Trans-ethnic and Ancestry-Specific Blood-Cell Genetics in 746,667 Individuals from 5 Global Populations.

Most loci identified by GWASs have been found in populations of European ancestry (EUR). In trans-ethnic meta-analyses for 15 hematological traits in 746,667 participants, including 184,535 non-EUR individuals, we identified 5,552 trait-variant associations at p < 5 × 10-9, including 71 novel associations not found in EUR populations. We also identified 28 additional novel variants in ancestry-specific, non-EUR meta-analyses, including an IL7 missense variant in South Asians associated with lymphocyte count in vivo and IL-7 secretion levels in vitro. Fine-mapping prioritized variants annotated as functional and generated 95% credible sets that were 30% smaller when using the trans-ethnic as opposed to the EUR-only results. We explored the clinical significance and predictive value of trans-ethnic variants in multiple populations and compared genetic architecture and the effect of natural selection on these blood phenotypes between populations. Altogether, our results for hematological traits highlight the value of a more global representation of populations in genetic studies.

Multimodal CRISPR perturbations of GWAS loci associated with coronary artery disease in vascular endothelial cells.

Genome-wide association studies have identified >250 genetic variants associated with coronary artery disease (CAD), but the causal variants, genes and molecular mechanisms remain unknown at most loci. We performed pooled CRISPR screens to test the impact of sequences at or near CAD-associated genetic variants on vascular endothelial cell functions. Using CRISPR knockout, inhibition and activation, we targeted 1998 variants at 83 CAD loci to assess their effect on three adhesion proteins (E-selectin, ICAM1, VCAM1) and three key endothelial functions (nitric oxide and reactive oxygen species production, calcium signalling). At a false discovery rate ≤10%, we identified significant CRISPR perturbations near 42 variants located within 26 CAD loci. We used base editing to validate a putative causal variant in the promoter of the FES gene. Although a few of the loci include genes previously characterized in endothelial cells (e.g. AIDA, ARHGEF26, ADAMTS7), most are implicated in endothelial dysfunction for the first time. Detailed characterization of one of these new loci implicated the RNA helicase DHX38 in vascular endothelial cell senescence. While promising, our results also highlighted several limitations in using CRISPR perturbations to functionally dissect GWAS loci, including an unknown false negative rate and potential off-target effects.

Olfactory Dysfunction Associated with Cognitive Decline in an Elderly Population.

BACKGROUND: In many neurological disorders, including Alzheimer disease, early olfactory dysfunction is observed. OBJECTIVE: In order to determine if deficits in olfactory memory are present in the elderly and if olfactory dysfunction correlates with cognitive impairment in the aging population, olfactory testing has been done on seniors from the NuAge cohort accepting to participate in the Olfactory Response Cognition and Aging (ORCA) secondary sub-study. The t-Mini Mental Statement Examination and the Telephone Interview for Cognitive Status tests were done to assess cognition levels. RESULTS: Overall, 94% of the ORCA cohort displayed olfactory dysfunction. Deficits in olfactory memory were also present. A correlation was observed between olfactory function and cognitive test scores. Moreover, in women who smoked, there was an association between olfactory memory and cognitive scores. CONCLUSION: Our results suggest that olfactory dysfunction may predict impending cognitive decline and highlights the need for olfactory training in seniors to improve olfaction and overall well-being.

Diet enriched in omega-3 fatty acids alleviates olfactory system deficits in APOE4 transgenic mice.

