[Understanding functional neurological disorders: From biological markers to pathophysiological models]. / Étiopathogénie des troubles neurologiques fonctionnels : marqueurs biologiques et modèles théoriques.

OBJECTIVES: Functional neurological disorders have witnessed intense research activity in the fields of structural and functional neuroimaging for more than twenty years. Thus, we propose a synthesis of recent research findings and etiological hypotheses that have been proposed so far. This work should help clinicians to better understand the nature of the mechanisms involved, but also help patients to increase their knowledge about the biological features underlying their functional symptoms. METHODS: We carried out a narrative review of international publications dealing with neuroimaging and biology of functional neurological disorders, from 1997 to 2023. RESULTS: Several brain networks underlie functional neurological symptoms. These networks play a role in the management of cognitive resources, in attentional control, emotion regulation, in agency and in the processing of interoceptive signals. The mechanisms of the stress response are also associated with the symptoms. The biopsychosocial model helps to better understand predisposing, precipitating, and perpetuating factors involved. The functional neurological phenotype results from the interaction between: i) a specific pre-existing vulnerability resulting from biological background and epigenetic modifications, and ii) exposure to stress factors, according to the stress-diathesis model. This interaction causes emotional disturbances including hypervigilance, lack of integration of sensations and affects, and emotional dysregulation. These characteristics in turn impact the cognitive, motor and affective control processes related with the functional neurological symptoms. CONCLUSIONS: A better knowledge of the biopsychosocial determinants of brain network dysfunctions is necessary. Understanding them would help developing targeted treatments, but is also critical for patients care.

Psychiatric disorders, personality and neuropsychological alterations in Erdheim-Chester disease.

Although neurological manifestations and changes in brain volumes have been described in Erdheim-Chester disease (ECD), it remains unknown whether ECD may be associated with psychiatric symptoms and cognitive dysfunctions. We assessed the presence of psychiatric disorders, changes in temperaments and characters, and neuropsychological performances in 32 ECD patients (mean age = 59) younger than 70, not treated with interferon alpha during the last 6 months, and without other serious illnesses. ECD patients exhibited high level of past depressive disorder (80%) and anxiety disorder, especially agoraphobia (29%). They revealed personality changes, especially with high agreeableness (t = 3.18, p < 0.005) and high conscientiousness (t = 3.81, p < 0.001). Neuropsychological assessments showed impairments in attention (GZ: t = 16.12, p < 0.0001, KL: t = 37.01, p < 0.0001) and episodic memory performances (STIR: t = - 3.01, p = 0.006, LTFR: t = - 2.87, p = 0.008, LTIR: t = - 3.63, p = 0.001). Executive functions, such as flexibility, inhibitory control, were unimpaired. Although it remains to be clarified whether these psychiatric symptoms and cognitive impairments may impact the daily functioning and the quality of life, the present study highlights the need to consider cognitive and emotional states in ECD management.

Factors Associated With Posttraumatic Stress Symptoms 3 and 6 Months After Hospitalization for COVID-19: A Longitudinal Multicenter Study.

Objective: To identify factors associated with posttraumatic stress symptoms (PTSS) 3 and 6 months after the discharge of patients hospitalized for COVID-19.Methods: Patients hospitalized for COVID-19 between March 1 and July 31, 2020, were included in a longitudinal study. Clinical assessments were conducted with online auto-questionnaires. PTSS were assessed with the Posttraumatic Stress Disorder Checklist Scale (PCLS). We screened for several putative factors associated with PTSS, including socio-demographic status, hospitalization in an intensive care unit, history of psychiatric disorder, the Hospital Anxiety and Depression Scale, the Peritraumatic Dissociative Experiences Questionnaire, and the home-to-hospital distance. Bivariate and multilinear regression analyses were performed to evaluate their association with PTSS.Results: 119 patients were evaluated 3 months after hospital discharge, and a subset of 94 were evaluated 6 months after discharge. The prevalence of PTSS was 31.9% after 3 months and 30.9% after 6 months. Symptoms of anxiety and depression and history of psychiatric disorder were independently associated with PTSS. Additionally, dissociative experiences during hospitalization (ß = 0.35; P < .001) and a longer home-to-hospital distance (ß = 0.07; P = .017) were specifically associated with PTSS 3 and 6 months after discharge, respectively.Conclusions: Patients with COVID-19 showed persistent high scores of PTSS up to 6 months after discharge from the hospital. In this specific pandemic setting, PTSS were associated with high rates of dissociative experiences during hospitalization and a longer home-to-hospital distance due to the saturation of health care facilities. These results can foster early identification and better prevention of PTSS after hospitalization for COVID-19.Trial Registration: ClinicalTrials.gov identifier: NCT04362930.

