset dementia in whom erotomania was the initial manifestation that led to a diagnosis of definite Behavioral Variant of Frontotemporal Dementia with a pathogenic missense mutation in the MAPT gene. Based on this case, we propose a hypothetical model for developing erotomania in patients with FTD.
... Indeed, theories of behavioural change in FTD have highlighted the importance of right prefrontal regions, in particular, in social functioning. 97 . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. ...
Degraded semantic memory is a prominent feature of frontotemporal dementia (FTD). It is classically associated with semantic dementia and anterior temporal lobe (ATL) atrophy, but semantic knowledge can also be compromised in behavioural-variant FTD (bvFTD). Motivated by understanding behavioural change in FTD, recent research has focused selectively on social-semantic knowledge, with proposals that the right ATL is specialised for social concepts. Previous studies have assessed very different types of social concepts and have not compared performance to that on matched non-social concepts. Consequently, it remains unclear to what extent various social concepts are (i) concurrently impaired in FTD, (ii) distinct from general semantic memory and (iii) differentially supported by the left and right ATL. This study assessed multiple aspects of social-semantic knowledge and general conceptual knowledge across cohorts with ATL-damage arising from either neurodegeneration or resection. We assembled a test battery measuring knowledge of multiple types of social concept. Performance was compared to non-social general conceptual knowledge, measured using the Cambridge Semantic Memory Test Battery and other matched non-social-semantic tests. Our transdiagnostic approach included bvFTD, semantic dementia and mixed intermediate cases to capture the FTD clinical spectrum, as well as age-matched healthy controls. People with unilateral left or right ATL resection for temporal lobe epilepsy (TLE) were also recruited to assess how selective damage to the left or right ATL impacts social- and non-social-semantic knowledge. Social- and non-social-semantic deficits were severe and highly correlated in FTD. Much milder impairments were found after unilateral ATL resection, with no left vs. right differences in social-semantic knowledge or general semantic processing, and with only naming showing a greater deficit following left vs. right damage. A principal component analysis of all behavioural measures in the FTD cohort extracted three components, interpreted as capturing: (1) FTD severity, (2) semantic memory and (3) executive function. Social and non-social measures both loaded heavily on the same semantic memory component, and scores on this factor were uniquely associated with bilateral ATL grey matter volume but not with the degree of ATL asymmetry. Together, these findings demonstrate that both social- and non-social-semantic knowledge degrade in FTD (semantic dementia and bvFTD) following bilateral ATL atrophy. We propose that social-semantic knowledge is part of a broader conceptual system underpinned by a bilaterally-implemented, functionally-unitary semantic hub in the ATLs. Our results also highlight the value of a transdiagnostic approach for investigating the neuroanatomical underpinnings of cognitive deficits in FTD.
... Deficits in the VAN could thus lead to an upregulation of the DMN. 20 However, we did not observe a stronger correlation between the seed in the posterior cingulate cortex and other parts of the DMN in patients than in controls, which is in line with a recent review that found inconsistent evidence for this hypothesise. 18 . ...
A lack of empathy, and particularly its affective components, is a core symptom of behavioural variant frontotemporal dementia (bvFTD). Visual exposure to images of a needle pricking a hand (pain condition) and Q-tips touching a hand (control condition) is an established functional magnetic resonance imaging (fMRI) paradigm used to investigate empathy for pain (EFP; pain condition minus control condition). EFP has been associated with increased blood oxygen level dependent (BOLD) signal in regions known to become atrophic in the early stages in bvFTD, including the anterior insula and the anterior cingulate. We therefore hypothesized that patients with bvFTD would display altered empathy processing in the EFP paradigm. Here we examined empathy processing using the EFP paradigm in 28 patients with bvFTD and 28 sex and age matched controls. Participants underwent structural MRI, task-based and resting-state fMRI. The Interpersonal Reactivity Index (IRI) was used as a measure of different facets of empathic function outside the scanner. The EFP paradigm was analysed at a whole brain level and using two regions-of-interest approaches, one based on a metanalysis of affective perceptual empathy versus cognitive evaluative empathy and one based on the control's activation pattern. In controls, EFP was linked to an expected increase of BOLD signal that displayed an overlap with the pattern of atrophy in the bvFTD patients (insula and anterior cingulate). Additional regions with increased signal were the supramarginal gyrus and the occipital cortex. These latter regions were the only ones that displayed increased BOLD signal in bvFTD patients. BOLD signal increase under the affective perceptual empathy but not the cognitive evaluative empathy region of interest was significantly greater in controls than in bvFTD patients. The control's rating on their empathic concern subscale of the IRI was significantly correlated with the BOLD signal in the EFP paradigm, as were an informant's ratings of the patient's empathic concern subscale. This correlation was not observed on other subscales of the IRI or when using the patient's self-ratings. Finally, controls and patients showed different connectivity patterns in empathy related networks during resting-state fMRI, mainly in nodes overlapping the ventral attention network. Our results indicate that reduced neural activity in regions typically affected by pathology in bvFTD is associated with reduced empathy processing, and a predictor of patient's capacity to experience affective empathy.