Olfactory dysfunction is observed in several neurological disorders including Mild Cognitive Impairment (MCI) and Alzheimer disease (AD). These deficits occur early and correlate with global cognitive performance, depression and degeneration of olfactory regions in the brain. Despite extensive human studies, there has been little characterization of the olfactory system in models of AD. In order to determine if olfactory structural and/or molecular phenotypes are observed in a model expressing a genetic risk factor for AD, we assessed the olfactory bulb (OB) in APOE4 transgenic mice. A significant decrease in OB weight was observed at 12 months of age in APOE4 mice concurrent with inflammation and decreased NeuN expression. In order to determine if a diet rich in omega-3s may alleviate the olfactory system phenotypes observed, we assessed WT and APOE4 mice on a docosahexaenoic acid (DHA) diet. APOE4 mice on a DHA diet did not present with atrophy of the OB, and the alterations in NeuN and IBA-1 expression were alleviated. Furthermore, alterations in caspase mRNA and protein expression in the APOE4 OB were not observed with a DHA diet. Similar to the human AD condition, OB atrophy is an early phenotype in the APOE4 mice and concurrent with inflammation. These data support a link between the structural olfactory brain region atrophy and the olfactory dysfunction observed in AD and suggest that inflammation and cell death pathways may contribute to the olfactory deficits observed. Furthermore, the results suggest that diets enriched in DHA may provide benefit to APOE4 allele carriers.

The therapeutic processes of avatar therapy: A content analysis of the dialogue between treatment-resistant patients with schizophrenia and their avatar.

OBJECTIVE: Because the therapeutic processes of Avatar Therapy remain equivocal, the current study aims to further extend our previous findings by analysing the evolution of the avatars' and patients' speech and changes in patient responses as sessions progressed. DESIGN: Eighteen patients with treatment-resistant schizophrenia were selected from two clinical trials on Avatar Therapy. Three coders analysed both the avatars' and patients' discourse during immersive therapy sessions using content analysis methods. RESULTS: Our analyses enabled the categorization of the avatar discourse into confrontational techniques (e.g., provocation) and positive techniques (e.g., reinforcement). Patients responded to these utterances using coping mechanism or by expressing emotions, beliefs, self-perceptions or aspirations. Through identification of mutual changes in the interaction between the patient and their avatar, a shift was observed over the sessions from confrontation to a constructive dialogue. Assertiveness, emotional responses and prevention strategies seemed to be central to the therapeutic process, and these usually occur in response to positive techniques. CONCLUSION: Investigating AT's therapeutic process may help to identify components to achieve positive outcomes and can enable the development of more effective treatments. Further studies should explore the association between these themes and therapeutic response to help predict which patients will better respond to Avatar Therapy.

14q32 and let-7 microRNAs regulate transcriptional networks in fetal and adult human erythroblasts.

In humans, fetal erythropoiesis takes place in the liver whereas adult erythropoiesis occurs in the bone marrow. Fetal and adult erythroid cells are not only produced at different sites, but are also distinguished by their respective transcriptional program. In particular, whereas fetal erythroid cells express γ-globin chains to produce fetal hemoglobin (HbF), adult cells express ß-globin chains to generate adult hemoglobin. Understanding the transcriptional regulation of the fetal-to-adult hemoglobin switch is clinically important as re-activation of HbF production in adult erythroid cells would represent a promising therapy for the hemoglobin disorders sickle cell disease and ß-thalassemia. We used RNA-sequencing to measure global gene and microRNA (miRNA) expression in human erythroblasts derived ex vivo from fetal liver (n = 12 donors) and bone marrow (n = 12 donors) hematopoietic stem/progenitor cells. We identified 7829 transcripts and 402 miRNA that were differentially expressed (false discovery rate <5%). The miRNA expression patterns were replicated in an independent collection of human erythroblasts using a different technology. By combining gene and miRNA expression data, we developed transcriptional networks which show substantial differences between fetal and adult human erythroblasts. Our analyses highlighted the miRNAs at the imprinted 14q32 locus in fetal erythroblasts and the let-7 miRNA family in adult erythroblasts as key regulators of stage-specific erythroid transcriptional programs. Altogether, our results provide a comprehensive resource to prioritize genes that may modify clinical severity in red blood cell (RBC) disorders, or genes that might be implicated in erythropoiesis by genome-wide association studies of RBC traits.

PHACTR1 splicing isoforms and eQTLs in atherosclerosis-relevant human cells.

