Maxime Bertoux

Psychiatric diagnosis depends on the clinician’s ability to infer mental states from complex and dynamically evolving interpersonal signals. During the psychiatric interview, clinicians do not only collect explicit symptoms; they continuously sample a rich array of non-verbal and paralinguistic cues including gaze, prosody, affective reciprocity, and interactional timing. These signals are central to psychiatric assessment, yet their contribution to diagnostic reasoning remains poorly formalized. In this Review, we propose a computational account of clinical impressions in psychiatry. We integrate evidence from phenomenological psychopathology, social cognition, and computational neuroscience. We argue that such impressions may arise when the clinician’s generative model of social interaction is persistently disconfirmed by subtle deviations in interpersonal behaviour, generating high-level social prediction errors experienced as a sense of incongruity or failed attunement. We formalize this process as VIBE: Violation of Interpersonal Bayesian Expectation. VIBE denotes a pre-reflective epistemic signal generated when observed interpersonal cues deviate from the clinician’s expected model of social reciprocity. It is not a diagnostic criterion but orients hypothesis generation by drawing attention to disturbances in interpersonal predictability. We hypothesize that VIBE may constitute a transdiagnostic mechanism: different disorders, from schizophrenia to autism spectrum disorder and mood disorders, may disrupt distinct dimensions of interpersonal prediction. The Praecox Feeling, first described by Rümke in 1942, can be read as the earliest clinical formalization of this process and as its schizophrenia-spectrum instance, in which the profile of interpersonal violations is consistent enough to be clinically recognizable. This framework recasts the diagnostic impression as an embodied inferential process rather than an opaque subjective faculty. Teaching clinicians to articulate, examine, and recalibrate these impressions could strengthen diagnostic reasoning, reduce bias, and improve therapeutic attunement. VIBE provides a bridge between phenomenological psychopathology and computational neuroscience, and offers a tractable, empirically testable model for studying the neurocomputational basis of psychiatric clinical judgement.

Understanding the order in which symptoms occur in genetic frontotemporal dementia (FTD) may provide valuable insight into disease progression. Here we use a methodology called Ordinal Subtype and Stage Inference (SuStaIn) in the GENetic FTD Initiative (GENFI) cohort to estimate a probable order in which symptoms occur, and identify different subtypes based on the pattern of symptom progression within the main genetic FTD mutation groups. 968 participants were included in the cross-sectional study: 280 C9orf72, 242 GRN and 101 MAPT mutation carriers, and 345 mutation-negative controls. 379 participants underwent longitudinal analysis: 162 C9orf72, 146 GRN and 71 MAPT mutation carriers. The standardised GENFI clinical assessment provided severity scores for all FTD-relevant symptoms ranging from 0 where symptoms are absent to 3 where symptoms are severe. Ordinal SuStaIn was run in each mutation group to generate symptom progression profiles for mutation carriers from each group. In the C9orf72 cohort, Ordinal SuStaIn identified three subtypes: subtype 1 with early behavioural and cognitive deficits, subtype 2 with impaired speech and swallowing, and subtype 3 with limb impairment. In the GRN cohort, SuStaIn identified two subtypes: subtype 1 with behavioural and cognitive deficits as well as limb motor involvement, and subtype 2 with early language impairment. The MAPT cohort was best described as a single subtype with a combination of cognitive (mainly semantic) and behavioural impairment with parkinsonism. SuStaIn stage significantly correlated with clinical severity scores for all the cohorts. The subtypes were somewhat longitudinally consistent, with a trend towards increased SuStaIn stage in each subtype over time. Identifying within-genotype data-driven subtypes of FTD is a novel approach for untangling the heterogeneity of this disorder, in turn drawing us closer to individualised care.

