Bases moléculaires et cellulaires d’un trouble neurodéveloppemental causé par l’haploinsuffisance de SYNGAP1

La déficience intellectuelle est la cause d’handicap la plus fréquente chez l’enfant. De nombreuses évidences convergent vers l’idée selon laquelle des altérations dans les gènes synaptiques puissent expliquer une fraction significative des affections neurodéveloppementales telles que la déficience intellectuelle ou encore l’autisme. Jusqu’à récemment, la majorité des mutations associées à la déficience intellectuelle a été liée au chromosome X ou à la transmission autosomique récessive. D’un autre côté, plusieurs études récentes suggèrent que des mutations de novo dans des gènes à transmission autosomique dominante, requis dans les processus de la plasticité synaptique peuvent être à la source d’une importante fraction des cas de déficience intellectuelle non syndromique. Par des techniques permettant la capture de l’exome et le séquençage de l’ADN génomique, notre laboratoire a précédemment reporté les premières mutations pathogéniques dans le gène à transmission autosomique dominante SYNGAP1. Ces dernières ont été associées à des troubles comportementaux tels que la déficience intellectuelle, l’inattention, des problèmes d’humeur, d’impulsivité et d’agressions physiques. D’autres patients sont diagnostiqués avec des troubles autistiques et/ou des formes particulières d’épilepsie généralisée. Chez la souris, le knock-out constitutif de Syngap1 (souris Syngap1+/-) résulte en des déficits comme l’hyperactivité locomotrice, une réduction du comportement associée à l’anxiété, une augmentation du réflexe de sursaut, une propension à l’isolation, des problèmes dans le conditionnement à la peur, des troubles dans les mémoires de travail, de référence et social. Ainsi, la souris Syngap1+/- représente un modèle approprié pour l’étude des effets délétères causés par l’haploinsuffisance de SYNGAP1 sur le développement de circuits neuronaux. D’autre part, il est de première importance de statuer si les mutations humaines aboutissent à l’haploinsuffisance de la protéine. SYNGAP1 encode pour une protéine à activité GTPase pour Ras. Son haploinsuffisance entraîne l’augmentation des niveaux d’activité de Ras, de phosphorylation de ERK, cause une morphogenèse anormale des épines dendritiques et un excès dans la concentration des récepteurs AMPA à la membrane postsynaptique des neurones excitateurs. Plusieurs études suggèrent que l’augmentation précoce de l’insertion des récepteurs AMPA au sein des synapses glutamatergiques contribue à certains phénotypes observés chez la souris Syngap1+/-. En revanche, les conséquences de l’haploinsuffisance de SYNGAP1 sur les circuits neuronaux GABAergiques restent inconnues. Les enjeux de mon projet de PhD sont: 1) d’identifier l’impact de mutations humaines dans la fonction de SYNGAP1; 2) de déterminer si SYNGAP1 contribue au développement et à la fonction des circuits GABAergiques; 3) de révéler comment l’haploinsuffisance de Syngap1 restreinte aux circuits GABAergiques affecte le comportement et la cognition. Nous avons publié les premières mutations humaines de type faux-sens dans le gène SYNGAP1 (c.1084T>C [p.W362R]; c.1685C>T [p.P562L]) ainsi que deux nouvelles mutations tronquantes (c.2212_2213del [p.S738X]; c.283dupC [p.H95PfsX5]). Ces dernières sont toutes de novo à l’exception de c.283dupC, héritée d’un père mosaïque pour la même mutation. Dans cette étude, nous avons confirmé que les patients pourvus de mutations dans SYNGAP1 présentent, entre autre, des phénotypes associés à des troubles comportementaux relatifs à la déficience intellectuelle. En culture organotypique, la transfection biolistique de l’ADNc de Syngap1 wild-type dans des cellules pyramidales corticales réduit significativement les niveaux de pERK, en fonction de l’activité neuronale. Au contraire les constructions plasmidiques exprimant les mutations W362R, P562L, ou celle précédemment répertoriée R579X, n’engendre aucun effet significatif sur les niveaux de pERK. Ces résultats suggèrent que ces mutations faux-sens et tronquante résultent en la perte de la fonction de SYNGAP1 ayant fort probablement pour conséquences d’affecter la régulation du développement cérébral. Plusieurs études publiées suggèrent que les déficits cognitifs associés à l’haploinsuffisance de SYNGAP1 peuvent émerger d’altérations dans le développement des neurones excitateurs glutamatergiques. Toutefois, si, et auquel cas, de quelle manière ces mutations affectent le développement des interneurones GABAergiques résultant en un déséquilibre entre l’excitation et l’inhibition et aux déficits cognitifs restent sujet de controverses. Par conséquent, nous avons examiné la contribution de Syngap1 dans le développement des circuits GABAergiques. A cette fin, nous avons généré une souris mutante knockout conditionnelle dans laquelle un allèle de Syngap1 est spécifiquement excisé dans les interneurones GABAergiques issus de l’éminence ganglionnaire médiale (souris Tg(Nkx2.1-Cre);Syngap1flox/+). En culture organotypique, nous avons démontré que la réduction de Syngap1 restreinte aux interneurones inhibiteurs résulte en des altérations au niveau de leur arborisation axonale et dans leur densité synaptique. De plus, réalisés sur des coupes de cerveau de souris Tg(Nkx2.1-Cre);Syngap1flox/+, les enregistrements des courants inhibiteurs postsynaptiques miniatures (mIPSC) ou encore de ceux évoqués au moyen de l’optogénétique (oIPSC) dévoilent une réduction significative de la neurotransmission inhibitrice corticale. Enfin, nous avons comparé les performances de souris jeunes adultes Syngap1+/-, Tg(Nkx2.1-Cre);Syngap1flox/+ à celles de leurs congénères contrôles dans une batterie de tests comportementaux. À l’inverse des souris Syngap1+/-, les souris Tg(Nkx2.1-Cre);Syngap1flox/+ ne présentent pas d’hyperactivité locomotrice, ni de comportement associé à l’anxiété. Cependant, elles démontrent des déficits similaires dans la mémoire de travail et de reconnaissance sociale, suggérant que l’haploinsuffisance de Syngap1 restreinte aux interneurones GABAergiques dérivés de l’éminence ganglionnaire médiale récapitule en partie certains des phénotypes cognitifs observés chez la souris Syngap1+/-. Mes travaux de PhD établissent pour la première fois que les mutations humaines dans le gène SYNGAP1 associés à la déficience intellectuelle causent la perte de fonction de la protéine. Mes études dévoilent, également pour la première fois, l’influence significative de ce gène dans la régulation du développement et de la fonction des interneurones. D’admettre l’atteinte des cellules GABAergiques illustre plus réalistement la complexité de la déficience intellectuelle non syndromique causée par l’haploinsuffisance de SYNGAP1. Ainsi, seule une compréhension raffinée de cette condition neurodéveloppementale pourra mener à une approche thérapeutique adéquate.

