Holter, Norway

Interactive Mirroring Games wIth sOcial Robot (IOGIOCO) and Robotic System Adapted Into a Clinical Scale (RISCALE)

Background: The importance of early intervention in Autism Spectrum Disorders (ASD) has been widely demonstrated, and developmental trajectories in ASD highlight the importance of nonverbal communication, such as intransitive gesture production, as a possible positive prognostic factor for language development. The use of technological tools in the therapy of individuals with ASD has also become increasingly important due to their increased engagement and responsiveness to technological objects, such as robots. We developed a training protocol using the humanoid robot NAO, called IOGIOCO (Interactive mirroring Games wIth sOCial rObot), based on the use of intransitive gestures embedded in naturalistic dialogues, stimulating a triadic interaction between child, robot and therapist. The training is divided into six levels; the first 2 levels were called "familiarization levels," and the other 4 were "training levels". The technological setup includes different complexity levels, from mirroring tasks to building spontaneous interactions. We previously tested the protocol on 10 preschool children with ASD (aged 2-6 years) in a pilot study founding promising results (Annunziata et al,2024). We therefore developed a Randomized Controlled Trial to test the efficacy of this intervention. The primary objective of the RISCALE study is to evaluate the effectiveness of NAO training in improving socio-communicative skills and acquiring communicative gestures using the ECSP-I scale as the primary outcome measure. A second objective stems from the technological experience acquired in these two years on the development of methods for the quantitative recording of social interaction (child-operator, child-NAO gaze contact, joint attention...). 2 scenarios have been identified in the scale that can be achieved both with the human operator and through the action of NAO: - the response to the adult's gesture of indication; - the differential response - Joint Attention and/or Behavior Regulation - to the activation of a mechanical toy). The two scenarios will be videotaped with Kinect equipment and measurable data will be acquired for quantitative analysis. The procedure will be validated on a sample of typically developing children (about 20); adapted and validated the instrument on the sample of typically developing children, then the administration and then the validation of the setup obtained on subjects with Autism Spectrum Disorder will take place. The aim is to evaluate whether and how the modes of visual exploration and joint attention change and/or differ pre- and post-training, and the differences that may be evident in the modes of interaction between child and operator and between child and robot. In time, therefore, the following will be provided: 1. to set, adapt and subsequently validate the video recording setting with the identification of the quantitative parameters detectable through technological tools (ECSP-I_rob) on a sample of typically developing children aged between 18 and 24 months 2. to set, adapt and subsequently validate the video recording setting with the measurement of the quantitative parameters detectable through technological tools (ECSP-I_rob) on a sample of children with Autism Spectrum Disorder under the age of 72 months 3. start training with NAO on a group of children with ASD aged 24-72 months with pre- and post-treatment ECSP-I administration. Objectives 1. To evaluate the effectiveness of the robot-based intervention on social-communicative skills and in the acquisition of intransitive gestures used for communicative purposes using the ECSP-I and the MacArthur questionnaire as an outcome measure. The rationale remains the one already detailed in the previous phase, namely that ASD children tend to have greater difficulty in paying attention to the variability and multiplicity of signals characterizing human social interaction (e.g. mimicry, gestures...), an aspect that could lead to a possible lower interest in interaction with an individual than in a technological object towards which they would seem more attentive, responsive and quick in response 2. identify and describe measurable parameters of "social" interaction within the rehabilitation session with NAO and operator and verify their evolution and differences at the beginning and end of treatment and between the different social partners. Translationality The present study will allow to verify the feasibility and usability of the experimental evaluation protocol based on the use of the social robot NAO. If its validity is demonstrated, this method could help to make habilitative interventions in children with ASD more motivating and effective, favoring the generalization of the skills acquired in the context of daily life. Methodology Study design Multicenter Experimental Randomized Open-Label Controlled Study Type of study Low-risk experimental study Case studies Phase 1: 20 typically developing children aged 18-24 months for ECSP-I_rob data acquisition (videotaped ECSP-I administration) Phase 2: 10 ASD children - videotaped ECSP-I administration Phase 3: 20 children diagnosed with ASD aged between 24 and 72 months, already in charge for rehabilitation treatment, who will subsequently be divided into two groups for treatment. Sample Recruitment The 20 typically developing children will be recruited for adaptation and validation of the ECSP-I scale to the NAO interaction system on a voluntary basis at