BACKGROUND: Genome-wide association studies (GWAS) have identified a variant (rs9349379) at the phosphatase and actin regulator 1 (PHACTR1) locus that is associated with coronary artery disease (CAD). The same variant is also an expression quantitative trait locus (eQTL) for PHACTR1 in human coronary arteries (hCA). Here, we sought to characterize PHACTR1 splicing pattern in atherosclerosis-relevant human cells. We also explored how rs9349379 modulates the expression of the different PHACTR1 splicing isoforms. METHODS: We combined rapid amplification of cDNA ends (RACE) with next-generation long-read DNA sequencing to discover all PHACTR1 transcripts in many human tissues and cell types. We measured PHACTR1 transcripts by qPCR to identify transcript-specific eQTLs. RESULTS: We confirmed a brain-specific long transcript, a short transcript expressed in monocytes and four intermediate transcripts that are different due to alternative splicing of two in-frame exons. In contrast to a previous report, we confirmed that the PHACTR1 protein is present in vascular smooth muscle cells. In 158 hCA from our collection and the GTEx dataset, rs9349379 was only associated with the expression levels of the intermediate PHACTR1 transcripts. CONCLUSIONS: Our comprehensive transcriptomic profiling of PHACTR1 indicates that this gene encodes six main transcripts. Five of them are expressed in hCA, where atherosclerotic plaques develop. In this tissue, genotypes at rs9349379 are associated with the expression of the intermediate transcripts, but not the immune-specific short transcript. This result suggests that rs9349379 may in part influence CAD by modulating the expression of intermediate PHACTR1 transcripts in endothelial or vascular smooth muscle cells found in hCA.

Genome-wide association study of erythrocyte density in sickle cell disease patients.

Deoxy-hemoglobin S polymerization into rigid fibers is the direct cause of the clinical sequelae observed in sickle cell disease (SCD). The rate of polymerization of sickle hemoglobin is determined primarily by intracellular hemoglobin concentration, itself dependent on the amount of sickle hemoglobin and on red blood cell (RBC) volume. Dense, dehydrated RBC (DRBC) are observed in SCD patients, and their number correlates with hemolytic parameters and complications such as renal dysfunction, leg ulcers and priapism. To identify new genes involved in RBC hydration in SCD, we performed the first genome-wide association study for DRBC in 374 sickle cell anemia (HbSS) patients. We did not find genome-wide significant results, indicating that variants that modulate DRBC have modest-to-weak effects. A secondary analysis demonstrated a nominal association (P=0.003) between DRBC in SCD patients and a variant associated with mean corpuscular hemoglobin concentration (MCHC) in non-anemic individuals. This intronic variant controls the expression of ATP2B4, the main calcium pump in erythrocytes. Our study highlights ATP2B4 as a promising target for modulation of RBC hydration in SCD patients.

Age-dependent differential expression of death-associated protein 6 (Daxx) in various peripheral tissues and different brain regions of C57BL/6 male mice.

Death-associated protein 6 (DAXX) is a ubiquitous protein implicated in various cellular processes such as apoptosis, tumorigenesis, development and transcription. The role of DAXX is however ambiguous and many contradictory results regarding its function in apoptosis upon various cellular stresses are described in the literature. In order to have a better understanding of the role of DAXX throughout the entire organism under physiological stress conditions, we have characterized the mRNA levels, protein expression and the proteolytic processing of DAXX in the normal aging process in peripheral organs and brain regions in C57BL/6 male mice. Overall, Daxx mRNA expression decreases with aging in the liver, kidney, heart, cortex and cerebellum. In contrast, an increase is observed in the striatum. The protein expression of DAXX and of its proteolytic fragments increases with aging in the kidney, heart and cortex. In liver and spleen, no changes are observed while in the striatum and cerebellum, certain forms increase and others decrease with age, suggesting that the functions of DAXX may be cell type dependent. This study provides important details regarding the expression and post-translational modifications of DAXX in aging in the entire organism and provides reference data for the deregulation observed in age-associated diseases.