Improving family functioning and child outcome in methadone maintained families: the Parents Under Pressure programme

Twelve families responded to posters displayed in a methadone clinic for inclusion in a pilot study assessing the viability and potential utility of an intensive, multi-component family-focused intervention, the Parents Under Pressure programme. The programme was designed to improve child behaviour, decrease parental stress and improve family functioning in methadone-maintained families by targeting affect regulation, mood, views of self as a parent, drug use and parenting skills. Nine of the families completed the programme delivered in their homes; eight were recontacted at 3 months. Each family reported significant improvements in three domains: parental functioning, parent - child relationship and parental substance use and risk behaviour. In addition to the changes in family functioning, the majority of families reported a decrease in concurrent alcohol use, HIV risk-taking behaviour and maintenance dose of methadone. The families reported high levels of satisfaction with the programme. It is recommended that future studies include independent measures (e.g. behavioural observations) of child outcome and parental functioning. The results were optimistic and provided the impetus to evaluate the treatment programme using a randomized controlled trial.

Integrated versus non-integrated management and care for clients with co-occurring mental health and substance use disorders: a qualitative systematic review of randomised controlled trials

The purpose of this paper is to conduct a qualitative review of randomised controlled trials in relation to the treatment of adults with co-occurring mental health and substance use disorder (MH/SUD). In particular, integrated approaches are compared with non-integrated approaches to treatment. Ten articles were identified for inclusion in the review. The findings are equivocal with regard to the superior efficacy of integrated approaches to treatment, although the many limitations of the studies need to be considered in our understanding of this finding. Clearly, this is an extremely challenging client group to engage and maintain in intervention research, and the complexity and variability of the problems render control particularly difficult. The lack of available evidence to support the superiority of integration is discussed in relation to these challenges. Much remains to be investigated with regard to integrated management and care for people with co-occurring and MH/SUD, particularly for specific combinations of dual diagnosis and giving consideration to the level of inter-relatedness between the disorders. (C) 2004 Elsevier Ltd. All rights reserved.