... In 2012, Seeley et al. 109 proposed a working model for bvFTD based on the concept that the disorder primarily affects the salience network (SN) through direct damage to Von Economo neurons that are predominantly localized in the insular cortex and the ACC, two essential structures for processing social-emotional-autonomic information. The fronto-insular regions (afferent salience system) process ascending moment-to-moment information regarding body state, allowing 'feeling state representations'. ...
... The ACC (efferent salience system) mobilizes visceral-autonomic responses to salience and recruits the control network (CN) to guide behaviour. 109 In this model, dysfunction in the anterior insula, as observed in the early stages of bvFTD, can lead to disinhibition or apathy depending on the inability to use 'feeling states' as avoiding or approaching signals. 109 Importantly in the consideration of repetitive behaviours in FTD, the SN communicates with subcortical structures, including the head of the caudate nucleus, the mediodorsal nucleus of the thalamus and dopaminergic brainstem nuclei, 110 forming a discrete loop that overlaps with the classic CSTC circuits and interacts with the default mode network and the CN. 111 Building upon Seeley's model, we hypothesize that dysfunction in the anterior insula underlies not only the socio-emotional deficits 109 but also contributes to the emergence of repetitive behaviours in bvFTD (Fig. 3). ...
... 109 In this model, dysfunction in the anterior insula, as observed in the early stages of bvFTD, can lead to disinhibition or apathy depending on the inability to use 'feeling states' as avoiding or approaching signals. 109 Importantly in the consideration of repetitive behaviours in FTD, the SN communicates with subcortical structures, including the head of the caudate nucleus, the mediodorsal nucleus of the thalamus and dopaminergic brainstem nuclei, 110 forming a discrete loop that overlaps with the classic CSTC circuits and interacts with the default mode network and the CN. 111 Building upon Seeley's model, we hypothesize that dysfunction in the anterior insula underlies not only the socio-emotional deficits 109 but also contributes to the emergence of repetitive behaviours in bvFTD (Fig. 3). 88 Dysfunctional processing of competing stimuli in the anterior insula may lead to misidentification of salient stimuli and abnormal 'feeling states', 112 creating a mismatch between expected and observed body states (interoceptive prediction error). ...
Repetitive behaviours are common manifestations of frontotemporal dementia (FTD). Patients with FTD exhibit various types of repetitive behaviours with unique behavioural and cognitive substrates, including compulsivity, lack of impulse control, stereotypy and hoarding. Other sources of repetitive behaviours, such as restrictive interests and insistence on sameness, may also be seen in FTD. Although repetitive behaviours are highly prevalent and potentially discriminatory in this population, their expression varies widely between patients, and the field lacks consensus about the classification of these behaviours. Terms used to describe repetitive behaviours in FTD are highly heterogeneous and may lack precise definitions. This lack of harmonization of the definitions for distinct forms of repetitive behaviour limits the ability to differentiate between pathological behaviours and impedes understanding of their underlying mechanisms.
This review examines established definitions of well-characterized repetitive behaviours in other neuropsychiatric disorders and proposes operational definitions applicable to patients with FTD. Building on extant models of repetitive behaviours in non-human and lesion work and models of social behavioural changes in FTD, we describe the potential neurocognitive bases for the emergence of different types of repetitive behaviours in FTD and their potential perpetuation by a predisposition towards habit formation. Finally, examples of distinct therapeutic approaches for different forms of repetitive behaviours are highlighted, along with future directions to accurately classify, measure and treat these symptoms when they impair quality of life.
... Respect invokes feelings of admiration and appreciation (Nakatani et al., 2019), and brain networks that support emotions are also likely important for this other-oriented value (Etkin et al., 2015;Nakatani et al., 2019;Sander and Nummenmaa, 2021). Through connections with the ventral striatum, amygdala, hypothalamus, and periaqueductal gray, the anterior cingulate cortex and ventral anterior insula are critical for generating and sensing internal changes in the body that arise during emotions, empathy, and reward (Seeley et al., 2012;Vogt, 2014;Etkin et al., 2015). Working together, this system allows people to detect salient information in the environment, to produce and experience emotions, and to nurture feelings of social connection (Decety, 2015). ...
