Sulfide quinone oxidoreductase contributes to voltage sensing of the mitochondrial permeability transition pore.

Pathological opening of the mitochondrial permeability transition pore (mPTP) is implicated in the pathogenesis of many disease processes such as myocardial ischemia, traumatic brain injury, Alzheimer's disease, and diabetes. While we have gained insight into mPTP biology over the last several decades, the lack of translation of this knowledge into successful clinical therapies underscores the need for continued investigation and use of different approaches to identify novel regulators of the mPTP with the hope of elucidating new therapeutic targets. Although the mPTP is known to be a voltage-gated channel, the identity of its voltage sensor remains unknown. Here we found decreased gating potential of the mPTP and increased expression and activity of sulfide quinone oxidoreductase (SQOR) in newborn Fragile X syndrome (FXS) mouse heart mitochondria, a model system of coenzyme Q excess and relatively decreased mPTP open probability. We further found that pharmacological inhibition and genetic silencing of SQOR increased mPTP open probability in vitro in adult murine cardiac mitochondria and in the isolated-perfused heart, likely by interfering with voltage sensing. Thus, SQOR is proposed to contribute to voltage sensing by the mPTP and may be a component of the voltage sensing apparatus that modulates the gating potential of the mPTP.

Multicenter Population Pharmacokinetics of Fentanyl in Neonatal Surgical Patients Using Dried Blood Spot Specimen Collection Demonstrates Maturation of Elimination Clearance.

BACKGROUND: Fentanyl is widely used for analgesia and sedation in neonates, but pharmacokinetic (PK) analysis in this population has been limited by the relatively large sample volumes required for plasma-based assays. METHODS: In this multicenter observational study of fentanyl kinetics in neonates up to 42 weeks of postmenstrual age (PMA) who received fentanyl boluses and continuous infusions, dried blood spots were used for small-volume sampling. A population PK analysis was used to describe fentanyl disposition in term and preterm neonates. Covariates for the model parameters, including body weight, PMA, birth status (preterm or term), and presence of congenital cardiac disease, were assessed in a stepwise manner. RESULTS: Clearance was estimated to be greater than adult clearance of fentanyl and varied with weight. Covariate selection did not yield a significant relationship for age as a continuous or dichotomous variable (term or preterm, the latter defined as birth with PMA of <37 weeks) and clearance. CONCLUSIONS: A supra-allometric effect on clearance was determined during covariate analyses (exponential scaling factor for body weight >0.75), as has been described in population PK models that account for maturation of intrinsic clearance (here, predominantly hepatic microsomal activity) in addition to scaling for weight, both of which impact clearance in this age group.

Time course of EEG power during creative problem-solving with insight or remote thinking.

Problem-solving often requires creativity and is critical in everyday life. However, the neurocognitive mechanisms underlying creative problem-solving remain poorly understood. Two mechanisms have been highlighted: the formation of new connections among problem elements and insight solving, characterized by sudden realization of a solution. In this study, we investigated EEG activity during a modified version of the remote associates test, a classical insight problem task that requires finding a word connecting three unrelated words. This allowed us to explore the brain correlates associated with the semantic remoteness of connections (by varying the remoteness of the solution word across trials) and with insight solving (identified as a Eurêka moment reported by the participants). Semantic remoteness was associated with power increase in the alpha band (8-12 Hz) in a left parieto-temporal cluster, the beta band (13-30 Hz) in a right fronto-temporal cluster in the early phase of the task, and the theta band (3-7 Hz) in a bilateral frontal cluster just prior to participants' responses. Insight solving was associated with power increase preceding participants' responses in the alpha and gamma (31-60 Hz) bands in a left temporal cluster and the theta band in a frontal cluster. Source reconstructions revealed the brain regions associated with these clusters. Overall, our findings shed new light on some of the mechanisms involved in creative problem-solving.

The prefrontal cortex: from monkey to man.