Clinical supervision: Its influence on client-rated working alliance and client symptom reduction in the brief treatment of major depression

Supervision of psychotherapists and counselors, especially in the early years of practice, is widely accepted as being important for professional development and to ensure optimal client outcomes. Although the process of clinical supervision has been extensively studied, less is known about the impact of supervision on psychotherapy practice and client symptom outcome. This study evaluated the impact of clinical supervision on client working alliance and symptom reduction in the brief treatment of major depression. The authors randomly assigned 127 clients with a diagnosis of major depression to 127 supervised or unsupervised therapists to receive eight sessions of problems-solving treatment. Supervised therapists were randomly assigned to either alliance skill- or alliance process-focused supervision and received eight supervision sessions. Before beginning treatment, therapists received one supervision session for brief training in the working alliance supervision approach and in specific characteristics of each case. Standard measures of therapeutic alliance and symptom change were used as dependent variables. The results showed a significant effect for both supervision conditions on working alliance from the first session of therapy, symptom reduction, and treatment retention and evaluation but no effect differences between supervision conditions. It was not possible to separate the effects of supervision from the single pretreatment session and is possible that allegiance effects might have inflated results. The scientific and clinical relevance of these findings is discussed.

Autobiographical memory specificity in response to verbal and pictorial cues in clinical depression

Background Depressed individuals have been consistently shown to exhibit problems in accessing specific memories of events from their past and instead tend to retrieve categorical summaries of events. The majority of studies examining autobiographical memory changes associated with psychopathology have tended to use word cues, but only one study to date has used images (with PTSD patients). Objective to determine if using images to cue autobiographical memories would reduce the memory specificity deficit exhibited by patients with depression in comparison to healthy controls. Methods Twenty-five clinically depressed patients and twenty-five healthy controls were assessed on two versions of the autobiographical memory test; cued with emotional words and images. Results Depressed patients retrieved significantly fewer specific memories, and a greater number of categorical, than did the controls. Controls retrieved a greater proportion of specific memories to images compared to words, whereas depressed patients retrieved a similar proportion of specific memories to both images and words. Limitations no information about the presence and severity of past trauma was collected. Conclusions results suggest that the overgeneral memory style in depression generalises from verbal to pictorial cues. This is important because retrieval to images may provide a more ecologically valid test of everyday memory experiences than word-cued retrieval.

A joint approach to treating dental phobia:a re-evaluation of a collaboration between community dental services and specialist psychotherapy services ten years on

Objective To audit the records of a group of patients who had previously benefited from cognitive behavioural therapy (CBT) for dental phobia.Aim To ascertain if they had returned to the use of intravenous (IV) sedation to facilitate dental treatment. Ten years ago these patients were routinely requiring IV sedation to facilitate dental treatment due to severe dental phobia.Method Sixty patients entered the original pilot project. Of those, 30 were offered CBT and 21 attended. Twenty of those patients (95.2%) were subsequently able to have dental treatment without IV sedation. In this follow-up study the electronic records of 19 of the 20 patients who had originally been successful with CBT were re-audited. Our purpose was to see if there was any record of subsequent IV sedation administration in the intervening ten years.Results Of the 19 successful CBT patients available to follow-up, 100% had not received IV sedation since the study ten years ago. This may suggest the initial benefit of CBT has endured over the ten-year period.Conclusion This study indicates that the use of CBT for patients with dental phobia proves beneficial not only in the initial treatment but that the benefits may endure over time. This results in a significant reduction in health risks to the patient from repeated IV sedation. It may also translate into significant financial savings for dental care providers. Our evidence for CBT as treatment for dental phobia suggests dental services should be implementing this approach now rather than pursuing further research. © 2011 Macmillan Publishers Limited. All rights reserved.

Intentional forgetting in dysphoria:investigating the inhibitory effects of thought substitution using independent cues

Background Individuals with clinical and subclinical depression (dysphoria) exhibit problems intentionally forgetting unwanted memories on the think/no-think (TNT) paradigm (Anderson & Green, 2001). However, providing substitute words to think about instead of the to-be-forgotten targets can improve forgetting in depressed patients. Objectives To determine if thought substitution can enhance forgetting in dysphoric participants and to examine the potential mechanisms (blocking or inhibition) that might underpin successful forgetting. Methods Thirty-six dysphoric and 36 non-dysphoric participants learned neutral word-pairs and then practiced responding with the targets to some cues (think trials) and suppressing responses to others (no think trials). Half the participants were provided with substitute words to recall instead of the original targets (aided suppression) and half were simply told to avoid thinking about the targets (unaided suppression). Finally, participants completed two recall tests for the targets; one cued with the original probes and one with independent probes. Results Regardless of suppression condition (aided or unaided), dysphoric participants exhibited impaired forgetting, relative to their non-dysphoric counterparts, but only when cued with the original probes. Furthermore, higher depression scores were associated with poorer forgetting. In the aided condition, successful forgetting was observed on both the original and independent probe tasks, which supports the inhibitory account of thought substitution. Limitations Non-clinical status of the dysphoric participants was not confirmed using a validated measure. Conclusions Findings do not support the utility of thought substitution as a method of improving the forgetting in depressed participants, but do support the inhibition account of thought substitution.