Myocardial Infarction-Associated SNP at 6p24 Interferes With MEF2 Binding and Associates With PHACTR1 Expression Levels in Human Coronary Arteries.

OBJECTIVE: Coronary artery disease (CAD), including myocardial infarction (MI), is the main cause of death in the world. Genome-wide association studies have identified dozens of single nucleotide polymorphisms (SNPs) associated with CAD/MI. One of the most robust CAD/MI genetic associations is with intronic SNPs in the gene PHACTR1 on chromosome 6p24. How these PHACTR1 SNPs influence CAD/MI risk, and whether PHACTR1 itself is the causal gene at the locus, is currently unknown. APPROACH AND RESULTS: Using genetic fine-mapping and DNA resequencing experiments, we prioritized an intronic SNP (rs9349379) in PHACTR1 as causal variant. We showed that this variant is an expression quantitative trait locus for PHACTR1 expression in human coronary arteries. Experiments in endothelial cell extracts confirmed that alleles at rs9349379 are differentially bound by the transcription factors myocyte enhancer factor-2. We engineered a deletion of this myocyte enhancer factor-2-binding site using CRISPR/Cas9 genome-editing methodology. Heterozygous endothelial cells carrying this deletion express 35% less PHACTR1. Finally, we found no evidence that PHACTR1 expression levels are induced when stimulating human endothelial cells with vascular endothelial growth factor, tumor necrosis factor-α, or shear stress. CONCLUSIONS: Our results establish a link between intronic SNPs in PHACTR1, myocyte enhancer factor-2 binding, and transcriptional functions at the locus, PHACTR1 expression levels in coronary arteries and CAD/MI risk. Because PHACTR1 SNPs are not associated with the traditional risk factors for CAD/MI (eg, blood lipids or pressure, diabetes mellitus), our results suggest that PHACTR1 may influence CAD/MI risk through as yet unknown mechanisms in the vascular endothelium.

Deep resequencing of GWAS loci identifies rare variants in CARD9, IL23R and RNF186 that are associated with ulcerative colitis.

Genome-wide association studies and follow-up meta-analyses in Crohn's disease (CD) and ulcerative colitis (UC) have recently identified 163 disease-associated loci that meet genome-wide significance for these two inflammatory bowel diseases (IBD). These discoveries have already had a tremendous impact on our understanding of the genetic architecture of these diseases and have directed functional studies that have revealed some of the biological functions that are important to IBD (e.g. autophagy). Nonetheless, these loci can only explain a small proportion of disease variance (~14% in CD and 7.5% in UC), suggesting that not only are additional loci to be found but that the known loci may contain high effect rare risk variants that have gone undetected by GWAS. To test this, we have used a targeted sequencing approach in 200 UC cases and 150 healthy controls (HC), all of French Canadian descent, to study 55 genes in regions associated with UC. We performed follow-up genotyping of 42 rare non-synonymous variants in independent case-control cohorts (totaling 14,435 UC cases and 20,204 HC). Our results confirmed significant association to rare non-synonymous coding variants in both IL23R and CARD9, previously identified from sequencing of CD loci, as well as identified a novel association in RNF186. With the exception of CARD9 (OR = 0.39), the rare non-synonymous variants identified were of moderate effect (OR = 1.49 for RNF186 and OR = 0.79 for IL23R). RNF186 encodes a protein with a RING domain having predicted E3 ubiquitin-protein ligase activity and two transmembrane domains. Importantly, the disease-coding variant is located in the ubiquitin ligase domain. Finally, our results suggest that rare variants in genes identified by genome-wide association in UC are unlikely to contribute significantly to the overall variance for the disease. Rather, these are expected to help focus functional studies of the corresponding disease loci.

The Relationship between Sense of Presence, Emotional Response, and Clinical Outcomes in Virtual Reality-Based Therapy for Treatment-Resistant Schizophrenia: An Exploratory Correlational Study.