The prefrontal cortex is so important to human beings that, if deprived of it, our behaviour is reduced to action-reactions and automatisms, with no ability to make deliberate decisions. Why does the prefrontal cortex hold such importance in humans? In answer, this review draws on the proximity between humans and other primates, which enables us, through comparative anatomical-functional analysis, to understand the cognitive functions we have in common and specify those that distinguish humans from their closest cousins. First, a focus on the lateral region of the prefrontal cortex illustrates the existence of a continuum between rhesus monkeys (the most studied primates in neuroscience) and humans for most of the major cognitive functions in which this region of the brain plays a central role. This continuum involves the presence of elementary mental operations in the rhesus monkey (e.g. working memory or response inhibition) that are constitutive of 'macro-functions' such as planning, problem-solving and even language production. Second, the human prefrontal cortex has developed dramatically compared to that of other primates. This increase seems to concern the most anterior part (the frontopolar cortex). In humans, the development of the most anterior prefrontal cortex is associated with three major and interrelated cognitive changes: (i) a greater working memory capacity, allowing for greater integration of past experiences and prospective futures; (ii) a greater capacity to link discontinuous or distant data, whether temporal or semantic; and (iii) a greater capacity for abstraction, allowing humans to classify knowledge in different ways, to engage in analogical reasoning or to acquire abstract values that give rise to our beliefs and morals. Together, these new skills enable us, among other things, to develop highly sophisticated social interactions based on language, enabling us to conceive beliefs and moral judgements and to conceptualize, create and extend our vision of our environment beyond what we can physically grasp. Finally, a model of the transition of prefrontal functions between humans and non-human primates concludes this review.

Economic and social values in the brain: evidence from lesions to the human ventromedial prefrontal cortex.

Making good economic and social decisions is essential for individual and social welfare. Decades of research have provided compelling evidence that damage to the ventromedial prefrontal cortex (vmPFC) is associated with dramatic personality changes and impairments in economic and social decision-making. However, whether the vmPFC subserves a unified mechanism in the social and non-social domains remains unclear. When choosing between economic options, the vmPFC is thought to guide decision by encoding value signals that reflect the motivational relevance of the options on a common scale. A recent framework, the "extended common neural currency" hypothesis, suggests that the vmPFC may also assign values to social factors and principles, thereby guiding social decision-making. Although neural value signals have been observed in the vmPFC in both social and non-social studies, it is yet to be determined whether they have a causal influence on behavior or merely correlate with decision-making. In this review, we assess whether lesion studies of patients with vmPFC damage offer evidence for such a causal role of the vmPFC in shaping economic and social behavior.

Antarctic evidence for an abrupt northward shift of the Southern Hemisphere westerlies at 32 ka BP.

High-resolution ice core records from coastal Antarctica are particularly useful to inform our understanding of environmental changes and their drivers. Here, we present a decadally resolved record of sea-salt sodium (a proxy for open-ocean area) and non-sea salt calcium (a proxy for continental dust) from the well-dated Roosevelt Island Climate Evolution (RICE) core, focusing on the time period between 40-26 ka BP. The RICE dust record exhibits an abrupt shift towards a higher mean dust concentration at 32 ka BP. Investigating existing ice-core records, we find this shift is a prominent feature across Antarctica. We propose that this shift is linked to an equatorward displacement of Southern Hemisphere westerly winds. Subsequent to the wind shift, data suggest a weakening of Southern Ocean upwelling and a decline of atmospheric CO2 to lower glacial values, hence making this shift an important glacial climate event with potentially important insights for future projections.

Millennial-scale variability of the Antarctic ice sheet during the early Miocene.