Glutamatergic and N-Acetylaspartate Metabolites in Bipolar Disorder: A Systematic Review and Meta-Analysis of Proton Magnetic Resonance Spectroscopy Studies.

The exact neurobiological mechanisms of bipolar disorder (BD) remain unknown. However, some neurometabolites could be implicated, including Glutamate (Glu), Glutamine (Gln), Glx, and N-acetylaspartate (NAA). Proton Magnetic Resonance Spectroscopy (1H-MRS) allows one to quantify these metabolites in the human brain. Thus, we conducted a systematic review and meta-analysis of the literature to compare their levels between BD patients and healthy controls (HC). The main inclusion criteria for inclusion were 1H-MRS studies comparing levels of Glu, Gln, Glx, and NAA in the prefrontal cortex (PFC), anterior cingulate cortex (ACC), and hippocampi between patients with BD in clinical remission or a major depressive episode and HC. Thirty-three studies were included. NAA levels were significantly lower in the left white matter PFC (wmPFC) of depressive and remitted BD patients compared to controls and were also significantly higher in the left dorsolateral PFC (dlPFC) of depressive BD patients compared to HC. Gln levels were significantly higher in the ACC of remitted BD patients compared to in HC. The decreased levels of NAA of BD patients may be related to the alterations in neuroplasticity and synaptic plasticity found in BD patients and may explain the deep white matter hyperintensities frequently observed via magnetic resonance imagery.

Identified Motivation as a Key Factor for School Engagement During the COVID-19 Pandemic-Related School Closure.

On March 16, 2020, French schools suddenly closed due to the COVID-19 pandemic, and middle school students were asked to study from home with no direct interactions with teachers or classmates. However, school plays an important role in the development of social, intellectual, and mental competencies and can counteract the negative effects of adverse life events on learning and early school dropout. In this study, we investigated how the unusual context of school closure during the COVID-19 pandemic affected school engagement. Specifically, we focused on inter-individual differences in the motivational determinants of school engagement. We thus performed an online survey of 170 students focusing on the time spent on mathematics assignments, motivation regulation, implicit theories of intelligence, such as adopting a growth or a fixed mindset about his/her intellectual abilities, and optimism. Importantly, the students participated in the online survey during the first lockdown period, with schools closed (T1), and the second lockdown period, with schools remaining open (T2). During T1, identified motivation positively predicted the time spent on math homework assignments: the more the students thought that working on math exercises was useful for their future life, the more time they spent studying. Importantly, the link between identified motivation and school engagement was specific to T1, when schools were closed, as indicated by a significant interaction between identified motivations by type of lockdown. These results suggest that having self-determined motivation is of particular importance when students are deprived of social and intellectual interactions with classmates and teachers. This finding paves the way toward the development of wise rational interventions that target identified motivation and can be applied during challenging societal times and adverse, common life events to keep students engaged with school.

Psychogenic non-epileptic seizure-status in patients admitted to the intensive care unit.

