Whole-brain gray matter maturation trajectories associated with autistic traits from adolescence to early adulthood.

A growing number of evidence supports a continued distribution of autistic traits in the general population. However, brain maturation trajectories of autistic traits as well as the influence of sex on these trajectories remain largely unknown. We investigated the association of autistic traits in the general population, with longitudinal gray matter (GM) maturation trajectories during the critical period of adolescence. We assessed 709 community-based adolescents (54.7% women) at age 14 and 22. After testing the effect of sex, we used whole-brain voxel-based morphometry to measure longitudinal GM volumes changes associated with autistic traits measured by the Social Responsiveness Scale (SRS) total and sub-scores. In women, we observed that the SRS was associated with slower GM volume decrease globally and in the left parahippocampus and middle temporal gyrus. The social communication sub-score correlated with slower GM volume decrease in the left parahippocampal, superior temporal gyrus, and pallidum; and the social cognition sub-score correlated with slower GM volume decrease in the left middle temporal gyrus, the right ventromedial prefrontal and orbitofrontal cortex. No longitudinal association was found in men. Autistic traits in young women were found to be associated with specific brain trajectories in regions of the social brain and the reward circuit known to be involved in Autism Spectrum Disorder. These findings support both the hypothesis of an earlier GM maturation associated with autistic traits in adolescence and of protective mechanisms in women. They advocate for further studies on brain trajectories associated with autistic traits in women.

Maternal immune activation during pregnancy is associated with more difficulties in socio-adaptive behaviors in autism spectrum disorder.

Autism spectrum disorder (ASD) are neurodevelopmental conditions characterised by deficits in social communication and interaction and repetitive behaviours. Maternal immune activation (MIA) during the mid-pregnancy is a known risk factor for ASD. Although reported in 15% of affected individuals, little is known about the specificity of their clinical profiles. Adaptive skills represent a holistic approach to a person's competencies and reflect specifically in ASD, their strengths and difficulties. In this study, we hypothesised that ASD individual with a history of MIA (MIA+) could be more severely socio-adaptively impaired than those without MIA during pregnancy (MIA-). To answer this question, we considered two independent cohorts of individuals with ASD (PARIS study and FACE ASD) screened for pregnancy history, and used supervised and unsupervised machine learning algorithms. We included 295 mother-child dyads with 14% of them with MIA+. We found that ASD-MIA+ individuals displayed more severe maladaptive behaviors, specifically in their socialization abilities. MIA+ directly influenced individual's socio-adaptive skills, independent of other covariates, including ASD severity. Interestingly, MIA+ affect persistently the socio-adaptive behavioral trajectories of individuals with ASD. The current study has a retrospective design with possible recall bias regarding the MIA event and, even if pooled from two cohorts, has a relatively small population. In addition, we were limited by the number of covariables available potentially impacted socio-adaptive behaviors. Larger prospective study with additional dimensions related to ASD is needed to confirm our results. Specific pathophysiological pathways may explain these clinical peculiarities of ASD- MIA+ individuals, and may open the way to new perspectives in deciphering the phenotypic complexity of ASD and for the development of specific immunomodulatory strategies.

Psychotropic drugs consumption during 2020 COVID-19 pandemic and lockdowns: Evidence of a surprising resilience of the drugs delivery system in France.