Millennial-scale ice sheet variability (1-15 kyr periods) is well documented in the Quaternary, providing insight into critical atmosphere-ocean-cryosphere interactions that can inform the mechanism and pace of future climate change. Ice sheet variability at similar frequencies is comparatively less known and understood prior to the Quaternary during times, where higher atmospheric pCO2 and warmer climates prevailed, and continental-scale ice sheets were largely restricted to Antarctica. In this study, we evaluate a high-resolution clast abundance dataset (ice-rafted debris) that captures East Antarctic ice sheet variability in the western Ross Sea during the early Miocene. This dataset is derived from a 100 m-thick mudstone interval in the ANtarctic DRILLing (ANDRILL or AND) core 2A, which preserves a record of precession and eccentricity variability. The sedimentation rates are of appropriate resolution to also characterize the signature of robust, subprecession cyclicity. Strong sub-precession (~10 kyr) cyclicity is observed, with an amplitude modulation in lockstep with eccentricity, indicating a relationship between high-frequency Antarctic ice sheet dynamics and astronomical forcing. Bicoherence analysis indicates that many of the observed millennial-scale cycles (as short as 1.2 kyr) are associated with nonlinear interactions (combination or difference tones) between each other and the Milankovitch cycles. The presence of these cycles during the Miocene reveals the ubiquity of millennial-scale ice sheet variability and sheds light on the interactions between Earth's atmosphere, ocean, and ice in climates warmer than the Quaternary.

Plasma lysosphingolipids in GRN-related diseases: Monitoring lysosomal dysfunction to track disease progression.

GRN mutations are among the main genetic causes of frontotemporal dementia (FTD). Considering the progranulin involvement in lysosomal homeostasis, we aimed to evaluate if plasma lysosphingolipids (lysoSPL) are increased in GRN mutation carriers, and whether they might represent relevant fluid-based biomarkers in GRN-related diseases. We analyzed four lysoSPL levels in plasmas of 131 GRN carriers and 142 non-carriers, including healthy controls and patients with frontotemporal dementias (FTD) carrying a C9orf72 expansion or without any mutation. GRN carriers consisted of 102 heterozygous FTD patients (FTD-GRN), three homozygous patients with neuronal ceroid lipofuscinosis-11 (CLN-11) and 26 presymptomatic carriers (PS-GRN), the latter with longitudinal assessments. Glucosylsphingosin d18:1 (LGL1), lysosphingomyelins d18:1 and isoform 509 (LSM18:1, LSM509) and lysoglobotriaosylceramide (LGB3) were measured by electrospray ionization-tandem mass spectrometry coupled to ultraperformance liquid chromatography. Levels of LGL1, LSM18:1 and LSM509 were increased in GRN carriers compared to non-carriers (p < 0.0001). No lysoSPL increases were detected in FTD patients without GRN mutations. LGL1 and LSM18:1 progressively increased with age at sampling, and LGL1 with disease duration, in FTD-GRN. Among PS-GRN carriers, LSM18:1 and LGL1 significantly increased over 3.4-year follow-up. LGL1 levels were associated with increasing neurofilaments in presymptomatic carriers. This study evidences an age-dependent increase of ß-glucocerebrosidase and acid sphingomyelinase substrates in GRN patients, with progressive changes as early as the presymptomatic phase. Among FTD patients, plasma lysoSPL appear to be uniquely elevated in GRN carriers, and thus might serve as suitable non-invasive disease-tracking biomarkers of progression, specific to the pathophysiological process. Finally, this study might add lysoSPL to the portfolio of fluid-based biomarkers, and pave the way to disease-modifying approaches based on lysosomal function rescue in GRN diseases.

Extension of the Clinicoradiologic Spectrum of Newly Described End-Truncating LAMB1 Variations.