Treatment moderation and secondary outcomes: Results from a randomized clinical trial

The present study pursued two objectives in the context of a randomized clinical trial of cognitive-behavioral therapy with parent (CBT/P) and group (GCBT) involvement. The first objective was to examine the variability in treatment outcome. There were three specific aims within the first objective, to evaluate: (1) youth characteristics (age, depressive, and externalizing disorders) as moderators of treatment outcome; (2) the differential outcome of the treatment approaches as a function of youth characteristics; and (3) the relative efficacy of the treatment approaches at each level of the moderators. ^ The second objective was to evaluate the efficacy of anxiety treatments along secondary depressive symptoms and externalizing behaviors. There were five specific aims within the second objective, to evaluate: (1) whether anxiety treatment yields reductions in secondary problems, (2) the efficacy of anxiety treatments in reducing secondary problems as a function of approach and youth characteristics, (3) whether reductions in anxiety symptoms significantly mediate changes in secondary problems, (4) the directionality of change in the hypothesized mediated relations, and (5) whether the hypothesized mediated relations are moderated by treatment approach and youth characteristics. The specific aims were pursued using data collected from 183 youth and their mothers. Research questions were tested using multiple regressions and structural equation modeling. ^ Age, depressive, and externalizing disorders were significant moderators. CBT/P relative to GCBT lowered anxiety more for younger than older youth. GCBT relative to CBT/P lowered anxiety more for older than younger youth. GCBT relative to CBT/P lowered anxiety more for depressed youth than non-depressed youth. GCBT relative to CBT/P lowered anxiety less for externalizing youth than non-externalizing youth. Treatment reduced depressive symptoms and externalizing problem behaviors. Reductions in anxiety mediated changes in depressive symptoms and externalizing problem behaviors. Reversed directionality was found in the relation between social anxiety and depressive symptoms. In CBT/P the direction of change was from depressive to social anxiety. The opposite was true in GCBT. Reductions in social anxiety mediated posttreatment changes in depressive symptoms in GCBT but not CBT/P. The reverse was true at follow-up. Reductions in social anxiety mediated changes in depressive symptoms for girls but not boys.^

Anxious children who received treatment grow -up: An 8-to-13 year follow-up study

This dissertation examined the long-term efficacy (8-to-13 years, M = 9.54, SD = 1.689) of exposure-based cognitive-behavioral therapy (CBT) for phobic and anxiety disorders in youths. Long-term efficacy was examined in terms of diagnostic recovery, symptom reductions, and clinically significant change. This dissertation also examined predictors of long-term efficacy (e.g., age, gender, and other clinical characteristics) as well as the relative long-term efficacy of CBT for Hispanic/Latino and European American youth. ^ Participants consisted of 67 youth (age range 15–26 years; M = 19.43, SD = 3.02 years at time of follow-up assessment), (47.8% females, 37.3% Hispanic/Latino) who had participated in one of two clinical trials (Silverman et al., 1999a, b). After providing informed consent to participate in the long term follow-up, youths completed a diagnostic interview and a battery of questionnaires. Results indicated that treatment gains were maintained about 9.5 years after treatment was completed. Maintenance of treatment gains was evident in terms of diagnostic recovery, symptom reductions, and clinically significant change. Long-term treatment gains extended to both ethnic groups and the two ethnic groups were functionally equivalent along most indices examined. Analyses of predictors of long-term outcome showed that parent self-reported pre-treatment depression, youth-reported pre-treatment depression, and youths retrospective reports of negative life events were significantly associated with less favorable long-term gains in terms of total symptoms of anxiety at long-term follow-up. In terms of long-term sequelae, youths with less successful post-treatment outcomes reported seeking-out additional treatment as well as using/abused substances and substance dependence significantly more than youths with successful post-treatment outcomes. Results are discussed in terms of the contribution of the present study to knowledge base about the long-term efficacy of exposure-based CBT procedures for phobic and anxiety disorders in youth. Findings also are discussed in terms of the need to modify CBT procedures to target youths with less successful post-treatment outcomes. Limitations and future directions are presented. ^

Evaluation of a mentored self -help intervention for the management of psychotic symptoms

