The limitations and challenges in the assessment of executive dysfunction associated with real-world functioning: The opportunity of serious games.

Nowadays, there is a broad range of methods for detecting and evaluating executive dysfunction ranging from clinical interview to neuropsychological evaluation. Nevertheless, a critical issue of these assessments is the lack of correspondence of the neuropsychological test's results with real-world functioning. This paper proposes serious games as a new framework to improve the neuropsychological assessment of real-world functioning. We briefly discuss the contribution and limitations of current methods of evaluation of executive dysfunction (paper-and-pencil tests, naturalistic observation methods, and Information and Communications Technologies) to inform on daily life functioning. Then, we analyze what are the limitations of these methods to predict real-world performance: (1) A lack of appropriate instruments to investigate the complexity of real-world functioning, (2) the vast majority of neuropsychological tests assess well-structured tasks, and (3) measurement of behaviors are based on simplistic data collection and statistical analysis. This work shows how serious games offer an opportunity to develop more efficient tools to detect executive dysfunction in everyday life contexts. Serious games provide meaningful narrative stories and virtual or real environments that immerse the user in natural and social environments with social interactions. In those highly interactive game environments, the player needs to adapt his/her behavioral performance to novel and ill-structured tasks which are suited for collecting user interaction evidence. Serious games offer a novel opportunity to develop better tools to improve diagnosis of the executive dysfunction in everyday life contexts. However, more research is still needed to implement serious games in everyday clinical practice.

Sensitivity and specificity of the INECO frontal screening (IFS) in the detection of patients with traumatic brain injury presenting executive deficits.

Executive dysfunction (EF) is a common feature of adult traumatic brain injury (TBI), especially in moderate to severe cases. Assessing EF usually requires the administration of an extensive neuropsychological battery, which is time consuming and expensive. The INECO frontal screening (IFS) is a brief, easy-to-administer screening test which has previously shown to be useful in the detection of executive deficits in different psychiatric and neurological populations. The aim of the present study was to assess the usefulness of the IFS in the detection of executive dysfunction in TBI patients. Twenty-eight TBI patients and thirty-two healthy controls were assessed with a battery that included classical executive tests and the IFS. Our results indicated that with a cutoff score of 26.25 points, the IFS showed good sensitivity and specificity in the detection of executive impairments in TBI patients. It also showed good positive and negative predicted values. Our results suggest that the IFS can be considered a useful tool for identifying executive dysfunction in patients with TBI.

Neurocognitive factorial structure of executive functions: Evidence from neurotypicals and frontotemporal dementia.

The latent structure of executive functions (EFs) remains controversial. Confirmatory factorial analysis (CFA) has provided support for both multidimensional (assumes EFs to be functionally separable but related components) and bifactor (proposes all components are nested within a common factor) models. However, these CFA models have never been compared in patient samples, nor regarding their neuroanatomical correlates. Here, we systematically contrast both approaches in neurotypicals and in a neurodegenerative lesion model (patients with the behavioral variant frontotemporal dementia, bvFTD), characterized by executive deficits associated with frontal neurodegeneration. First, CFA was used to test the models' fit in a sample of 341 neurotypicals and 29 bvFTD patients based on performance in an executive frontal screening battery which assesses working memory, motor inhibition, verbal inhibition, and abstraction capacity. Second, we compared EFs factor and observed scores between patients and matched controls. Finally, we used voxel-based morphometry (VBM) to compare the grey matter correlates of factor and observed scores. CFA results showed that both models fit the data well. The multidimensional model, however, was more sensitive than the bifactor model and the observed scores to detect EFs impairments in bvFTD patients. VBM results for the multidimensional model revealed common and unique grey matter correlates for EFs components across prefrontal-insular, posterior, and temporal cortices. Regarding the bifactor model, only the common factor was associated with prefrontal-insular hubs. Observed scores presented scant, non-frontal grey matter associations. Converging behavioral and neuroanatomical evidence from healthy populations and a neurodegenerative model of EFs supports an underlying multidimensional structure.