BACKGROUND: Psychogenic non-epileptic seizure-status (PNES-status), defined by psychogenic non-epileptic seizures (PNES) over 30 min, are often misdiagnosed as status epilepticus. We aimed to describe the features of patients who experienced PNES-status, admitted to an intensive care unit (ICU). METHODS: We screened the patients hospitalized in our epilepsy unit during a 4-year period, with a diagnosis of PNES-status and ICU admission. RESULTS: Among 171 patients with PNES, we identified 25 patients (15%) who presented 39 episodes of PNES-status leading to ICU admission. Some 76% of the patients were women. The median age at the time of the PNES-status episode was 35 years. Half (48%) alleged a history of epilepsy, but epilepsy was confirmed in only 12%. A history of psychiatric disease was found in 68%. PNES were present in 85% of patients before PNES-status, and semiology of PNES and PNES-status was similar for 79% of the patients, including hyperkinetic movements in 95% of the episodes and suspected loss of consciousness in 87%. Benzodiazepines were administrated in 77% of the episodes, antiepileptic drugs in 87%, and antibiotherapy for a ICU-related infection in 15% of the episodes. Oral intubation was performed in 41% of the episodes. Blood tests showed normal levels of creatine phosphokinase and leucocytes in 90% and 95% of the episodes, respectively. No epileptic activity was found during per-event electroencephalography but interictal epileptic activity was found in 10% of the episodes. CONCLUSION: Hyperkinetic PNES-status should always be considered as a differential diagnosis of status epilepticus, with a high risk of iatrogenic consequences.

Mind-Wandering Changes in Dysphoria.

Changes in mind-wandering (MW) and involuntary autobiographical memory (IAM) in dysphoria have been explored with conflicting results. The aim of this study was to evaluate both MW and IAM in a group of 23 stable dysphoric participants compared to 37 controls and to compare their thoughts characteristics (i.e., specificity, visual perspective, time orientation, and emotional valence). To make this study comparable with previous research, we used two different monotonous vigilance tasks (with and without verbal interference stimuli). Our results showed a significantly greater focus on MW thoughts in dysphoria. The characteristics of spontaneous thoughts content did not differ significantly between our dysphoric participants and controls, which is not in favor of strong emotional dysfunction. Our results suggest a difficulty to regulate the occurrence of self-generated thoughts rather than their content, that may confer to dysphoric subjects increased cognitive risk to develop a major depressive episode.

A transdiagnostic perspective of constructs underlying obsessive-compulsive and related disorders: An international Delphi consensus study.

BACKGROUND: The Research Domain Criteria seeks to bridge knowledge from neuroscience with clinical practice by promoting research into valid neurocognitive phenotypes and dimensions, irrespective of symptoms and diagnoses as currently conceptualized. While the Research Domain Criteria offers a vision of future research and practice, its 39 functional constructs need refinement to better target new phenotyping efforts. This study aimed to determine which Research Domain Criteria constructs are most relevant to understanding obsessive-compulsive and related disorders, based on a consensus between experts in the field of obsessive-compulsive and related disorders. METHODS: Based on a modified Delphi method, 46 experts were recruited from Australia, Africa, Asia, Europe and the Americas. Over three rounds, experts had the opportunity to review their opinion in light of feedback from the previous round, which included how their response compared to other experts and a summary of comments given. RESULTS: Thirty-four experts completed round one, of whom 28 (82%) completed round two and 24 (71%) completed round three. At the final round, four constructs were endorsed by ⩾75% of experts as 'primary constructs' and therefore central to understanding obsessive-compulsive and related disorders. Of these constructs, one came from the Positive Valence System (Habit), two from the Cognitive Control System (Response Selection/Inhibition and Performance Monitoring) and the final construct was an additional item suggested by experts (Compulsivity). CONCLUSION: This study identified four Research Domain Criteria constructs that, according to experts, cut across different obsessive-compulsive and related disorders. These constructs represent key areas for future investigation, and may have potential implications for clinical practice in terms of diagnostic processes and therapeutic management of obsessive-compulsive and related disorders.

Correction: Performance in delayed non-matching to sample task predicts the diagnosis of obsessive-compulsive disorder.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Impaired decision making following escalation of cocaine self-administration predicts vulnerability to relapse in rats.

Impairments in cost-benefit decision making represent a cardinal feature of drug addiction. However, whether these alterations predate drug exposure, thereby contributing to facilitating loss of control over drug intake, or alternatively arise as a result of drug use and subsequently confer vulnerability to relapse has yet to be determined. Male Sprague-Dawley rats were trained to self-administer (SA) cocaine during 19 daily long-access (12-h) sessions; conditions reliably shown to promote escalation. One week after cocaine SA, rats underwent an extinction/relapse test immediately followed by conditioned stimuli-, stress-, and drug-primed reinstatement challenges. The influence of escalated cocaine intake on decision making was measured over time by four test sessions of a rodent analogue of the Iowa Gambling Task (rGT), once prior to cocaine exposure and then 1 day, 1 week, and 1 month after the last SA session. Substantial individual variability was observed in the influence of escalated cocaine SA on decision-making performance. A subset of rats displayed pronounced deficits, while others showed unaffected or even improved performance on the rat Gambling Task (rGT) 24 hours after the last SA session. When challenged with a relapse test after 1 week of forced abstinence, animals that showed impaired decision making following SA displayed an increased propensity to respond for cocaine under extinction. These data suggest that decision-making deficits in individuals with drug addiction are not antecedent to-but arise as a consequence of-drug exposure. Moreover, these data indicate that susceptibility to the deleterious effects of drugs on decision making confers vulnerability toward relapse.