Objectives: To refine the clinical spectrum of a very recently identified phenotype associated with LAMB1 end-truncating pathogenic variations. Methods: Detailed clinical, neuropsychological, and MRI investigation of 6 patients from 2 unrelated families segregating end-truncating LAMB1 variations. Results: All patients harbored a LAMB1 end-truncating pathogenic variation. The specific association of a hippocampal type episodic memory dysfunction and a diffuse leukoencephalopathy was observed in all 4 patients aged older than 50 years, slightly worsening over time in 2 patients with several years of follow-up. Additional unspecific neurologic symptoms are reported, such as episodes of numbness, language troubles, or faintness in these 4 patients and the 2 younger ones. Discussion: The association of an extensive leukoencephalopathy with an episodic memory dysfunction of the hippocampal type is strongly suggestive of a LAMB1 end-truncating variation in adults older than 50 years. Early cognitive complaints and imaging abnormalities might exist decades before. Additional transient manifestations can be observed, and this association should lead to LAMB1 screening to avoid unnecessary invasive investigations.

Applying a modified metabarcoding approach for the sequencing of macrofungal specimens from fungarium collections.

Premise: Fungaria are an underutilized resource for understanding fungal biodiversity. The effort and cost of producing DNA barcode sequence data for large numbers of fungal specimens can be prohibitive. This study applies a modified metabarcoding approach that provides a labor-efficient and cost-effective solution for sequencing the fungal DNA barcodes of hundreds of specimens at once. Methods: We applied a two-step PCR approach using nested, barcoded primers to sequence the fungal nrITS2 region of 766 macrofungal specimens using the Illumina platform. The specimens represent a broad taxonomic sampling of the Dikarya. Of these, 382 Lactarius specimens were analyzed to identify molecular operational taxonomic units (MOTUs) using a phylogenetic approach. The raw sequences were trimmed, filtered, assessed, and analyzed using the DADA2 amplicon de-noising toolkit and Biopython. The sequences were compared to the NCBI and UNITE databases and Sanger nrITS sequences from the same specimens. Results: The taxonomic identities derived from the nrITS2 sequence data were >90% accurate across all specimens sampled. A phylogenetic analysis of the Lactarius sequences identified 20 MOTUs. Discussion: The results demonstrate the capacity of these methods to produce nrITS2 sequences from large numbers of fungarium specimens. This provides an opportunity to more effectively use fungarium collections to advance fungal diversity identification and documentation.

Behavioural disinhibition in frontotemporal dementia investigated within an ecological framework.

Disinhibition is a core symptom in behavioural variant frontotemporal dementia (bvFTD) particularly affecting the daily lives of both patients and caregivers. Yet, characterisation of inhibition disorders is still unclear and management options of these disorders are limited. Questionnaires currently used to investigate behavioural disinhibition do not differentiate between several subtypes of disinhibition, encompass observation biases and lack of ecological validity. In the present work, we explored disinhibition in an original semi-ecological situation, by distinguishing three categories of disinhibition: compulsivity, impulsivity and social disinhibition. First, we measured prevalence and frequency of these disorders in 23 bvFTD patients and 24 healthy controls (HC) in order to identify the phenotypical heterogeneity of disinhibition. Then, we examined the relationships between these metrics, the neuropsychological scores and the behavioural states to propose a more comprehensive view of these neuropsychiatric manifestations. Finally, we studied the context of occurrence of these disorders by investigating environmental factors potentially promoting or reducing them. As expected, we found that patients were more compulsive, impulsive and socially disinhibited than HC. We found that 48% of patients presented compulsivity (e.g., repetitive actions), 48% impulsivity (e.g., oral production) and 100% of the patients group showed social disinhibition (e.g., disregards for rules or investigator). Compulsivity was negatively related with emotions recognition. BvFTD patients were less active if not encouraged in an activity, and their social disinhibition decreased as activity increased. Finally, impulsivity and social disinhibition decreased when patients were asked to focus on a task. Summarising, this study underlines the importance to differentiate subtypes of disinhibition as well as the setting in which they are exhibited, and points to stimulating area for non-pharmacological management.

Effort avoidance as a core mechanism of apathy in frontotemporal dementia.