Frontotemporal Dementias in Latin America: History, Epidemiology, Genetics, and Clinical Research.

Introduction: The historical development, frequency, and impact of frontotemporal dementia (FTD) are less clear in Latin America than in high-income countries. Although there is a growing number of dementia studies in Latin America, little is known collectively about FTD prevalence studies by country, clinical heterogeneity, risk factors, and genetics in Latin American countries. Methods: A systematic review was completed, aimed at identifying the frequency, clinical heterogeneity, and genetics studies of FTD in Latin American populations. The search strategies used a combination of standardized terms for FTD and related disorders. In addition, at least one author per Latin American country summarized the available literature. Collaborative or regional studies were reviewed during consensus meetings. Results: The first FTD reports published in Latin America were mostly case reports. The last two decades marked a substantial increase in the number of FTD research in Latin American countries. Brazil (165), Argentina (84), Colombia (26), and Chile (23) are the countries with the larger numbers of FTD published studies. Most of the research has focused on clinical and neuropsychological features (n = 247), including the local adaptation of neuropsychological and behavioral assessment batteries. However, there are little to no large studies on prevalence (n = 4), biomarkers (n = 9), or neuropathology (n = 3) of FTD. Conclusions: Future FTD studies will be required in Latin America, albeit with a greater emphasis on clinical diagnosis, genetics, biomarkers, and neuropathological studies. Regional and country-level efforts should seek better estimations of the prevalence, incidence, and economic impact of FTD syndromes.

Early onset consumption of coca paste associated with executive-attention vulnerability markers linked to caudate-frontal structural and functional abnormalities.

Coca paste is the most popular form of smoked cocaine (SC) in Latin America and also the most widespread among adolescents in vulnerable sectors of society, thus representing a significant public health concern. Despite evidence suggesting that abnormal executive-attention function is predictive of addiction to stimulant drugs, no study to date has compared clinically relevant neuropsychological (NPS) and physiological variables between individuals with histories of smoked cocaine dependence (SCD) and insufflated cocaine hydrochloride dependence (ICD). In this study we evaluated 25 SCD and 22 ICD subjects matched by poly-consumption profiles, and 25 healthy controls (CTR) matched by age, gender, education, and socioeconomic status. An exhaustive NPS battery was used to assess cognitive domains (attention, executive functions, fluid intelligence, memory, language and social cognition). We complemented this assessment with structural (MRI) and functional (fMRI) neuroimaging data. We found that executive function and attention impairments could be explained by the administration route of cocaine, with strongest impairments for the SCD group. SCD also presented reduced grey matter density relative to ICD and CTR in the bilateral caudate, a key area for executive and attentional function. Functional connectivity between left caudate and inferior frontal regions mediated the association between brain structure and behavioral performance. Our results highlight the relevance of assessing the route of administration of stimulants, both in clinical and research settings.

Multidimensional Clinical Assessment in Frontotemporal Dementia and Its Spectrum in Latin America and the Caribbean: A Narrative Review and a Glance at Future Challenges.