The COVID-19 pandemic imposed two lockdowns of eight and six weeks in France. While access to care was reduced during lockdown periods, these stressful situations with the pandemic and lockdown periods may have a negative impact on mental health, especially in vulnerable subgroups. Monitoring of psychotropic drugs consumption in France is a comprehensive and reliable tool for indirectly analyzing the mental health of French people. This historical cohort study (n = 767 147) investigated the short-term and long-term evolution of the weekly trend of psychotropic drugs users in 2020 by performing a Seasonal Trend decomposition time series analysis. Rate of progression of consumers per week increased from 186 in the last week of 2019 to 261 per week in the last week of 2020 (+40.3%). Our results did not show a significant break in psychotropic drugs consumption trends during the year 2020 and its two lockdowns. The increase in trend regarding psychotropic drugs consumptions was greatest in young people (<15 years) and patients not being socially deprived. Despite the increase in consumers with restrictive health measures, the French drugs delivery system has been able to adapt with the support of government and pharmacy network. This point should be kept in mind as the necessary reforms to the health care system are undertaken. The COVID-19 pandemic has a negative impact on mental health and two lockdowns occurred in France with reduced access to care. In this context, monitoring of psychotropic drugs consumption is a comprehensive and reliable tool for analyzing the mental health of French people. We hypothesized that the psychotropic drugs consumption has increased during the 2020 COVID-19 pandemic, testifying to French people mental health deterioration, with psychotropic drugs consumption breaks during lockdowns, especially during the first "grand national lockdown", due to the closure or difficulties for accessing to health care structures. By carrying out a historical cohort study among Pays de la Loire residents (n = 767 147), we investigated evolution of the weekly trend of psychotropic drugs users in 2020 compared to 2019 by performing a Seasonal Trend decomposition time series analysis. Between 2019 to 2020, we found a + 40.3% rate of progression of consumers per week. During the year 2020, changes in trend regarding psychotropic drugs consumptions was observed in various sub-groups, e.g. greater in the youngest (< 15 years), which may indicate a vulnerable group strongly impacted by COVID-19 negative consequences, and patients not being socially deprived, which may indicate a group with probably an easier access to care. Lockdown periods were not associated with a significant change in psychotropic drug use, suggesting a form of resilience in the French health care system to maintain its capacity to deliver psychotropic treatments. We mainly discussed that despite the increase in consumers and the policies of restricting access to care during lockdown periods, the French drugs delivery system has been able to adapt thanks to supportive policy actions (extension of the prescriptions validity without the need for a renewal by a physician during periods of lockdowns), an efficient pharmacy network with a collaborative practice of health actors that need to be developed and/or conserved to face potential future health crises.

Gender differences in psychosocial function and self-reported health status in late-diagnosed autistic adults: results from the FACE-ASD national cohort.

BACKGROUND: While adult outcome in autism spectrum disorder (ASD) is generally measured using socially valued roles, it could also be understood in terms of aspects related to health status - an approach that could inform on potential gender differences. METHODS: We investigated gender differences in two aspects of outcome related to health-status, i.e. general functioning and self-perceived health status, and co-occurring health conditions in a large multi-center sample of autistic adults. Three hundred and eighty-three participants were consecutively recruited from the FondaMental Advanced Centers of Expertise for ASD cohort (a French network of seven expert centers) between 2013 and 2020. Evaluation included a medical interview, standardized scales for autism diagnosis, clinical and functional outcomes, self-perceived health status and verbal ability. Psychosocial function was measured using the Global Assessment of Functioning scale. RESULTS: While autistic women in this study were more likely than men to have socially valued roles, female gender was associated with poorer physical and mental health (e.g. a 7-fold risk for having three or more co-occurring physical health conditions) and a poorer self-perceived health status. Psychosocial function was negatively associated with depression and impairment in social communication. Half of the sample had multiple co-occurring health conditions but more than 70% reported that their visit at the Expert Center was their first contact with mental health services. CONCLUSIONS: To improve objective and subjective aspects of health outcome, gender differences and a wide range of co-occurring health conditions should be taken into account when designing healthcare provision for autistic adults.

Prevention of Suicidal Relapses in Adolescents With a Smartphone Application: Bayesian Network Analysis of a Preclinical Trial Using In Silico Patient Simulations.