Avatar therapy (AT) is a novel virtual reality-based psychotherapy that has been developed to treat auditory verbal hallucinations (AVH) in treatment-resistant schizophrenia. Various psychotherapeutic components, such as emotions and sense of presence, could contribute to clinical outcomes. However, the interplay between sense of presence, emotions, and clinical response has seldom been investigated. This study aimed to explore the relations between sense of presence, emotions, and clinical outcomes in AT. To conduct this investigation, data from previous and ongoing AT trials were used. Sense of presence and emotions were assessed using standardized questionnaires. AVH were evaluated using the Psychotic Symptom Rating Scales. While sense of presence was positively associated with positive emotions such as control and serenity, no significant associations were found for negative emotions. Moreover, a higher level of sense of presence was associated with a bigger decrease in AVH. Overall, positive emotions seem to be associated with sense of presence in AT. Sense of presence also seems to be involved in the therapeutic outcome, thereby suggesting that this could be an important component related to clinical response. More studies are needed to confirm these trends, which could be generalized to other virtual reality-based psychotherapies.

Is There a Dose-Response Relationship Between Cannabis Use and Violence? A Longitudinal Study in Individuals with Severe Mental Disorders.

Introduction: Recent longitudinal studies point toward the existence of a positive relationship between cannabis use and violence in people with severe mental disorders (SMD). However, the existence of a dose-response relationship between the frequency/severity of cannabis use and violence has seldom been investigated. Therefore, this study aims to determine if such a relationship exists in a psychiatric population. Methods: To do so, a total of 98 outpatients (81 males and 17 females, all over 18 years of age) with SMD were recruited at the Institut universitaire de santé mentale de Montréal (Montréal, Canada) and included in the analyses. Clinical evaluations were conducted every 3 months for a year. Substance use, violent behaviors, and potential covariables were assessed through self-reported assessments, urinary testing, as well as clinical, criminal, and police records. Using generalized estimating equations, the association between cannabis use frequency (nonusers, occasional, regular, and frequent users) and violence was investigated, as well as the association between the severity of cannabis use and violent behaviors. Results: It was found that cannabis use frequency and severity were significant predictors of violent behaviors. After adjustment for time, age, sex, ethnicity, diagnoses, impulsivity, and use of alcohol and stimulants, odds ratios were of 1.91 (p<0.001) between each frequency profile and 1.040 (p<0.001) for each increase of one point of the severity of cannabis use score (ranging from 0 to 79). Conclusions: Despite the high attrition rate, these findings may have important implications for clinicians as cannabis use may have serious consequences in psychiatric populations. Nevertheless, the mechanisms underlying this association remain unclear.

Stochastic and reversible aggregation of mRNA with expanded CUG-triplet repeats.

Transcripts containing expanded CNG repeats, which are found in several neuromuscular diseases, are not exported from the nucleus and aggregate as ribonuclear inclusions by an unknown mechanism. Using the MS2-GFP system, which tethers fluorescent proteins to a specific mRNA, we followed the dynamics of single CUG-repeat transcripts and RNA aggregation in living cells. Single transcripts with 145 CUG repeats from the dystrophia myotonica-protein kinase (DMPK) gene had reduced diffusion kinetics compared with transcripts containing only five CUG repeats. Fluorescence recovery after photobleaching (FRAP) experiments showed that CUG-repeat RNAs display a stochastic aggregation behaviour, because individual RNA foci formed at different rates and displayed different recoveries. Spontaneous clustering of CUG-repeat RNAs was also observed, confirming the stochastic aggregation revealed by FRAP. The splicing factor Mbnl1 colocalized with individual CUG-repeat transcripts and its aggregation with RNA foci displayed the same stochastic behaviour as CUG-repeat mRNAs. Moreover, depletion of Mbnl1 by RNAi resulted in decreased aggregation of CUG-repeat transcripts after FRAP, supporting a direct role for Mbnl1 in CUG-rich RNA foci formation. Our data reveal that nuclear CUG-repeat RNA aggregates are labile, constantly forming and disaggregating structures, and that the Mbnl1 splicing factor is directly involved in the aggregation process.