Frontotemporal dementia (FTD) is the third most common form of dementia across all age groups and is a leading cause of early-onset dementia. The Frontotemporal dementia (FTD) includes a spectrum of diseases that are classified according to their clinical presentation and patterns of neurodegeneration. There are two main types of FTD: behavioral FTD variant (bvFTD), characterized by a deterioration in social function, behavior, and personality; and primary progressive aphasias (PPA), characterized by a deficit in language skills. There are other types of FTD-related disorders that present motor impairment and/or parkinsonism, including FTD with motor neuron disease (FTD-MND), progressive supranuclear palsy (PSP), and corticobasal syndrome (CBS). The FTD and its associated disorders present great clinical heterogeneity. The diagnosis of FTD is based on the identification through clinical assessments of a specific clinical phenotype of impairments in different domains, complemented by an evaluation through instruments, i.e., tests and questionnaires, validated for the population under study, thus, achieving timely detection and treatment. While the prevalence of dementia in Latin America and the Caribbean (LAC) is increasing rapidly, there is still a lack of standardized instruments and consensus for FTD diagnosis. In this context, it is important to review the published tests and questionnaires adapted and/or validated in LAC for the assessment of cognition, behavior, functionality, and gait in FTD and its spectrum. Therefore, our paper has three main goals. First, to present a narrative review of the main tests and questionnaires published in LAC for the assessment of FTD and its spectrum in six dimensions: (i) Cognitive screening; (ii) Neuropsychological assessment divided by cognitive domain; (iii) Gait assessment; (iv) Behavioral and neuropsychiatric symptoms; (v) Functional assessment; and (vi) Global Rating Scale. Second, to propose a multidimensional clinical assessment of FTD in LAC identifying the main gaps. Lastly, it is proposed to create a LAC consortium that will discuss strategies to address the current challenges in the field.

The relationship between executive functions and fluid intelligence in multiple sclerosis.

BACKGROUND & OBJECTIVE: Deficits in cognitive functions dependent upon the integrity of the prefrontal cortex have been described in Multiple Sclerosis (MS). In a series of studies we have shown that fluid intelligence (g) is a substantial contributor to frontal deficits and that, for some classical "executive" tasks, frontal deficits were entirely explained by g. However, for another group of frontal tasks deficits remained once g was introduced as a covariate. This second set of tests included multitasking and theory of mind tasks. In the present study, we aimed at determining the role of fluid intelligence in frontal deficits seen in patients with MS. METHODS: A group of patients with Relapsing Remitting MS (n = 36) and a group of control subjects (n = 42) were assessed with a battery of classical executive tests (which included the Wisconsin Card Sorting Test, Verbal Fluency, and Trail Making Test B), a multitasking test, a theory of mind test and a fluid intelligence test. RESULTS: MS patients showed significant deficits in the fluid intelligence task. We found differences between patients and control subjects in all tests except for the multitasking test. The differences in the classical executive tests became non-significant once fluid intelligence was introduced as a covariate, but differences in theory of mind remained. CONCLUSIONS: The present results suggest that fluid intelligence can be affected in MS and that this impairment can play a role in the executive deficits described in MS.

Evaluating the reliability of neurocognitive biomarkers of neurodegenerative diseases across countries: A machine learning approach.

Accurate early diagnosis of neurodegenerative diseases represents a growing challenge for current clinical practice. Promisingly, current tools can be complemented by computational decision-support methods to objectively analyze multidimensional measures and increase diagnostic confidence. Yet, widespread application of these tools cannot be recommended unless they are proven to perform consistently and reproducibly across samples from different countries. We implemented machine-learning algorithms to evaluate the prediction power of neurocognitive biomarkers (behavioral and imaging measures) for classifying two neurodegenerative conditions -Alzheimer Disease (AD) and behavioral variant frontotemporal dementia (bvFTD)- across three different countries (>200 participants). We use machine-learning tools integrating multimodal measures such as cognitive scores (executive functions and cognitive screening) and brain atrophy volume (voxel based morphometry from fronto-temporo-insular regions in bvFTD, and temporo-parietal regions in AD) to identify the most relevant features in predicting the incidence of the diseases. In the Country-1 cohort, predictions of AD and bvFTD became maximally improved upon inclusion of cognitive screenings outcomes combined with atrophy levels. Multimodal training data from this cohort allowed predicting both AD and bvFTD in the other two novel datasets from other countries with high accuracy (>90%), demonstrating the robustness of the approach as well as the differential specificity and reliability of behavioral and neural markers for each condition. In sum, this is the first study, across centers and countries, to validate the predictive power of cognitive signatures combined with atrophy levels for contrastive neurodegenerative conditions, validating a benchmark for future assessments of reliability and reproducibility.