C9orf72 encodes a protein that is important for both typical neurodevelopment and homeostatic processes across the lifespan. Pathogenic C9orf72 repeat expansions constitute the most common genetic cause of frontotemporal lobar degeneration (FTLD). Collectively, preclinical models and clinical neuroimaging studies have observed smaller thalamic volumes in C9orf72 -associated FTLD, including in asymptomatic young adult C9orf72 repeat expansion carriers across 18 to 30 years old, supportive of potential neurodevelopmental origins. However, it is unknown whether asymptomatic young adult C9orf72 expansion carriers demonstrate volume differences in specific thalamic nuclei, as reported in older asymptomatic carriers and symptomatic patients; if so, normative transcriptomic patterns could reveal relevant neurodevelopmental and/or FTLD-related neurodegenerative processes. This study investigated volumetric MRI differences of the thalamic nuclei in asymptomatic young adult C9orf72 expansion carriers compared to non-carriers, and examined spatial associations with normative thalamic transcriptomics from 8 weeks post-conception through middle age. Young adult C9orf72 expansion carriers ( n =72) and non-carriers ( n =48) were enrolled in the Frontotemporal Dementia Prevention Initiative across Europe, Canada, and the USA (ages: 18-30 years; sex: 57% female). Spatial associations between young adult thalamic nuclei volumes and normative transcriptomics from the Allen Human Brain Atlas were examined using complementary data-driven and hypothesis-driven approaches. Spatial expression patterns of transcripts of interest were characterized across prenatal and postnatal neurodevelopment using BrainSpan data. Smaller volumes of the pulvinar, mediodorsal, and lateral nuclei were observed in young adult C9orf72 expansion carriers compared to non-carriers. These nuclei showed higher normative expression of transcripts involved concurrently in neurodevelopmental and C9orf72 -associated FTLD neurodegenerative processes (including lysosomal, autophagic, and small GTPase functions), and lower normative expression of CALB1 , a marker of prenatal human thalamic development. Normative expression of CALB2 (another human thalamic development marker) yielded positive correlations with C9orf72 across prenatal development to adulthood. These findings identify candidate transcripts that may provide insight into the molecular architecture leading to smaller thalamic nuclei volumes in C9orf72 -associated FTLD.

Individuals with autosomal dominant frontotemporal dementia (FTD) exhibit considerable variability in disease onset and progression. Both modifiable and non-modifiable factors—such as sex, educational attainment or geographic region of residence—may contribute to this heterogeneity, potentially through their influence on cognitive reserve. The aim of the present study was to investigate the role of cognitive reserve modulators within the Genetic Frontotemporal dementia Initiative (GENFI) cohort. To this end, we used functional MRI (i.e. spatial chronnectome measures) and neurodegenerative markers (i.e. plasma neurofilament light chains levels) to determine disease stage using a Discriminative Event-Based Model (DEBM). We then examined how potential modulators influence the relationship between disease stage and cognitive performance. We analysed a total of 711 participants, including 106 patients with genetic FTD, 325 presymptomatic mutation carriers and 280 non-carriers healthy controls. Female participants showed a weaker association between disease stage and cognitive performance compared to males (P < 0.001), with difference becoming progressively more pronounced across symptomatic stages. Educational attainment exhibited a similar effect: individuals with higher education demonstrated an attenuated association compared to those with secondary or primary schooling (P < 0.001), with differences already detectable at prodromal disease stages. The effect of geographical region of residence was associated with education levels, but appeared to have an indirect and less strong influence. In summary, sex and educational attainment significantly affect the development and maintenance of cognitive reserve in individuals with genetic FTD. These findings underscore the importance of identifying disease-modifying interventions since the presymptomatic stages of the disease.

