A zebrafish model for C9orf72 ALS reveals RNA toxicity as a pathogenic mechanism

The exact mechanism underlying amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) associated with the GGGGCC repeat expansion in C9orf72 is still unclear. Two gain-of-function mechanisms are possible: repeat RNA toxicity and dipeptide repeat protein (DPR) toxicity. We here dissected both possibilities using a zebrafish model for ALS. Expression of two DPRs, glycine-arginine and proline-arginine, induced a motor axonopathy. Similarly, expanded sense and antisense repeat RNA also induced a motor axonopathy and formed mainly cytoplasmic RNA foci. However, DPRs were not detected in these conditions. Moreover, stop codon-interrupted repeat RNA still induced a motor axonopathy and a synergistic role of low levels of DPRs was excluded. Altogether, these results show that repeat RNA toxicity is independent of DPR formation. This RNA toxicity, but not the DPR toxicity, was attenuated by the RNA-binding protein Pur-alpha and the autophagy-related protein p62. Our findings demonstrate that RNA toxicity, independent of DPR toxicity, can contribute to the pathogenesis of C9orf72-associated ALS/FTD

Related to Anxiety: Arbitrarily Applicable Relational Responding and Experimental Psychopathology Research on Fear and Avoidance

Humans have an unparalleled ability to engage in arbitrarily applicable relational responding (AARR). One of the consequences of this ability to spontaneously combine and relate events from the past, present, and future may, in fact, be a propensity to suffer. For instance, maladaptive fear and avoidance of remote or derived threats may actually perpetuate anxiety. In this narrative review, we consider contemporary AARR research on fear and avoidance as it relates to anxiety. We first describe laboratory-based research on the emergent spread of fear- and avoidance-eliciting functions in humans. Next, we consider the validity of AARR research on fear and avoidance and address the therapeutic implications of the work. Finally, we outline challenges and opportunities for a greater synthesis between behavior analysis research on AARR and experimental psychopathology

Optimizing exposure therapy: Strengths and limitations of the extinction model

Exposure involves the (repeated) confrontation with fear-eliciting stimuli or situations in the absence of the feared outcome and is a key-component in the treatment of clinical fears and anxiety. Several meta-analyses have demonstrated large effect sizes and response rates of exposure treatment. However, these effects are not always maintained in the long-term, leaving room for the further enhancement of clinical treatment. The first part of this dissertation (Chapter 1) introduces and evaluates fear conditioning as a laboratory model for the acquisition and treatment of clinical fears and anxiety. In addition, we discuss how recent developments in learning theory can address some of the frequently heard critiques on simple fear conditioning. In the second part of this dissertation, we report on empirical studies that focus on optimizing exposure treatment. In Chapter 2 and 3, respectively the type and order of stimuli presented during extinction were manipulated. In Chapter 2, we investigated whether manipulating the typicality of the extinction stimulus can attenuate return of fear. We found that using a generalization stimulus during extinction that is a typical exemplar of the feared category resulted in less fear responding to a new exemplar of that feared category compared to using an atypical exemplar. In Chapter 3, we developed a fear extinction procedure to compare the outcomes of a hierarchical versus random approach of exposure. A set of morphs between the danger (CS+) and safety (CS-) cue were presented in a hierarchical order (i.e., starting with the CS-, then the morph most similar to the CS-, followed by the morph most similar to that one etc., until reaching the CS+) versus in a random order. No differences between the hierarchical and random approach were found in fear responding as tested one day later. In Chapter 4 and 5 we explore the effects of manipulations of expectancy violation (i.e., the mismatch between the expected and actual outcome), which according to inhibitory learning theory (ILT) drives inhibitory learning during exposure and long-term fear reduction. In Chapter 4, we investigated the role of expectancy violation in virtual reality exposure therapy (VRET). Both the experimental and correlational analyses failed to confirm that expectancy violation predicted treatment outcome. In Chapter 5, the effect of providing safety information before extinction - similar to types of psychoeduction before exposure - was investigated. ILT predicts that providing this type of information interferes with subsequent expectancy violation during extinction. We could not confirm that providing safety information was detrimental for the generalization of fear reduction to another context. In the third part of this dissertation (Chapter 6), we reflect on the extinction procedures that we used in the empirical chapters and evaluate the validity of extinction research in providing insights on (how to conduct) clinical exposure therapy. Finally, our findings and conclusions are embedded in a more general discussion of some of the strengths and challenges of ILT.status: publishe

De ontwikkeling van een multidisciplinaire richtlijn voor het betrekken van de context in de geestelijke gezondheidszorg

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VIRTUS:virtual reality exposure training for adolescents with social anxiety - a randomized controlled trial

While virtual reality exposure (VRE) has shown effectiveness in treating social anxiety in adults, research on its efficacy for adolescents remains limited. Given that adolescence is a critical period for early intervention, this study aims to address this gap by evaluating the efficacy and acceptability of VRE compared to in vivo exposure (IVE) in a non-referred sample of socially anxious adolescents. Additionally, we seek to identify mechanisms of change-such as expectancy violation, habituation, and self-efficacy-as well as predictors of treatment response, including clinical, personality, and VR-related factors. Using a randomized controlled trial (RCT), 120 adolescents (ages 12-16) with subclinical to moderate social anxiety will be assigned to one of three conditions: VRE, IVE, or a waitlist control (WL). Participants in the active conditions will undergo a seven-session exposure-based intervention (either in VR or in vivo). Primary (SPAI-18, LSAS-avoidance) and secondary (SPWSS) measures of social anxiety, along with general well-being indicators (e.g., resilience, depression, psychosocial functioning), will be assessed at baseline, post-treatment, and 3- and 6-month follow-ups. A series of linear mixed model (LMM) analyses will be used to examine and compare the effects of the interventions. We hypothesize that both VRE and IVE will significantly reduce social anxiety symptoms compared to WL at post-assessment, with comparable long-term efficacy between the two exposure methods. Additionally, thematic analyses will be conducted to explore participants' experiences and acceptance of VRE and IVE through qualitative interviews. The findings of this study aim to advance digital mental health research by evaluating the potential of VRE as an early intervention and identifying mechanisms and predictors to inform personalized treatments for socially anxious youth.Trial registrationClinicaltrials.gov: NCT06379633, registered on April, 23, 2024

Drosophila screen connects nuclear transport genes to DPR pathology in c9ALS/FTD

Hexanucleotide repeat expansions in C9orf72 are the most common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal degeneration (FTD) (c9ALS/FTD). Unconventional translation of these repeats produces dipeptide repeat proteins (DPRs) that may cause neurodegeneration. We performed a modifier screen in Drosophila and discovered a critical role for importins and exportins, Ran-GTP cycle regulators, nuclear pore components, and arginine methylases in mediating DPR toxicity. These findings provide evidence for an important role for nucleocytoplasmic transport in the pathogenic mechanism of c9ALS/FTD