Multimodal neurocognitive markers of interoceptive tuning in smoked cocaine.

Contemporary neurocognitive models of drug addiction have associated this condition with changes in interoception -namely, the sensing and processing of body signals that fulfill homeostatic functions relevant for the onset and maintenance of addictive behavior. However, most previous evidence is inconsistent, behaviorally unspecific, and virtually null in terms of direct electrophysiological and multimodal markers. To circumvent these limitations, we conducted the first assessment of the relation between cardiac interoception and smoked cocaine dependence (SCD) in a sample of (a) 25 participants who fulfilled criteria for dependence on such a drug, (b) 22 participants addicted to insufflated clorhidrate cocaine (only for behavioral assessment), and (c) 25 healthy controls matched by age, gender, education, and socioeconomic status. We use a validated heartbeat-detection (HBD) task and measured modulations of the heart-evoked potential (HEP) during interoceptive accuracy and interoceptive learning conditions. We complemented this behavioral and electrophysiological data with offline structural (MRI) and functional connectivity (fMRI) analysis of the main interoceptive hubs. HBD and HEP results convergently showed that SCD subjects presented ongoing psychophysiological measures of enhanced interoceptive accuracy. This pattern was associated with a structural and functional tuning of interoceptive networks (reduced volume and specialized network segregation). Taken together, our findings provide the first evidence of an association between cardiac interoception and smoked cocaine, partially supporting models that propose hyper-interoception as a key aspect of addiction. More generally, our study shows that multimodal assessments of interoception could substantially inform the clinical and neurocognitive characterization of psychophysiological and neurocognitive adaptations triggered by addiction.

The IFS (INECO Frontal Screening) and level of education: Normative data.

Level of education is known to confound neuropsychological test performance. The INECO Frontal Screening (IFS) is an easy-to-use and brief measure of several domains of executive function, which has previously shown reliably clinical usefulness and superior psychometric performance when compared to other frontal screening instruments. However, previous studies with the IFS have been limited to participants with high levels of education, preventing its generalizability to populations with less than 12 years of formal education. This is crucial, as less than half of the Latin American population and a large percentage of immigrants in developed countries attain high school education. The aim of this study was to generate IFS normative data in a sample stratified by age and education levels. One hundred and sixty one healthy adults were assessed with the IFS as well as measures of global cognitive screening, namely, the Addenbrooke Cognitive Examination Revised and the Mini-Mental State Examination. Multiple lineal regression analysis showed significant effects for education and nonsignificant effects for age. A correction grid for IFS raw scores was developed and cut-off scores were calculated. The correction grid and cut-off scores may be useful in the interpretation of IFS scores in participants with low education.

Brain structural correlates of executive and social cognition profiles in behavioral variant frontotemporal dementia and elderly bipolar disorder.

An early stage of behavioral variant frontotemporal dementia (bvFTD) often displays a mix of behavioral disturbances and personality changes hindering a differential diagnosis from elderly bipolar disorder (BD), making this process a big challenge. However, no studies have compared these pathologies from neuropsychological and neuroanatomical perspectives. The aim of the present study was to compare the executive functions (EF) and social cognition profiles as well as the structural neuroimaging of bvFTD and elderly patients with BD. First, we compared the executive and social cognition performances of 16 bvFTD patients, 13 BD patients and 22 healthy controls. Second, we compared grey matter volumes in both groups of patients and controls using voxel-based morphometry. Lastly, we examined the brain regions where atrophy might be associated with specific impairments in bvFTD and BD patients. Compared to controls, bvFTD patients showed deficits in working memory, abstraction capacity, inhibitory control, cognitive flexibility, verbal fluency and theory of mind (ToM). Patients with BD showed lower performance than controls in terms of abstraction capacity and verbal inhibitory control. In bvFTD patients, atrophy of frontal, temporal and insular cortices was related to EF deficits. Atrophy of the amygdala, the hippocampus, the parahippocampal gyrus, the putamen, the insula, the precuneus, the right temporo-parietal junction and superior temporal pole was associated to ToM impairments. No significant associations between atrophy and EF performance were observed in BD patients. BvFTD patients showed greater EF and ToM deficits than BD patients. Moreover, compared to BD, bvFTD patients exhibited a significant decrease in GM volume in frontal, temporal and parietal regions. Our results provide the first comparison of EF, social cognition and neuroanatomical profiles of bvFTD and elderly BD patients. These findings shed light on differential diagnosis of these disorders and may have important clinical implications.