Background and Objectives: Converging evidence hints at neurodevelopmental effects in genetic frontotemporal degeneration (FTD). In cross-sectional studies, for some genes, young adult FTD variant carriers show differences in brain volumes and cognition compared to familial non-carriers. However, longitudinal trajectories may more sensitively capture FTD-related neurodevelopmental vs. neurodegenerative changes than cross-sectional approaches. This study examined longitudinal trajectories of brain volumes, executive function, and plasma biomarkers in young adult carriers compared to familial non-carriers, as measures of neurodevelopmental and neurodegenerative outcomes of FTD-causing variants. Methods: This longitudinal cohort study comprised participants, aged 18-30 years, from the FTD Prevention Initiative across Europe, Canada, and the USA. Genetic groups included C9orf72 (47%), MAPT (30%), and GRN (23%). Linear mixed-effects models were computed to assess longitudinal outcomes across age between groups, controlling for sex, scanner (for brain volumes), and education (for executive function); random effects accounted for between-subject variability nested within family membership. Results: Variant carriers ( n =147) and familial non-carriers ( n =113) did not differ in age (mean±SD, 25.9±3.2 years), sex (53% female), or number of visits (2.1±1.7). Young adult C9orf72 repeat expansion carriers exhibited smaller thalamic volumes than non-carriers at the reference age of 26 years ( b =-982.8mm ³ , SE=317.0, p= 0.0046, f ² =0.32), with relatively stable trajectories across ages 18-30 (i.e., no change over time). Trajectories of rostral anterior cingulate volumes differed in C9orf72 carriers and non-carriers across age, where carriers showed relatively stable trajectories and non-carriers showed age-appropriate declines ( b =64.4mm ³ , SE=29.9, p= 0.035, f ² =0.07). For MAPT and GRN , there were little to no differences in total brain, cortical, or subcortical volumes between groups and over time. No longitudinal differences were observed between carriers and non-carriers in executive function, or plasma NfL or GFAP for any genetic group. Discussion: C9orf72 repeat expansions were linked to smaller average thalamic volumes and stable trajectories between ages 18 to 30, supporting potential neurodevelopmental origins. The modest evidence supporting an absence of difference in neurodegenerative biomarkers and executive function suggests minimal early neurodegeneration and functional preservation in young adulthood.

INTRODUCTION: Affective disturbances are common across behavioral variant frontotemporal degeneration (bvFTD), primary psychiatric disorders (PPD), and Alzheimer's disease (AD). Objective markers are needed for differential and transdiagnostic characterization. We tested whether artificial intelligence (AI)‐based analysis of natural speech could provide such markers. METHODS: Speech from 112 participants (bvFTD = 31, AD = 28, PPD = 15, controls = 39) was analyzed using a fine‐tuned speech emotion recognition model estimating valence, arousal, dominance, and entropy. Group differences were assessed with analyses of covariance, diagnostic utility with logistic regression, and neuroanatomical correlates with voxel‐based morphometry. RESULTS: Group‐specific affective profiles emerged. Overall, PPD exhibited a lower valence. bvFTD and AD showed a reduced arousal and a higher dominance. Affective dimensions predicted bvFTD with 80.4% accuracy (area under the curve = 0.732) and mapped onto fronto‐insular and temporal networks. Entropy was identified as a transdiagnostic marker. DISCUSSION: AI‐based speech analysis provides objective, scalable biomarkers for differential diagnosis, transdiagnostic characterization, and disease monitoring.

Language is essential to social communication. Its complexity and hierarchical organisation, from low-level operations to high-order integrative processes, may provide valuable diagnostic insights beyond classical aphasia syndromes. However, systematic investigations in these conditions, particularly in behavioural variant frontotemporal dementia (bvFTD), remain scarce. To refine differential diagnosis, an exhaustive characterisation of language functions is required. We systematically compared multi-level language functioning across bvFTD, Alzheimer’s disease (AD) and primary psychiatric disorders (PPD), within an integrative neurolinguistic framework distinguishing lexical, syntactic and discursive levels, together with a cross-modal transposition/transcoding dimension. A total of 85 patients (including 34 with bvFTD, 30 with AD, 21 with PPD) and 40 matched healthy controls underwent an extensive language assessment using the GREMOTs battery. Composite, quantitative as well as qualitative indices were computed for each linguistic level. Structural MRI data were analysed using voxel-based morphometry (p < 0.05 corrected for multiple comparisons). All clinical groups exhibited lexical impairments relative to controls, with bvFTD presenting the most severe and widespread deficits across fluency, naming and comprehension (partial eta-squared, ηp², ranging from .18 to .49). AD and PPD showed milder lexical inefficiencies (ηp²=.11—.39 and ηp²=.07—.29, respectively). Syntactic processing was also more impaired in bvFTD (ηp²= .03—.27) than in AD and PPD (ηp²=.02—.07 and ηp²=.00—.15, respectively). At the discourse-level, bvFTD patients displayed key deficits (ηp²=.05—.29), with pervasive pragmatic breakdowns whereas AD and PPD showed milder integrative deficits with preserved global coherence (ηp²=.00—.17 and ηp²=.02—.13). Transcoding and transposing tasks revealed minor deficits, mainly in bvFTD (ηp²=.01—.25). A logistic regression identified that a subset of 12/23 tasks accurately classified 85.9% of bvFTD cases (sensitivity: 57.6%; specificity: 95.6%). The analysis of the types of responses (including errors) allowed to provide a more comprehensive group profiling. In bvFTD, the decrease of language performance related to widespread frontotemporal and posterior (including cerebellar) atrophy, whereas AD showed more restricted frontal and temporal involvement. PPD displayed smaller fronto-temporal, insular and precuneal associations. In conclusion, these findings delineate a graded, multi-level linguistic profile across neurodegenerative and psychiatric conditions. bvFTD is mainly characterised by pervasive lexical and discursive–pragmatic impairments, alongside syntactic difficulties, while AD and PPD primarily show lexical inefficiencies with preserved syntax. Convergent neural evidence supports a distributed network model of language integrating frontal–insular control and temporal semantic systems. Embedding such multi-level assessments into clinical practice could enhance diagnostic precision and provide valid cognitive endpoints for future trials.