Regulatory modules function in a non-autonomous manner to control transcription of the mbp gene.

Multiple regulatory modules contribute to the complex expression programs realized by many loci. Although long thought of as isolated components, recent studies demonstrate that such regulatory sequences can physically associate with promoters and with each other and may localize to specific sub-nuclear transcription factories. These associations provide a substrate for putative interactions and have led to the suggested existence of a transcriptional interactome. Here, using a controlled strategy of transgenesis, we analyzed the functional consequences of regulatory sequence interaction within the myelin basic protein (mbp) locus. Interactions were revealed through comparisons of the qualitative and quantitative expression programs conferred by an allelic series of 11 different enhancer/inter-enhancer combinations ligated to a common promoter/reporter gene. In a developmentally contextual manner, the regulatory output of all modules changed markedly in the presence of other sequences. Predicted by transgene expression programs, deletion of one such module from the endogenous locus reduced oligodendrocyte expression levels but unexpectedly, also attenuated expression of the overlapping golli transcriptional unit. These observations support a regulatory architecture that extends beyond a combinatorial model to include frequent interactions capable of significantly modulating the functions conferred through regulatory modules in isolation.

Changes in Quality of Life in Treatment-Resistant Schizophrenia Patients Undergoing Avatar Therapy: A Content Analysis.

Avatar Therapy has a significant impact on symptoms, beliefs, and quality of life of patients with treatment-resistant schizophrenia. However, little is known about how these changes are implemented into their lives and to which aspects of their lives these improvements relate. Ten consecutive patients enrolled in an ongoing clinical trial were assessed using semi-guided interviews before as well as three months after Avatar Therapy. These encounters have been recorded and transcribed so that the discourse could be thoroughly analyzed, leading to the generation of an extensive theme grid. As the cases were analyzed, the grid was adapted in a back-and-forth manner until data saturation occurred. The content analysis allowed the identification of nine main themes representing different aspects of the patients' lives, each of which was subdivided into more specific codes. By analyzing the evolution of their frequency, it was observed that, following therapy, patients presented with fewer psychotic symptoms, better self-esteem, more hobbies and projects, and an overall improved lifestyle and mood. Finally, investigating the impact of Avatar Therapy on quality of life allows for a deeper understanding of how people with treatment-resistant schizophrenia can achieve meaningful changes and move towards a certain recovery process.

Unsupervised Machine Learning Driven Analysis of Verbatims of Treatment-Resistant Schizophrenia Patients Having Followed Avatar Therapy.

(1) Background: The therapeutic mechanisms underlying psychotherapeutic interventions for individuals with treatment-resistant schizophrenia are mostly unknown. One of these treatment techniques is avatar therapy (AT), in which the patient engages in immersive sessions while interacting with an avatar representing their primary persistent auditory verbal hallucination. The aim of this study was to conduct an unsupervised machine-learning analysis of verbatims of treatment-resistant schizophrenia patients that have followed AT. The second aim of the study was to compare the data clusters obtained from the unsupervised machine-learning analysis with previously conducted qualitative analysis. (2) Methods: A k-means algorithm was performed over the immersive-session verbatims of 18 patients suffering from treatment-resistant schizophrenia who followed AT to cluster interactions of the avatar and the patient. Data were pre-processed using vectorization and data reduction. (3): Results: Three clusters of interactions were identified for the avatar's interactions whereas four clusters were identified for the patient's interactions. (4) Conclusion: This study was the first attempt to conduct unsupervised machine learning on AT and provided a quantitative insight into the inner interactions that take place during immersive sessions. The use of unsupervised machine learning could yield a better understanding of the type of interactions that take place in AT and their clinical implications.

Enhancing Predictive Power: Integrating a Linear Support Vector Classifier with Logistic Regression for Patient Outcome Prognosis in Virtual Reality Therapy for Treatment-Resistant Schizophrenia.