Apathy is a core symptom in patients with behavioural variant frontotemporal dementia (bvFTD). It is defined by the observable reduction in goal-directed behaviour, but the underlying mechanisms are poorly understood. According to decision theory, engagement in goal-directed behaviour depends on a cost-benefit optimization trading off the estimated effort (related to the behaviour) against the expected reward (related to the goal). In this framework, apathy would thus result from either a decreased appetence for reward, or from an increased aversion to effort. Here, we phenotyped the motivational state of 21 patients with bvFTD and 40 matched healthy controls using computational analyses of behavioural responses in a comprehensive series of behavioural tasks, involving both expression of preference (comparing reward value and effort cost) and optimization of performance (adjusting effort production to the reward at stake). The primary finding was an elevated aversion to effort, consistent across preference and performance tasks in patients with bvFTD compared to controls. Within the bvFTD group, effort avoidance was correlated to cortical atrophy in the dorsal anterior cingulate cortex and to apathy score measured on a clinical scale. Thus, our results highlight elevated effort aversion (not reduced reward appetence) as a core dysfunction that might generate apathy in patients with bvFTD. More broadly, they provide novel behavioural tests and computational tools to identify the dysfunctional mechanisms producing motivation deficits in patients with brain damage.

Bearing allostatic load: insights into a more equitable future within cardio-oncology.

Chronic stress is often regarded as a significant cause of morbidity and mortality; however, the mechanistic link between stress and various disease states has not yet been fully characterized. We explore the concept of allostatic load, a measurement of the physiological burden of chronic stress, as well as its potential role in disease pathogenesis as it relates to cardiovascular disease, cancer, and health-related disparities. Building from this framework, we then posit the potential implications of allostatic load on patient care and research in cardio-oncology. We identify allostatic load as a potential clinically actionable tool to improve health equity in cardio-oncology.

Disentangling Clinical Profiles of Apathy in Behavioral Variant Frontotemporal Dementia.

BACKGROUND: Apathy is highly frequent in behavioral variant frontotemporal dementia (bvFTD). It is presumed to involve different pathophysiological mechanisms and neuroanatomical regions. OBJECTIVE: We explored the hypothesis that subgroups showing distinct profiles of apathy and distinct patterns of atrophy within frontal lobes could be disentangled in bvFTD. METHODS: Using data-driven clustering applied to 20 bvFTD patients, we isolated subgroups according to their profiles on the three subscales of the Dimensional Apathy Scale (DAS). We explored their apathy profiles and atrophy patterns. Apathy profiles were characterized through both subjective measures of apathy by questionnaires and measures including objective behavioral metrics. Atrophy patterns were obtained by voxel-based morphometry, contrasting each bvFTD subgroup with healthy controls (N = 16). RESULTS: By clustering based on DAS dimensions, we disentangled three subgroups of bvFTD patients, with distinct apathy profiles and atrophy patterns. One subgroup, which presented the smallest pattern of atrophy (including orbitofrontal cortex) with a right asymmetry, was characterized by high self-reported emotional and initiation apathy and by a self-initiation deficit reversible by external guidance. In other subgroups showing more diffuse bilateral atrophies extending to lateral prefrontal cortex, apathy was not reversible by external guidance and more difficulty to focus on goal-management was observed, especially in the subgroup with the largest atrophy and highest levels of executive apathy. CONCLUSION: Distinct clinical profiles of apathy, corresponding to distinct anatomical subtypes of bvFTD, were identified. These findings have implications for clinicians in a perspective of precision medicine as they could contribute to personalize treatments of apathy.

Modeling propofol-induced cardiotoxicity in the isolated-perfused newborn mouse heart.