Performance in delayed non-matching to sample task predicts the diagnosis of obsessive-compulsive disorder.

Electrical stimulation studies have recently evidenced the involvement of orbitofrontal cortex (OFC) in obsessive-compulsive disorder (OCD). In addition, lateral OFC is activated in healthy subjects during delayed non-matching-to-sample task (DNMS). In the present study, we hypothesized that OCD results from a specific defect of lateral OFC processing that can be evidenced via a DNMS task. To this end, we compared the DNMS performances of 20 OCD patients vs 20 demographically matched healthy controls. As predicted, our results showed that OCD patients performed worse than healthy controls at DNMS task. To test for the specificity of this behavioral impairment, we furthermore compared OCD patients and healthy subjects on a different task not involving directly the lateral OFC: the delayed match-to-sample task (DMS). As expected, OCD patients are more impaired for both the DNMS and the DMS task, compared with healthy subjects. Moreover, OCD patients tend statistically to perform worse for the DNMS task than for DMS task. Our results suggest the DNMS task specifically target the malfunctioning areas in OCD, such as the lateral OFC. In light of these results, lateral OFC should therefore be the focus of future therapeutic interventions.

What attitude towards a patient with somatoform disorder? / Quelle attitude face à un patient ayant un trouble somatoforme ?

The diagnosis of a somatic symptom disorder must be based on both a negative approach - eliminating another psychiatric or non-psychiatric disorder that would better explain the symptoms - and a positive one, which is, based on the search for characteristic thoughts, emotions or behaviours as well as biological or psychological factors that may promote, trigger or sustain the disorder. Additional tests and specialized medical consultations should not be prescribed solely to reassure the patient; they may actually worsen the condition. The management will move away from the outdated notion of "medically unexplained symptoms" to rely on: the acknowledgment of the painful, debilitating and involuntary nature of the symptoms; the proposal of a positive diagnosis acceptable by the patient and an explanatory model compatible with his or her representations, aimed at putting an end to dysfunctional health care utilization; the proposal of therapeutic objectives aimed at functional rather than symptomatic recovery; the negotiation of pharmacological (selective or mixed serotonin reuptake inhibitor if necessary) and non-pharmacological interventions, especially when it comes to limiting the factors that sustain the disorder; the coordination of the various healthcare professionals.

Le diagnostic de trouble somatoforme doit reposer sur une démarche tout autant négative ­ éliminer un autre trouble psychiatrique ou non psychiatrique qui expliquerait mieux les symptômes ­ que positive, c'est-à-dire fondée sur la recherche de pensées, d'émotions ou de comportements caractéristiques et de facteurs biologiques ou psychologiques pouvant favoriser, déclencher ou pérenniser le trouble. Examens complémentaires et avis médicaux spécialisés ne doivent pas avoir pour seul but de rassurer le patient ; ils peuvent en effet s'avérer iatrogènes. La prise en charge doit se détourner de la notion désuète de « symptômes médicalement inexpliqués ¼ pour s'appuyer sur : la reconnaissance du caractère pénible, invalidant et non volontaire des symptômes ; la proposition d'un diagnostic positif acceptable et d'un modèle explicatif compatible avec les représentations du patient, visant à mettre un terme à l'errance diagnostique ; la proposition d'objectifs thérapeutiques visant un rétablissement fonctionnel plus que symptomatique ; la négociation des moyens pharmacologiques (inhibiteur sélectif ou mixte de recapture de la sérotonine si nécessaire) et non pharmacologiques, en particulier la lutte contre les facteurs d'entretien du trouble ; la coordination des soins entre les divers intervenants

Medial prefrontal disengagement during self-focus in formerly depressed patients prone to rumination.