... In certain neurodegenerative disorders, respectful behavior also declines when atrophy progresses through the orbitofrontal cortex and connected neural networks. The behavioral variant of frontotemporal dementia (bvFTD) is a neurodegenerative disorder in which there is selective tissue loss in the orbitofrontal cortex as well as the ventral anterior insula, anterior cingulate cortex, amygdala, and anterior temporal lobes (Seeley et al., 2012). In bvFTD, changes in social behavior, personality, and emotion (e.g., apathy, loss of empathy, and compulsivity) are common (Rosen et al., 2005;Rankin et al., 2006;Sturm et al., 2006Sturm et al., , 2016. ...
Cultural values such as respect influence cognition, emotion, and behavior by modulating brain functioning. This mini-review discusses the cultural differences of respect as an essential human value, and the neural underpinnings accompanying them. Although neuroscientific studies are limited, we outline potential brain structures and networks that contribute to respect and use clinical examples to illustrate how behavior changes when these neural systems fail. A better understanding of the neuroanatomical basis of respect and its neural manifestations across cultures will help to advance current conceptualizations of the biology of human values.
... In short, it can be described as the switch button of attention. Disturbances in this network lie at the root of many neuropsychiatric, neurodevelopmental diseases, and degenerative diseases such as dementia (Kapur 2003, Klin et al. 2003, Seeley et al. 2012, Uddin 2015, Wang et al. 2017. Since this area is rich in dopaminergic, serotoninergic, and noradrenergic receptors, the dysfunctioning of this neural network increases abnormally in delusions and hallucinations. ...
... Since this area is rich in dopaminergic, serotoninergic, and noradrenergic receptors, the dysfunctioning of this neural network increases abnormally in delusions and hallucinations. Hence it is tried to be controlled with antipsychotics (Kapur 2003, Klin et al. 2003, Seeley et al. 2012, Uddin 2015, Wang et al. 2017. ...
Hypnosis, a practice often misunderstood and surrounded by misconceptions, has a rich historical lineage dating back to ancient civilizations. Our review explores the relationship between neuroanatomy, genetics, and hypnotic susceptibility, investigating organic factors influencing an individual's responsiveness to hypnosis. This review highlights the importance of hypnosis as a high-level cognitive activity, especially in pain and anxiety management, and emphasizes the potential benefits of integrating hypnosis into healthcare practices. Recent advancements in neuroimaging have provided insights into the neurological mechanisms of hypnosis, while genetic research has expanded its applications. However, persistent misconceptions hinder its acceptance. This article offers a multidisciplinary basic exploration of hypnosis, focusing on its origins, historical development related to psychiatry, the basic neuroimaging findings mainly affecting the limbic system responsible for emotion, and genetic underpinnings. We aim to inspire clinicians, social scientists, and healthcare professionals to effectively integrate the scientific basics of hypnosis into therapeutic practice, contributing to a better understanding of its role in augmenting outcomes.
... The DMN is a specific network of brain regions that become engaged during random episodic silent thinking, i.e. unconstrained thoughts (selfgenerated thoughts) as opposed to more focused episodic memory activity, 20 and is involved in cognitive processing. 21 The salience network is critical for social-emotional functioning, 22 communication, self-awareness and some aspects of cognition. 23 Alterations in these functional networks have been reported in typical AD patients, specifically reduced functional connectivity in the DMN and increased functional connectivity in the salience network. ...
Posterior cortical atrophy and logopenic progressive aphasia are atypical clinical presentations of Alzheimer’s disease. Resting-state functional connectivity studies have shown functional network disruptions in both phenotypes, particularly involving the language network in logopenic progressive aphasia and the visual network in posterior cortical atrophy. However, little is known about how connectivity differs both within and between brain networks in these atypical Alzheimer’s disease phenotypes. A cohort of 144 patients was recruited by the Neurodegenerative Research Group at Mayo Clinic, Rochester, MN, USA, and underwent structural and resting-state functional MRI. Spatially preprocessed data were analysed to explore the default mode network and the salience, sensorimotor, language, visual and memory networks. The data were analysed at the voxel and network levels. Bayesian hierarchical linear models adjusted for age and sex were used to analyse within- and between-network connectivity. Reduced within-network connectivity was observed in the language network in both phenotypes, with stronger evidence of reductions in logopenic progressive aphasia compared to controls. Only posterior cortical atrophy showed reduced within-network connectivity in the visual network compared to controls. Both phenotypes showed reduced within-network connectivity in the default mode and sensorimotor networks. No significant change was noted in the memory network, but a slight increase in the salience within-network connectivity was seen in both phenotypes compared to controls. Between-network analysis in posterior cortical atrophy showed evidence of reduced visual-to-language network connectivity, with reduced visual-to-salience network connectivity, compared to controls. An increase in visual-to-default mode network connectivity was noted in posterior cortical atrophy compared to controls. Between-network analysis in logopenic progressive aphasia showed evidence of reduced language-to-visual network connectivity and an increase in language-to-salience network connectivity compared to controls. Findings from the voxel-level and network-level analysis were in line with the Bayesian hierarchical linear model analysis, showing reduced connectivity in the dominant network based on diagnosis and more crosstalk between networks in general compared to controls. The atypical Alzheimer’s disease phenotypes were associated with disruptions in connectivity, both within and between brain networks. Phenotype-specific differences in connectivity patterns were noted in the visual network for posterior cortical atrophy and the language network for logopenic progressive aphasia.