Infants and children are vulnerable to developing propofol infusion syndrome (PRIS) and young age is a risk factor. Cardiac involvement is often prominent and associated with death. However, the mechanisms of pediatric PRIS are poorly understood because of the paucity of investigation and lack of a gold standard animal model. Unfortunately, in vivo modeling of PRIS in a newborn mouse is not feasible and would be complicated by confounders. Thus, we focused on propofol-induced cardiotoxicity and aimed to develop an ex-vivo model in the isolated-perfused newborn mouse heart. We hypothesized that the model would recapitulate the key cardiac features of PRIS seen in infants and children and would corroborate prior in vitro observations. Isolated perfused newborn mouse hearts were exposed to a toxic dose of propofol or intralipid for 30-min. Surface electrocardiogram, ventricular contractile force, and oxygen extraction were measured over time. Real-time multiphoton laser imaging was utilized to quantify calcein and tetramethylrhodamine ethyl ester fluorescence. Propidium iodide uptake was assessed following drug exposure. A toxic dose of propofol rapidly induced dysrhythmias, depressed ventricular contractile function, impaired the mitochondrial membrane potential, and increased open probability of the permeability transition pore in propofol-exposed hearts without causing cell death. These features mimicked the hallmarks of pediatric PRIS and corroborated prior observations made in isolated newborn cardiomyocyte mitochondria. Thus, acute propofol-induced cardiotoxicity in the isolated-perfused developing mouse heart may serve as a relevant ex-vivo model for pediatric PRIS.

Assessment of Open Probability of the Mitochondrial Permeability Transition Pore in the Setting of Coenzyme Q Excess.

The mitochondrial permeability transition pore (mPTP) is a voltage-gated, nonselective, inner mitochondrial membrane (IMM) mega-channel important in health and disease. The mPTP mediates leakage of protons across the IMM during low-conductance opening and is specifically inhibited by cyclosporine A (CsA). Coenzyme Q (CoQ) is a regulator of the mPTP, and tissue-specific differences have been found in CoQ content and open probability of the mPTP in forebrain and heart mitochondria in a newborn mouse model of fragile X syndrome (FXS, Fmr1 knockout). We developed a technique to determine the voltage threshold for mPTP opening in this mutant strain, exploiting the role of the mPTP as a proton leak channel. To do so, oxygen consumption and membrane potential (ΔΨ) were simultaneously measured in isolated mitochondria using polarography and a tetraphenylphosphonium (TPP+) ion-selective electrode during leak respiration. The threshold for mPTP opening was determined by the onset of CsA-mediated inhibition of proton leak at specific membrane potentials. Using this approach, differences in voltage gating of the mPTP were precisely defined in the context of CoQ excess. This novel technique will permit future investigation for enhancing the understanding of physiological and pathological regulation of low-conductance opening of the mPTP.

A temporal classification method based on behavior time series data in patients with behavioral variant of frontotemporal dementia and apathy.

Background Apathy is a common behavioral syndrome that occurs across neurological and psychiatric disorders. An influential theoretical framework defined apathy as the quantitative reduction of self-generated voluntary and purposeful behaviors. There is evidence in the literature of the multidimensional nature of apathy with cognitive, behavioral, and emotional dimensions. To date, apathy has been assessed using various scales and questionnaires. Alternative objective and ecological measurements of apathy are needed. New method We used the ECOCAPTURE protocol and an ethological approach to investigate behavior in bvFTD patients under ecological conditions (a waiting room) while they freely explored a novel environment. Data were collected by behavioral coding from 7-minute video using an ethogram and transformed into behavior time series data. We present an approach considering behavioral kinetics to assess behavior. We aimed to construct a new behavior analysis method, called ECOCAPTURE kinetics, using temporal classification for behavior time series data analysis. To develop our classifier, we retained a nonelastic Euclidian metric, combined with a convolutional approach. Results We applied the ECOCAPTURE kinetics method to a cohort of 20 bvFTD patients and 18 healthy controls. We showed that bvFTD patients can be classified according to their behavioral kinetics into three groups. Each subgroup was characterized by specific behavior disorders and neuropsychological profile. Comparison with Existing Method(s) The ECOCAPTURE kinetics method is different from those of the classical approach of measuring behavior, producing time budgets, frequency of behavior occurrences, or kinematic diagrams. Conclusions This approach can be extended to any behavioral study encoding time.