Neuropsychological assessment of social cognition has traditionally focused on mentalizing and emotions recognition. Recently developed digital measures allow clinicians to capture direct markers of abnormal social interactions, but they have not yet been used to distinguish neurological from psychiatric populations. This study examined prosodic alterations and explored structural neural correlates in behavioral variant frontotemporal degeneration (bvFTD) versus late-onset or atypical psychiatric disorders (LOAPD) and healthy controls (HCs). We analyzed audio recordings from 31 patients with bvFTD, 15 patients with LOAPD, and 39 HCs across two speech samples: an anamnestic interview and a narrative task. Fundamental frequency (f₀) metrics were extracted to assess between-group differences and to identify voxel-based morphometry correlates of prosodic alteration. Compared with HCs, patients with bvFTD showed a reduced f₀ range in both the anamnestic interview (p = .025, η² = .09, 95% CI [-23.83, -1.04]) and the narrative task (p = .002, η² = .14, 95% CI [-36.21, -4.74]). In the anamnestic interview, both bvFTD (p = .010, 95% CI [-36.59, -6.23]) and LOAPD (p = .012, 95% CI [-46.30, -8.81]) groups exhibited lower f₀ variability than HCs; no differences were observed during the narrative task. In bvFTD, reduced prosodic measures correlated with atrophy in the left superior frontal gyrus and the right middle and inferior temporal gyri (p < .05, family-wise error corrected). Patients with bvFTD demonstrate a narrowed pitch span and reduced intonational variability, linked to disruptions in frontotemporal networks integrating emotional and semantic cues into speech. These findings highlight the relevance of prosodic alterations as a target for further research in bvFTD and assessment. (PsycInfo Database Record (c) 2025 APA, all rights reserved).

Accurate diagnosis of frontotemporal dementia (FTD) with right anterior temporal lobe (RATL) predominance remains challenging due to lack of clinical characterization, and standardized terminology. The recent research of the International Working Group (IWG) identified common symptoms but also unveiled broad terminologies lacking precision and operationalization, with risk of misdiagnoses, inappropriate referrals and poor clinical management. Based on the published evidence (91267 articles screened) and expert opinion (105 FTD specialists across 52 centers) by using the nominal group technique, the IWG delineates three primary domains of impairment causing behavioral, memory and language problems: (i) multimodal knowledge of non-verbal information including people, living beings, landmarks, flavors/odors, sounds, bodily sensations, emotions and social cues; (ii) socioemotional behavior encompassing emotion expression, social response and motivation; and (iii) prioritization for focus on specific interests, hedonic valuation and personal preferences. This study establishes a consensus on clinical profile, phenotypic nomenclature, and future directions to enhance diagnostic precision and therapeutic interventions.