BACKGROUND: Medial prefrontal cortex (MPFC) activity during self-referential processing has been associated with rumination and found aberrant in depression. We investigated whether this aberrant activity reflects a trait marker that persists in remitted patients. METHODS: Twenty-five patients fully remitted from major depression for at least 6 months, and 29 matched healthy controls were scanned with fMRI while presented with personality trait words in two conditions: Self condition asked whether the trait described themselves; General condition asked whether the trait was generally desirable. Contrasts-of-interest were examined in a factorial model and rumination correlates were examined in 2-sample t-tests with Ruminative Response Style score as covariate. All findings were reported at a conservative p < 0.05, with whole-brain peak-level family-wise error correction. RESULTS: Self-referential processing increased anterior cortical midline activity to a similar extent in both groups. Dorsal anterior cingulate cortex (MNI(x,y,z) = -12,20,26) and dorsal MPFC (MNI(x,y,z) = -6,46,40) activity during self-referential processing was positively associated with rumination in healthy control subjects and negatively associated with rumination in remitted patients. LIMITATIONS: A longitudinal design tracking the relationship between rumination and MPFC activity would have aided the interpretation of our findings as to whether high ruminators are exhibiting an adaptive process to maintain remission or whether it represents a maladaptive process considering that high ruminators have an increased vulnerability for relapse. CONCLUSIONS: The association between increased anterior cortical midline activity during self-referential processing and rumination differentiated healthy controls from formerly depressed patients. Self-referential neural processing during remission from depression may depend on the cognitive tendencies to ruminate.

The impact of self-distancing on emotion explosiveness and accumulation: An fMRI study.

Emotions unfold over time with episodes differing in explosiveness (i.e., profiles having a steep vs. a gentle start) and accumulation (i.e., profiles increasing over time vs. going back to baseline). In the present fMRI study, we wanted to replicate and extend previous findings on the psychological and neural mechanisms underlying emotion explosiveness and accumulation. Specifically, we aimed to: (a) replicate the finding that different neural mechanisms are associated with emotion explosiveness and accumulation, (b) replicate the finding that adopting a self-distanced (vs. self-immersed) perspective decreases emotion explosiveness and accumulation at the level of self-report, and (c) examine whether adopting a self-distanced (vs. self-immersed) perspective similarly modulates activity in the brain regions associated with emotion explosiveness and accumulation. Participants in an fMRI scanner were asked to adopt a self-immersed or self-distanced perspective while reading and thinking about negative social feedback, and to report on felt changes in negative affect during that period using an emotion intensity profile tracking approach. We replicated previous findings showing that emotion explosiveness and accumulation were related to activity in regions involved in self-referential processing (such as the medial prefrontal cortex) and sustained visceral arousal (such as the posterior insula), respectively. The finding that adopting a self-distanced (vs. self-immersed) perspective lowers emotion explosiveness and accumulation was also replicated at a self-report level. However, perspective taking did not impact activity in the neural correlates of emotion explosiveness and accumulation.

Meta-analysis of central and peripheral γ-aminobutyric acid levels in patients with unipolar and bipolar depression.

BACKGROUND: Many studies have measured central and peripheral γ-aminobutyric acid (GABA) levels in patients with depression. We performed a meta-analysis to provide an objective overview of GABA changes in those with unipolar or bipolar depression. METHODS: After a systematic database search, original data were extracted with the help of seminal authors to calculate standardized mean differences. We compared GABA levels between patients with current major depressive episodes and controls, between euthymic patients and controls, and in patients before and after treatment. We performed meta-regressions to explore the influence of demographic and clinical variables on GABA significant mean differences. RESULTS: For unipolar depression, central and peripheral GABA levels were diminished in currently depressed patients, but normal in euthymic patients, compared with the healthy controls. For bipolar disorder, GABA levels were diminished in medication-free patients, but seemed to be normalized in medicated patients, compared with the healthy controls. We found no significant association with demographic or clinical variables. LIMITATIONS: There was a great heterogeneity across studies, probably because of the substantial variation of clinical characteristics in the included samples. Many subanalyses were performed to assess how the diagnosis, medications, or the type of measurements of peripheral or central GABA levels may affect the main results. CONCLUSION: The GABA levels evolved differentially in patients with unipolar and bipolar disorders. Our results suggest that GABA levels could represent a biomarker of symptomatic states in patients with unipolar disorder and would be normalized by mood stabilizers in those with bipolar disorder.