Cognitive behavioral therapy has been shown to be promising for the treatment of individuals experiencing psychotic symptoms, who are often diagnosed with schizophrenia. Using a non-random non-equivalent comparison group design (n = 26), this study explores whether an individually mentored self-help and self-paced intervention based upon cognitive behavioral approaches to auditory hallucinations or "hearing voices" makes a significant positive difference for individuals with major mental disorder diagnoses and psychotic symptoms who are residing in the community and receiving community mental health services. The mentored self-help intervention uses a workbook (Coleman & Smith, 1997) that stemmed from the British psychiatric survivor and "voice hearers"' movements and from cognitive behavioral approaches to treating psychotic symptoms. Thirty individuals entered the study. Pre- and post-intervention assessments of 15 participants in the intervention group and 11 participants in the comparison group were carried out using standardized instruments, including the Rosenberg Self-Esteem Scale, the Brief Psychiatric Rating Scale, and the Hoosier Assurance Plan Inventory - Adult. Four specific research questions address whether levels of self-esteem, overall psychotic symptoms, depression-anxiety, and disruption in life improved in the intervention group, relative to the comparison group. Pre- and post-assessment scores were analyzed using repeated measures analysis of variance. Results showed no significant difference on any measure, with the exception of the Brief Psychiatric Rating subscale for Anxious Depression, which showed a statistically significant pre-post difference with a strong effect size. A conservative interpretation of this single positive result is that it is due to chance. An alternative interpretation is that the mentored self-help intervention made an actual improvement in the level of depression-anxiety experienced by participants. If so, this is particularly important given high levels of depression and suicide among individuals diagnosed with schizophrenia. This alternative interpretation supports further research on the intervention utilized in this study. ^

Treatment for Complicated Grief : State of the Science and Ways Forward

Peer reviewed

Design and protocol for the Focusing on Clozapine Unresponsive Symptoms (FOCUS) trial : a randomised controlled trial

Acknowledgements Thank you to all the participants who agreed to take part in the trial. This study was supported NHS Research Scotland (NRS), through Chief Scientist Office (CSO) and the Scottish Mental Health Research Network, and the Clinical Research Network-Mental Health. We are grateful to the Psychosis Research Unit (PRU) Service User Reference Group (SURG) for their consultation regarding the design of the study and contribution to the developments of study related materials. We are grateful to our Independent Trial Steering Committee and Independent Data Monitoring Committee for provided oversight of the trial. Funding This project was funded by the National Institute for Health Research Health Technology Assessment (NIHR HTA) programme (project number10/101/02) and will be published in full in Health Technology Assessment. Visit the HTA programme website for further project information. The views and opinions expressed therein are those of the authors and do not necessarily reflect those of the HTA programme, NIHR, NHS or the Department of Health.

Personalidade e sua relação com transtornos de ansiedade e de humor: Uma análise da produção científica brasileira na abordagem cognitivo-comportamental

Personality is one of the most controversial and intriguing theme in Psychology. In a general way, it could be understood as a set of rigid patters of feelings, thoughts, and behaviors from an individual. The aim of this investigation was describe how Brazilian researches in Psychology that use cognitive, behavioral, and cognitive-behavioral therapy referential have been approaching the subject Personality in their work. We also intended to determine the frequency of publications on Personality Disorders to compare this data with the bibliographical production on Anxiety and Mood Disorders. Moreover, we tried to describe how the Personality construct - and even Personality Disorders construct - has been addressed in the work on the Anxiety and Mood Disorders chosen for this review. The PePSIC Periódicos Eletrônicos em Psicologia - e SciELO.ORG - Scientific Electronic Library Online - databases were used for research. We investigated 53 journals, including two specific Cognitive Therapies and Behavioral-Cognitive Therapy (TCC) periodicals. Within each journal, we undertook a systematic survey on publications on the themes: Personality, Personality Disorder, Panic Disorder, Social Phobia, Obsessive-Compulsive Disorder (OCD), Generalized Anxiety Disorder, Major Depression, Dysthymia and Bipolar Disorder. A preliminary research has resulted in 218 articles. A second filter has obtained 81 articles in which we the focused on this review. There were found thirty-eight articles on Anxiety Disorders, twenty-five on Mood Disorders and eighteen on Personality Disorders. It was found that 90% of the papers on Anxiety Disorders make no reference to the term Personality or make it in a discrete way. This number rises to 96% to Personality Disorder group. Analyzing the specific journals on TCC we verified that 97% of the articles on Anxiety and Humor disorders do not cite the term Personality or cite but not explore it. This results point to the low rate of studies addressing the Personality and personality disturbs. Then, we can suggest that the difficulty on treating this Axis II disturbs has been worsened by lack of knowledge produced on the subject, either for lack of interest among researchers or because of the methodological obstacles found on this field.