the NEARLab of the Politecnico di Miano and will be evaluated by a properly trained TNPEE of Fondazione Don Gnocchi Children with ASD will be recruited from among the subjects who belong to the outpatient clinics or outpatient rehabilitation treatments at IRCCS Fondazione Don Gnocchi. The sample will be recruited sequentially among children in charge for rehabilitation treatment, who have a diagnosis of Autism Spectrum Disorder confirmed with the main gold-standard tools. Sample size The calculation of the sample size is based on the primary objective of the study, i.e. the evaluation with the ECSP-I scale of the treated group and the control group. Using the Mann-Whitney Test for independent samples to compare the two groups, with a standard deviation estimate of 0.56 and a study design with a 1:1 ratio between the treated group and the control group, it is calculated that a sample of 10 subjects from each group is required to highlight an expected difference of 0.8 points on the scale with a study power of 80% and a level of significance of 5%. Statistical analysis A sequential design will be adopted for the comparison between the two groups. The adoption of this design will allow to obtain a sample of 20 participants for pre- and post-training comparison and to offer the training provided for the experimental group (group A) also to the initially control group (group B) without substantial burdens for the standard therapy procedure; it will also allow to verify the change due exclusively to the passage of time and standard therapy (T0 and T1 comparison for group B) and to carry out a follow-up (T1 and T2 comparison for group A). We also expect greater adherence to the trial, as parents would be enticed to participate by inclusion in an additional pathway to standard therapy (and not simply participation as a control group). Given the expected number of participants, and the scores of the ECSP-I scale that are expressed in ordered categories (Optimal Levels), the comparison between the measurements provided for by the sequential design (T0, T1 and T2) will be carried out with non-parametric statistical tests: - Wilcoxon Exact Test, for longitudinal comparison of each group. - test for independent samples in the exact form test for independent samples in the exact form (Mann-Whitney Exact Test), for the comparison between the experimental group and the control group. - The 2 groups will also be compared through a multivariate analysis, conducted by applying the ANCOVA model adjusted for months of age and baseline scale values to correct for potential imbalances due to the low sample size. Procedures Phase 1: ADMINISTRATION OF ECSP-I SCALE on a typically developing sample The 20 typically developing children will be recruited for the adaptation and validation of the two scenes of the ECSP-I scale to the NAO interaction system on a voluntary basis at the NEARLab of the Politecnico di Miano and the scale will be administered by a properly trained TNPEE of Fondazione Don Gnocchi Phase 2: ADMINISTRATION OF THE ECSP-I SCALE and robot-adapted scenes to a sample of children with ASD The ECSP-I scale and scenes adapted to the social robot will be administered to a sample of children with Autism Spectrum Disorder in order to gain experience and collect data about the administration of this scale to a clinical sample of 10 children. The administration will be videotaped and encoded with the supervision of the developers. Phase 3: Recruitment and randomization of the sample of children with ASD. 20 children with Autism Spectrum Disorder will be recruited, subjected to T0 assessment. Phase 4: The sample will then be divided into two groups: - a group A and group B, which will carry out training with the social robot (see Appendix A for the training protocol) at 2 different times. Phase 5: All the recruited sample will be subjected, at different times, to rehabilitation training with NAO following the protocol in the Appendix. The training will last 12 weeks, with one session per week, lasting 20-30 minutes. Phase 6: Re-evaluation to T1 and T2 according to the treatment scheme (see Table 3). Evaluation tools - Griffiths Mental Development Scales III ed (GMDS-III) [30] - Adaptive Behavior Assessment System II ed (ABAS II) [31] - Autism Diagnostic Observation Shedule (ADOS 2) [32, 33] - Autism Diagnostic Interwiev Revised (ADI-R) [34] - McArthur-Bates Questionnaire, First Vocabulary of the Child (PVB) Gestures and Words: total number of gestures [35] - Early Social Communication Scale (ECSP-I) [27] - Adapted scenes of the ECSP-I with NAO Social Robot (ECSP-I_rob) (quantitative measurement of interaction data) Criticality The main critical issue concerns the recruitment of subjects and their availability during the study period and the continuity of the intervention. For this reason, an extended recruitment period has been hypothesized, which will cover a large part of the entire duration period of the study. Expected results - Verification of the sensitivity of the ECSP-I in grasping the improvement of socio-communicative skills, in particular in the use of gestures. - Improvement in the use of gestures learned during training, in terms of: - Correctly learned gestures used in the therapeutic setting in known scenarios; - Learned gestures correctly used in the therapeutic setting in new scenarios (first step of generalization); - Increase in the number of gestures used in daily life (second phase of generalization; Mc Arthur questionnaire); - Measurement of social interaction parameters detectable with technological tools.