... The opposite are 'cold' executive functions, which are rather related Table 1 Social cognitive impairments in bvFTD in comparison to other diseases and in relation to pathology and neural correlates to lateral PFC and are purely cognitive, such as attention, working memory, cognitive flexibility, and inhibition [46,49]. Some 'hot' regions are known to form the salience network, which has been shown to play a role in weighting context-dependent internal and external stimuli by adapting to and responding with corresponding behavior, in contrast to the default mode network, which is deactivated during cognitively demanding tasks [50]. Hypoperfusion in the salience network with parallel hyperperfusion in the default mode network characterizes the behavioral dysregulation in bvFTD, which is opposingly activated in AD [51,52]. ...
... While affective empathy is independent of executive or social cognitive functions, cognitive empathy and moral judgment correlate with executive functioning, emotion recognition and ToM [129]. The early compromise of the salience network, which affects 'hot' functions, such as apathy and disinhibition, may be followed by neurodegeneration in additional brain regions, for example the lateral PFC, which mediates later 'cold' executive cognitive impairments [46,49,50]. Indeed it was found that changes in social cognition in bvFTD may develop through early compromise of ventromedial structures and progressive changes in the dorsolateral PFC [52]. ...
Behavioral variant frontotemporal dementia (bvFTD) belongs to the spectrum of frontotemporal lobar degeneration (FTLD) and is characterized by frontal dysfunction with executive deficits and prominent socio-emotional impairments. Social cognition, such as emotion processing, theory of mind, and empathy may significantly impact daily behavior in bvFTD. Abnormal protein accumulation of tau or TDP-43 are the main causes of neurodegeneration and neurocognitive decline. However, differential diagnosis is difficult due to the heterogeneous pathology in bvFTD and the high clinicopathological overlap with other FTLD syndromes, especially in late disease stages. Despite recent advances, social cognition in bvFTD has not yet received sufficient attention, nor has its association with underlying pathology. This narrative review evaluates social behavior and social cognition in bvFTD, by relating these symptoms to neural correlates and underlying molecular pathology or genetic subtypes. Negative and positive behavioral symptoms, such as apathy and disinhibition, share similar brain atrophy and reflect social cognition. More complex social cognitive impairments are probably caused by the interference of executive impairments due to increasing neurodegeneration. Evidence suggests that underlying TDP-43 is associated to neuropsychiatric and early social cognitive dysfunction, while patients with underlying tau pathology are marked by strong cognitive dysfunction with increasing social impairments in later stages. Despite many current research gaps and controversies, finding distinct social cognitive markers in association to underlying pathology in bvFTD is essential for validating biomarkers, for clinical trials of novel therapies, and for clinical practice.
... Alzheimer disease, in contrast to bvFTD, targets a large-scale network often referred to as the "default mode network" (DMN -including posterior cingulate-precuneus, medial temporal, lateral temporoparietal, and dorsomedial prefrontal regions) which deactivates during cognitively demanding tasks (Greicius et al., 2003;Raichle, 2015). Data suggest that progressive damage to either network (SN or DMN) intensifies activity and connectivity in the other network, perhaps due to disrupted inhibitory interactions between the two networks (Seeley et al., 2012). Therefore the SN, in charge of emotional response, is disrupted in bvFTD but enhanced in AD, which may explain the opposite emotional profiles in AD (emotional intensification) and bvFTD (emotional blunting). ...
Steeper delay discounting (i.e., the extent to which future rewards are perceived as less valuable than immediate ones) has been proposed as a transdiagnostic process across different health conditions, in particular psychiatric disorders. Impulsive decision-making is a hallmark of different neurodegenerative conditions but little is known about delay discounting in the domain of neurodegenerative conditions. We reviewed studies on delay discounting in patients with Parkinson's disease (PD) and in patients with dementia (Alzheimer's disease / AD or frontotemporal dementia / FTD). We proposed that delay discounting could be an early marker of the neurodegenerative process. We developed the idea that altered delay discounting is associated with overlapping but distinct neurocognitive mechanisms across neurodegenerative diseases: dopaminergic-related disorders of reward processing in PD, memory/projection deficits due to medial temporal atrophy in AD, modified reward processing due to orbitofrontal atrophy in FTD. Neurodegeneration could provide a framework to decipher the neuropsychological mechanisms of value-based decision-making. Further, delay discounting could become a marker of interest in clinical practice, in particular for differential diagnosis.