Performance of Patients with Early Parkinson Disease on an Executive and Social Cognition Battery.

OBJECTIVE: To demonstrate the usefulness of incorporating the Executive and Social Cognition Battery (ESCB) to detect executive and social cognition deficits, which are otherwise not captured by more "classical" executive tests in early Parkinson disease (PD). BACKGROUND: PD is a neurodegenerative disorder that includes executive and social cognition deficits. While cognitive assessment in PD still relies on classical executive tasks to detect frontal deficits, these traditional tests often fail to uncover subtle, yet relevant, frontal impairment. METHODS: We evaluated 39 PD patients and 47 controls with a battery of classical executive tests and the ESCB. The ESCB includes a series of tasks that more closely resemble real-life activities and have been previously shown to be useful in detecting executive deficits in other neuropsychiatric disorders with frontal involvement. RESULTS: We observed that both batteries used in a complementary way yielded better results, as 15 of the 39 patients presented deficits only on some of the ESCB tests, but not on the classical battery, while 5 patients presented deficits only on some tests of the classical battery, but not on the ESCB. Fourteen patients presented deficits on some tests of either battery, and 5 patients did not present deficits on any of the tests. CONCLUSIONS: We found that, used along with traditional neuropsychological tasks, the ESCB may be useful in providing a more comprehensive evaluation of frontal dysfunction among patients with PD, thus contributing to the early diagnosis of cognitive disorders in this patient population.

Posterior cortical atrophy: a single case cognitive and radiological follow-up.

Posterior cortical atrophy (PCA) is a rare neurodegenerative syndrome characterized by initial predominant visuoperceptual deficits followed by a progressive decline in other cognitive functions. This syndrome has not been as thoroughly described as other dementias, particularly from a neuropsychological evolution perspective with only a few studies describing the evolution of its cognitive progression. In this investigation we review the literature on this rare condition and we perform a 7-year neuropsychological and neuroradiological follow-up of a 64-year-old man with PCA. The subject's deficits initially appeared in his visuoperceptual skills with later affectation appearing in language and other cognitive functions, this being coherent with the patient's parieto-temporal atrophy evolution.

Rule reactivation and capture errors in goal directed behaviour.

In everyday life people may act automatically, following "unwanted" lines of action which are triggered by contextual cues and may interfere with current goals. Such occurrences are known as "capture errors" in reference to errors that occur when a more salient behaviour takes place when a similar, but less salient, action was intended. Clinical neuropsychological studies suggest that reactivation of previous rules may play an important role in behavioural interference, but such reactivation has been little studied in normal subjects and simple experimental tasks. In the present study we develop this theme, presenting data on 4 subjects who spontaneously showed capture errors in verbal fluency tasks, and developing a new experimental paradigm specifically designed to elicit such interference in normal subjects. In the new paradigm, 101 normal subjects performed a simple series of working memory tasks, including occasional stimuli whose answer matched both the current and the previous rule. We found that normal controls indeed tend to commit more mistakes after the presentation of a stimulus whose answer is consistent with a current and preceding rule. In this case, however, the errors produced are not necessarily associated with a shift back to the old rule, suggesting that rule reactivation leads to a more general interference effect. We discuss the importance of our data from both theoretical and clinical perspectives.

The relationship between executive functions and fluid intelligence in euthymic Bipolar Disorder patients.