Personality and Neuropsychological Profiles in Friedreich Ataxia.

Friedreich ataxia, an autosomal recessive mitochondrial disease, is the most frequent inherited ataxia. Many studies have attempted to identify cognitive and affective changes associated with the disease, but conflicting results have been obtained, depending on the tests used and because many of the samples studied were very small. We investigated personality and neuropsychological characteristics in a cohort of 47 patients with genetically confirmed disease. The neuropsychological battery assessed multiple cognition domains: processing speed, attention, working memory, executive functions, verbal memory, vocabulary, visual reasoning, emotional recognition, and social cognition. Personality was assessed with the Temperament and Character Inventory, and depressive symptoms were assessed with the Beck Depression Inventory. We found deficits of sustained attention, processing speed, semantic capacities, and verbal fluency only partly attributable to motor deficit or depressed mood. Visual reasoning, memory, and learning were preserved. Emotional processes and social cognition were unimpaired. We also detected a change in automatic processes, such as reading. Personality traits were characterized by high persistence and low self-transcendence. The mild cognitive impairment observed may be a developmental rather than degenerative problem, due to early cerebellum dysfunction, with the impairment of cognitive and emotional processing. Disease manifestations at crucial times for personality development may also have an important impact on personality traits.

Bidirectional regulation over the development and expression of loss of control over cocaine intake by the anterior insula.

RATIONALE: Increasing evidence suggests that the anterior insular cortex (AIC) plays a major role in cocaine addiction, being implicated in both impaired insight and associated decision-making and also craving and relapse. However, the nature of the involvement of the insula in the development and maintenance of cocaine addiction remains unknown, thereby limiting our understanding of its causal role in addiction. We therefore investigated whether pre- and post-training bilateral lesions of the AIC differentially influenced the development and the expression of the escalation of cocaine self-administration during extended access to the drug. METHODS: In a series of experiments, Sprague Dawley rats received bilateral excitotoxic lesions of the AIC either prior to, or after 3 weeks of training under 12-h extended self-administration conditions, which are known to promote a robust escalation of intake. We also investigated the influence of AIC lesions on anxiety, as measured in an elevated plus maze and sensitivity to conditioned stimuli (CS)- or drug-induced reinstatement of an extinguished instrumental response. RESULTS: Whereas, post-escalation lesions of the AIC, as anticipated, restored control over cocaine intake and prevented drug-induced reinstatement, pre-training lesions resulted in a facilitation of the development of loss of control with no influence over the acquisition of cocaine self-administration or anxiety. CONCLUSIONS: AIC lesions differentially affect the development and maintenance of the loss of control over cocaine intake, suggesting that the nature of the contribution of cocaine-associated interoceptive mechanisms changes over the course of escalation and may represent an important component of addiction.

The neural basis of emotions varies over time: different regions go with onset- and offset-bound processes underlying emotion intensity.

According to theories of emotion dynamics, emotions unfold across two phases in which different types of processes come to the fore: emotion onset and emotion offset. Differences in onset-bound processes are reflected by the degree of explosiveness or steepness of the response at onset, and differences in offset-bound processes by the degree of accumulation or intensification of the subsequent response. Whether onset- and offset-bound processes have distinctive neural correlates and, hence, whether the neural basis of emotions varies over time, still remains unknown. In the present fMRI study, we address this question using a recently developed paradigm that allows to disentangle explosiveness and accumulation. Thirty-one participants were exposed to neutral and negative social feedback, and asked to reflect on its contents. Emotional intensity while reading and thinking about the feedback was measured with an intensity profile tracking approach. Using non-negative matrix factorization, the resulting profile data were decomposed in explosiveness and accumulation components, which were subsequently entered as continuous regressors of the BOLD response. It was found that the neural basis of emotion intensity shifts as emotions unfold over time with emotion explosiveness and accumulation having distinctive neural correlates.