BACKGROUND: Recently, artificial intelligence technologies and machine learning methods have offered attractive prospects to design and manage crisis response processes, especially in suicide crisis management. In other domains, most algorithms are based on big data to help diagnose and suggest rational treatment options in medicine. But data in psychiatry are related to behavior and clinical evaluation. They are more heterogeneous, less objective, and incomplete compared to other fields of medicine. Consequently, the use of psychiatric clinical data may lead to less accurate and sometimes impossible-to-build algorithms and provide inefficient digital tools. In this case, the Bayesian network (BN) might be helpful and accurate when constructed from expert knowledge. Medical Companion is a government-funded smartphone application based on repeated questions posed to the subject and algorithm-matched advice to prevent relapse of suicide attempts within several months. OBJECTIVE: Our paper aims to present our development of a BN algorithm as a medical device in accordance with the American Psychiatric Association digital healthcare guidelines and to provide results from a preclinical phase. METHODS: The experts are psychiatrists working in university hospitals who are experienced and trained in managing suicidal crises. As recommended when building a BN, we divided the process into 2 tasks. Task 1 is structure determination, representing the qualitative part of the BN. The factors were chosen for their known and demonstrated link with suicidal risk in the literature (clinical, behavioral, and psychometrics) and therapeutic accuracy (advice). Task 2 is parameter elicitation, with the conditional probabilities corresponding to the quantitative part. The 4-step simulation (use case) process allowed us to ensure that the advice was adapted to the clinical states of patients and the context. RESULTS: For task 1, in this formative part, we defined clinical questions related to the mental state of the patients, and we proposed specific factors related to the questions. Subsequently, we suggested specific advice related to the patient's state. We obtained a structure for the BN with a graphical representation of causal relations between variables. For task 2, several runs of simulations confirmed the a priori model of experts regarding mental state, refining the precision of our model. Moreover, we noticed that the advice had the same distribution as the previous state and was clinically relevant. After 2 rounds of simulation, the experts found the exact match. CONCLUSIONS: BN is an efficient methodology to build an algorithm for a digital assistant dedicated to suicidal crisis management. Digital psychiatry is an emerging field, but it needs validation and testing before being used with patients. Similar to psychotropics, any medical device requires a phase II (preclinical) trial. With this method, we propose another step to respond to the American Psychiatric Association guidelines. TRIAL REGISTRATION: ClinicalTrials.gov NCT03975881; https://clinicaltrials.gov/ct2/show/NCT03975881.

Mobile App for Parental Empowerment for Caregivers of Children With Autism Spectrum Disorders: Prospective Open Trial.

BACKGROUND: Conflicting data emerge from literature regarding the actual use of smartphone apps in medicine; some considered the introduction of smartphone apps in medicine to be a breakthrough, while others suggested that, in real-life, the use of smartphone apps in medicine is disappointingly low. Yet, digital tools become more present in medicine daily. To empower parents of a child with autism spectrum disorder, we developed the Smartautism smartphone app, which asks questions and provides feedback, using a screen with simple curves. OBJECTIVE: The purpose of this study was to evaluate usage of the app by caregivers of individuals with autism spectrum disorders. METHODS: We conducted a prospective longitudinal exploratory open study with families that have a child with autism spectrum disorder. Data were recorded over a period of 6 months, and the outcome criteria were (1) overall response rates for a feedback screen and qualitative questionnaires, and (2) response rates by degree of completion and by user interest, based on attrition. RESULTS: Participants (n=65) had a very high intent to use the app during the 6-month period (3698/3900 instances, 94.8%); however, secondary analysis showed that only 46% of participants (30/65) had constant response rates over 50%. Interestingly, these users were characterized by higher use and satisfaction with the feedback screen when compared to low (P<.001) and moderate (P=.007) users. CONCLUSIONS: We found that real or perceived utility is an important incentive for parents who use empowerment smartphone apps. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.1136/bmjopen-2016-012135.

Neural correlates of three types of negative life events during angry face processing in adolescents.