Distinct cognitive deficits have been described in Bipolar disorder (BD), including executive impairments, commonly attributed to frontal dysfunction. However, recent attention has been paid to the heterogeneity of cognitive functioning in this population, suggesting that the executive deficits observed in BD might be due to a loss in fluid intelligence (g). Following our previous line of investigation in multiple neurological and psychiatric conditions we aimed at determining the role of g in frontal deficits in BD. Euthymic BD patients (n = 51) and healthy controls (n = 37) were assessed with Wisconsin Card Sorting Test (WCST), Verbal Fluency, Trail Making Test B (TMTB), a multitasking test, and a theory of mind test. A general cognitive battery was used to derive a measure of g. As in other neuropsychiatric conditions, significant patient-control differences in WCST, Verbal Fluency and TMTB were removed when g was introduced as a covariate. Deficits remained significant in the multitasking test. We suggest that neuropsychological assessment in BD should include tests of general intelligence, together with one or more specific tasks that allow for the assessment of residual frontal deficits, putatively associated with anterior frontal functioning.

Tackling variability: A multicenter study to provide a gold-standard network approach for frontotemporal dementia.

Biomarkers represent a critical research area in neurodegeneration disease as they can contribute to studying potential disease-modifying agents, fostering timely therapeutic interventions, and alleviating associated financial costs. Functional connectivity (FC) analysis represents a promising approach to identify early biomarkers in specific diseases. Yet, virtually no study has tested whether potential FC biomarkers prove to be reliable and reproducible across different centers. As such, their implementation remains uncertain due to multiple sources of variability across studies: the numerous international centers capable conducting FC research vary in their scanning equipment and their samples' socio-cultural background, and, more troublingly still, no gold-standard method exists to analyze FC. In this unprecedented study, we aim to address both issues by performing the first multicenter FC research in the behavioral-variant frontotemporal dementia (bvFTD), and by assessing multiple FC approaches to propose a gold-standard method for analysis. We enrolled 52 bvFTD patients and 60 controls from three international clinics (with different fMRI recording parameters), and three additional neurological patient groups. To evaluate FC, we focused on seed analysis, inter-regional connectivity, and several graph-theory approaches. Only graph-theory analysis, based on weighted-matrices, yielded consistent differences between bvFTD and controls across centers. Also, graph metrics robustly discriminated bvFTD from the other neurological conditions. The consistency of our findings across heterogeneous contexts highlights graph-theory as a potential gold-standard approach for brain network analysis in bvFTD. Hum Brain Mapp 38:3804-3822, 2017. © 2017 Wiley Periodicals, Inc.

Analysis of errors in verbal fluency tasks in patients with chronic schizophrenia

Background and Objectives: Even if verbal fluency deficits have been described in Schizophrenia, error pattern in this test has not been analyzed in detail in the literature. The pattern analysis of such errors could contribute to the understanding of the factors that influence poor task performance in schizophrenia. In this study we analyzed the intrusion and perseveration errors in verbal fluency tasks in patients with chronic schizophrenia. Methods: 87 patients diagnosed with Chronic Schizophrenia and 87 healthy controls were included in this investigation and were assessed with four Phonological and Semantic Verbal Fluency tasks. Results: The results of this study showed that at least half of schizophrenic patients produced perseverative errors on verbal fluency and about made intrusion errors. The severity of negative symptoms, the severity of Formal Thought Disorder and pharmacological variables were significant moderators to errors in Verbal Fluency performance. Conclusions: Errors in Verbal Fluency can be explained by the interaction of different variables in patients with schizophrenia. Schizophrenia is a psychological pathology with great phenomenological complexity and its particularities can only be explained by the consideration of the multiple factors involved in its manifestation

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Brain Network Organization and Social Executive Performance in Frontotemporal Dementia.