(1) Background: Approximately 30% of schizophrenia patients are known to be treatment-resistant. For these cases, more personalized approaches must be developed. Virtual reality therapeutic approaches such as avatar therapy (AT) are currently undergoing investigations to address these patients' needs. To further tailor the therapeutic trajectory of patients presenting with this complex presentation of schizophrenia, quantitative insight about the therapeutic process is warranted. The aim of the study is to combine a classification model with a regression model with the aim of predicting the therapeutic outcomes of patients based on the interactions taking place during their first immersive session of virtual reality therapy. (2) Methods: A combination of a Linear Support Vector Classifier and logistic regression was conducted over a dataset comprising 162 verbatims of the immersive sessions of 18 patients who previously underwent AT. As a testing dataset, 17 participants, unknown to the dataset, had their first immersive session presented to the combinatory model to predict their clinical outcome. (3) Results: The model accurately predicted the clinical outcome for 15 out of the 17 participants. Classification of the therapeutic interactions achieved an accuracy of 63%. (4) Conclusion: To our knowledge, this is the first attempt to predict the outcome of psychotherapy patients based on the content of their interactions with their therapist. These results are important as they open the door to personalization of psychotherapy based on quantitative information about the interactions taking place during AT.

Dyadic Interactions of Treatment-Resistant Schizophrenia Patients Having Followed Virtual Reality Therapy: A Content Analysis.

(1) Background: Very little is known about the inner therapeutic processes of psychotherapy interventions for patients suffering from treatment-resistant schizophrenia. Avatar therapy (AT) is one such modalities in which the patient is undergoing immersive sessions in which they interact with an Avatar representing their main persistent auditory verbal hallucination. The aim of this study is to identify the most prevalent dyadic interactions between the patient and the Avatar in AT for patient's suffering from TRS. (2) Methods: A content analysis of 256 verbatims originating from 32 patients who completed AT between 2017 and 2022 at the Institut universitaire en santé mentale de Montréal was conducted to identify dyadic interactions between the patients and their Avatar. (3) Results: Five key dyads were identified to occur on average more than 10 times for each participant during the immersive sessions across their AT: (Avatar: Reinforcement, Patient: Self-affirmation), (Avatar: Provocation, Patient: Self-affirmation), (Avatar: Coping mechanisms, Patient: Prevention), (Patient: Self-affirmation, Avatar: Reinforcement), and (Patient: Self-appraisal, Avatar: Reinforcement). (4) Conclusion: These dyads offer a first qualitative insight to the interpersonal dynamics and patient-avatar relationships taking place during AT. Future studies on the implication of such dyadic interactions with the therapeutic outcome of AT should be conducted considering the importance of dyadic relationships in psychotherapy.

Avatar Intervention for Cannabis Use Disorder in Individuals with Severe Mental Disorders: A Pilot Study.

Cannabis use disorder (CUD) is a complex issue, even more so when it is comorbid with a severe mental disorder (SMD). Available interventions are at best slightly effective, and their effects are not maintained over time. Therefore, the integration of virtual reality (VR) may increase efficacy; however, it has not yet been investigated in the treatment of CUD. A novel approach, avatar intervention for CUD, uses existing therapeutic techniques from other recommended therapies (e.g., cognitive behavioral methods, motivational interviewing) and allows participants to practice them in real-time. During immersive sessions, participants are invited to interact with an avatar representing a significant person related to their drug use. This pilot clinical trial aimed to evaluate the short-term efficacity of avatar intervention for CUD on 19 participants with a dual diagnosis of SMD and CUD. Results showed a significant moderate reduction in the quantity of cannabis use (Cohen's d = 0.611, p = 0.004), which was confirmed via urinary quantification of cannabis use. Overall, this unique intervention shows promising results. Longer-term results, as well as comparison with classical interventions in a larger sample, are warranted through a future single-blind randomized controlled trial.