Negative life events (NLE) contribute to anxiety and depression disorders, but their relationship with brain functioning in adolescence has rarely been studied. We hypothesized that neural response to social threat would relate to NLE in the frontal-limbic emotional regions. Participants (N = 685) were drawn from the Imagen database of 14-year-old community adolescents recruited in schools. They underwent functional MRI while viewing angry and neutral faces, as a probe to neural response to social threat. Lifetime NLEs were assessed using the 'distress', 'family' and 'accident' subscales from a life event dimensional questionnaire. Relationships between NLE subscale scores and neural response were investigated. Links of NLE subscales scores with anxiety or depression outcomes at the age of 16 years were also investigated. Lifetime 'distress' positively correlated with ventral-lateral orbitofrontal and temporal cortex activations during angry face processing. 'Distress' scores correlated with the probabilities of meeting criteria for Generalized Anxiety Disorder or Major Depressive Disorder at the age of 16 years. Lifetime 'family' and 'accident' scores did not relate with neural response or follow-up conditions, however. Thus, different types of NLEs differentially predicted neural responses to threat during adolescence, and differentially predicted a de novo internalizing condition 2 years later. The deleterious effect of self-referential NLEs is suggested.

The Brain's Response to Reward Anticipation and Depression in Adolescence: Dimensionality, Specificity, and Longitudinal Predictions in a Community-Based Sample.

OBJECTIVE: The authors examined whether alterations in the brain's reward network operate as a mechanism across the spectrum of risk for depression. They then tested whether these alterations are specific to anhedonia as compared with low mood and whether they are predictive of depressive outcomes. METHOD: Functional MRI was used to collect blood-oxygen-level-dependent (BOLD) responses to anticipation of reward in the monetary incentive task in 1,576 adolescents in a community-based sample. Adolescents with current subthreshold depression and clinical depression were compared with matched healthy subjects. In addition, BOLD responses were compared across adolescents with anhedonia, low mood, or both symptoms, cross-sectionally and longitudinally. RESULTS: Activity in the ventral striatum was reduced in participants with subthreshold and clinical depression relative to healthy comparison subjects. Low ventral striatum activation predicted transition to subthreshold or clinical depression in previously healthy adolescents at 2-year follow-up. Brain responses during reward anticipation decreased in a graded manner between healthy adolescents, adolescents with current or future subthreshold depression, and adolescents with current or future clinical depression. Low ventral striatum activity was associated with anhedonia but not low mood; however, the combined presence of both symptoms showed the strongest reductions in the ventral striatum in all analyses. CONCLUSIONS: The findings suggest that reduced striatal activation operates as a mechanism across the risk spectrum for depression. It is associated with anhedonia in healthy adolescents and is a behavioral indicator of positive valence systems, consistent with predictions based on the Research Domain Criteria.

Psychodynamic-oriented psychological assessment predicts evolution to schizophrenia at 8-year follow-up in adolescents hospitalized for a manic/mixed episode: interest of an overall subjective rating.

Little is known concerning the prognostic significance of manic/mixed episodes in adolescents. In particular, whether the use of psychodynamic-oriented projective psychological testing predicts evolution to schizophrenia at follow-up has not been established. Eighty subjects, aged 12-20years old, consecutively hospitalized for a manic or mixed episode between 1994 and 2003 were recruited. All patients were contacted in 2005-2006 for a follow-up assessment. For the subgroup of adolescents (N=40) who had psychodynamic-oriented psychological testing (Rorschach and TAT), two scores regarding psychosocial risk and schizophrenia risk were computed using the clinical global impression (CGI) assessment based on an overall subjective rating given by a panel of expert psychologists who reviewed all protocols. At follow-up (average 8years), 25 (62.5%) patients, 16 females and nine males, were assessed: 14 still had a diagnosis of bipolar disorder; eight changed to schizo-affective disorder and three to schizophrenia. Inter-rater reliability of both CGI-risk scores (psychosocial risk and schizophrenia risk) showed good clinical consensus with intraclass correlation and Kappa scores ranging from 0.53 to 0.75. Univariate analysis showed that CGI-psychosocial risk score (p=0.017), type of index episode (p=0.049) and CGI-schizophrenia risk score (p=0.09) were associated with transition to schizophrenia spectrum disorder at follow-up. Age, sex, socioeconomic status, duration of stay and the presence of psychotic features at index episode were not associated with the transition. We conclude that the CGI assessment appears to be valid to score risk of poor outcome using psychodynamic-oriented psychological testing and that these scores may predict, in part, the transition to schizophrenia in adolescents with a history of manic/mixed episode.