OBJECTIVES: Behavioral variant frontotemporal dementia (bvFTD) is characterized by early atrophy in the frontotemporoinsular regions. These regions overlap with networks that are engaged in social cognition-executive functions, two hallmarks deficits of bvFTD. We examine (i) whether Network Centrality (a graph theory metric that measures how important a node is in a brain network) in the frontotemporoinsular network is disrupted in bvFTD, and (ii) the level of involvement of this network in social-executive performance. METHODS: Patients with probable bvFTD, healthy controls, and frontoinsular stroke patients underwent functional MRI resting-state recordings and completed social-executive behavioral measures. RESULTS: Relative to the controls and the stroke group, the bvFTD patients presented decreased Network Centrality. In addition, this measure was associated with social cognition and executive functions. To test the specificity of these results for the Network Centrality of the frontotemporoinsular network, we assessed the main areas from six resting-state networks. No group differences or behavioral associations were found in these networks. Finally, Network Centrality and behavior distinguished bvFTD patients from the other groups with a high classification rate. CONCLUSIONS: bvFTD selectively affects Network Centrality in the frontotemporoinsular network, which is associated with high-level social and executive profile.

Integration of Intention and Outcome for Moral Judgment in Frontotemporal Dementia: Brain Structural Signatures.

BACKGROUND: Moral judgment has been proposed to rely on a distributed brain network. This function is impaired in behavioral variant frontotemporal dementia (bvFTD), a condition involving damage to some regions of this network. However, no studies have investigated moral judgment in bvFTD via structural neuroimaging. METHODS: We compared the performance of 21 bvFTD patients and 19 controls on a moral judgment task involving scenarios that discriminate between the contributions of intentions and outcomes. Voxel-based morphometry was used to assess (a) the atrophy pattern in bvFTD patients, (b) associations between gray matter (GM) volume and moral judgments, and (c) structural differences between bvFTD subgroups (patients with relatively preserved moral judgment and patients with severer moral judgment impairments). RESULTS: Patients judged attempted harm as more permissible and accidental harm as less permissible than controls. The groups' performance on accidental harm was associated with GM volume in the precuneus. In controls, it was al- so associated with the ventromedial prefrontal cortex (VMPFC). Also, both groups' performance on attempted harm was associated with GM volume in the temporoparietal junction. Patients exhibiting worse performance displayed smaller GM volumes in the precuneus and temporal pole. CONCLUSIONS: Results suggest that moral judgment abnormalities in bvFTD are associated with impaired integration of intentions and outcomes, which depends on an extended brain network. In bvFTD, moral judgment seems to critically depend on areas beyond the VMPFC.

Feeling, learning from and being aware of inner states: interoceptive dimensions in neurodegeneration and stroke.

Interoception is a complex process encompassing multiple dimensions, such as accuracy, learning and awareness. Here, we examined whether each of those dimensions relies on specialized neural regions distributed throughout the vast interoceptive network. To this end, we obtained relevant measures of cardiac interoception in healthy subjects and patients offering contrastive lesion models of neurodegeneration and focal brain damage: behavioural variant fronto-temporal dementia (bvFTD), Alzheimer's disease (AD) and fronto-insular stroke. Neural correlates of the three dimensions were examined through structural and functional resting-state imaging, and online measurements of the heart-evoked potential (HEP). The three patient groups presented deficits in interoceptive accuracy, associated with insular damage, connectivity alterations and abnormal HEP modulations. Interoceptive learning was differentially impaired in AD patients, evidencing a key role of memory networks in this skill. Interoceptive awareness results showed that bvFTD and AD patients overestimated their performance; this pattern was related to abnormalities in anterior regions and associated networks sub-serving metacognitive processes, and probably linked to well-established insight deficits in dementia. Our findings indicate how damage to specific hubs in a broad fronto-temporo-insular network differentially compromises interoceptive dimensions, and how such disturbances affect widespread connections beyond those critical hubs. This is the first study in which a multiple lesion model reveals fine-grained alterations of body sensing, offering new theoretical insights into neuroanatomical foundations of interoceptive dimensions.This article is part of the themed issue 'Interoception beyond homeostasis: affect, cognition and mental health'.