An ecological approach to identify distinct neural correlates of disinhibition in frontotemporal dementia.

Disinhibition is a core symptom of many neurodegenerative diseases, particularly frontotemporal dementia, and is a major cause of stress for caregivers. While a distinction between behavioural and cognitive disinhibition is common, an operational definition of behavioural disinhibition is still missing. Furthermore, conventional assessment of behavioural disinhibition, based on questionnaires completed by the caregivers, often lacks ecological validity. Therefore, their neuroanatomical correlates are non-univocal. In the present work, we used an original behavioural approach in a semi-ecological situation to assess two specific dimensions of behavioural disinhibition: compulsivity and social disinhibition. First, we investigated disinhibition profile in patients compared to controls. Then, to validate our approach, compulsivity and social disinhibition scores were correlated with classic cognitive tests measuring disinhibition (Hayling Test) and social cognition (mini-Social cognition & Emotional Assessment). Finally, we disentangled the anatomical networks underlying these two subtypes of behavioural disinhibition, taking in account the grey (voxel-based morphometry) and white matter (diffusion tensor imaging tractography). We included 17 behavioural variant frontotemporal dementia patients and 18 healthy controls. We identified patients as more compulsive and socially disinhibited than controls. We found that behavioural metrics in the semi-ecological task were related to cognitive performance: compulsivity correlated with the Hayling test and both compulsivity and social disinhibition were associated with the emotion recognition test. Based on voxel-based morphometry and tractography, compulsivity correlated with atrophy in the bilateral orbitofrontal cortex, the right temporal region and subcortical structures, as well as with alterations of the bilateral cingulum and uncinate fasciculus, the right inferior longitudinal fasciculus and the right arcuate fasciculus. Thus, the network of regions related to compulsivity matched the "semantic appraisal" network. Social disinhibition was associated with bilateral frontal atrophy and impairments in the forceps minor, the bilateral cingulum and the left uncinate fasciculus, regions corresponding to the frontal component of the "salience" network. Summarizing, this study validates our semi-ecological approach, through the identification of two subtypes of behavioural disinhibition, and highlights different neural networks underlying compulsivity and social disinhibition. Taken together, these findings are promising for clinical practice by providing a better characterisation of inhibition disorders, promoting their detection and consequently a more adapted management of patients.

Functional connectivity correlates of reduced goal-directed behaviors in behavioural variant frontotemporal dementia.

We explored the resting state functional connectivity correlates of apathy assessed as a multidimensional construct, using behavioral metrics, in behavioral variant frontotemporal dementia (bvFTD). We recorded the behavior of 20 bvFTD patients and 16 healthy controls in a close-to-real-life situation including a free phase (FP-in which actions were self-initiated) and a guided phase (GP-in which initiation of actions was facilitated by external guidance). We investigated the activity time and walking episode features as quantifiers of apathy. We used the means ((FP + GP)/2) and the differences (FP-GP) calculated for these metrics as well as measures by questionnaires to extract apathy dimensions by factor analysis. We assessed two types of fMRI-based resting state connectivity measures (local activity and seed-based connectivity) and explored their relationship with extracted apathy dimensions. Apathy in bvFTD was associated with lower time spent in activity combined with walking episodes of higher frequency, lower acceleration and higher duration. Using these behavioral metrics and apathy measures by questionnaires, we disentangled two dimensions: the global reduction of goal-directed behaviors and the specific deficit of self-initiation. Global apathy was associated with lower resting state activity within prefrontal cortex and lower connectivity of salience network hubs while the decrease in self-initiation was related to increased connectivity of parietal default-mode network hubs. Through a novel dimensional approach, we dissociated the functional connectivity correlates of global apathy and self-initiation deficit. We discussed in particular the role of the modified connectivity of lateral parietal cortex in the volitional process.