Exploring the Gut-Brain-Behavior Axis With Biomarkers, Probiotic Efficacy, and Artificial Intelligence Algorithms

With an increased prevalence of autism spectrum disorder (ASD) worldwide and in Taiwan, ASD demands urgent attention due to its lasting impact, unclear causes, and limited diagnostic and treatment options. Recent studies highlight disruptions in the gut-brain axis, particularly in ASD. Building on PI Gau's prior research on altered gut microbiota in autism spectrum disorder (ASD), this proposed 4-year study aims to develop evidence-based probiotic intervention (GKB7) and treatment biomarkers for behavioral interventions (Naturalistic Developmental Behavioral Interventions, NDBI, and Program for the Education and Enrichment of Relational Skills, PEERS®) through comprehensive assessments. The ultimate goal is to establish probiotic treatments and diagnostic/treatment biomarkers for ASD utilizing a deep-learning multimodal auxiliary platform. Specific Aims: S.I To conduct a randomized, double-blind, placebo-controlled trial to assess the treatment effects of Clostridium butyricum GKB7 on ASD. S.II To investigate the effect of NDBI intervention trials using metagenomics as the outcome measure. S.III To evaluate the effect of PEERS® interventional trials with metagenomics as the outcome measure. S.IV To develop an artificial intelligence (machine/deep learning) multimodal auxiliary prediction platform that integrates environmental, behavioral/clinical, neurocognitive/imaging, and metagenomic data for ASD diagnosis, subtyping, and impairment prediction. S.V To identify microbiome and metabolomic biomarkers and endophenotypes of ASD, and to establish Gut-Brain-Behavioral Axes in ASD.

Chatbot-based Assistant to Improve Problem-solving Skills in Parents of Children With ASD

A report by the World Health Organization reveals that Autism Spectrum Disorder (ASD), which is among the most prevalent and significant developmental disorders affecting children, is diagnosed in roughly one out of every 100 children around the world. This condition can cause a range of disabilities and changes in how a child communicates and interacts socially. Parenting a child with ASD is a continuous and demanding journey, often marked by heightened stress and mental health challenges for the caregivers. These parents must navigate an array of daily pressures, such as limited influence over their child's behaviors, concerns about the child's cognitive progress and their acquisition of adaptive skills, as well as the relentless requirements of caregiving and time management. They also grapple with worries regarding their bond with their child and the looming uncertainties about the child's long-term prospects. As children with ASD grow, their evolving needs can introduce new complexities. In comparison to parents of neurotypical children, those raising children with ASD encounter a significantly greater number of stress-inducing factors. The problem-solving ability is a key factor in helping parents cope with these stressors, improve their mental health, and have a positive impact on their child and other family members. There is a pressing need to find widely accepted interventions that can improve problem-solving skills and reduce distress in parents of children with ASD. Problem-Solving Skills Training (PSST) focuses on developing practical problem-solving abilities to enhance coping mechanisms and reduce psychological distress. Although PSST has demonstrated remarkable success in various populations, its application specifically for parents of children with ASD remains understudied. Given the unique challenges faced by ASD caregivers, there is a pressing need to investigate how PSST might be adapted and implemented to support this specific population's mental health and problem-solving capabilities. Considering the convenience, low cost and popularity of Chatbot, Chatbot-based PSST (C-PSST) will be administered in this study. A pilot study will be proposed to evaluate the effectiveness of C-PSST. A total of 20 caregivers of children will be recruited to receive the C-PSST and usual service. Through this proposed project, we shall determine (i) whether the C-PSST is acceptable and feasible for parents of children with ASD, (ii) whether it can improve problem-solving abilities and well-being, reduce depressive symptoms, and improve the quality of life in caregivers of children with ASD. The findings will provide evidence for C-PSST in Chinese caregivers, inform evidence-based practice to provide mental health support to caregivers of children with ASD, and provide essential guidance for practitioners (such as nurses and social workers), and policymakers to improve the quality of life in families of children with ASD.

fMRI Tracking taVNS in ASD

In this study, the Investigators main goal is to establish and validate new imaging biomarkers for evaluating and tracking changes in functional networks and dynamic brain states that occur over 1-month transcutaneous auricular vagus nerve stimulation (taVNS) treatment in individuals with autism spectrum disorder (ASD) at home. In this double-blinded sham-controlled clinical trial, Investigators will recruit up to 16 patients with ASD and co-occurring anxiety symptoms from the outpatient clinics at MUSC, SPARK, Epic, and social media (i.e., Project Rex, SCARO). Each participant will first receive the baseline behavior evaluation using a neuropsychiatric battery. Then, participants will have a high-resolution structural MRI scan and four runs of resting-state fMRI scans (~30-min in total) at MUSC 30 Bee Street Center for Biomedical Imaging. This will be followed by an in-person training session with the subject (and legal guardian if applicable), where they will learn how to self-administer taVNS and ask any pertinent questions. Participants will self-administer taVNS (or sham) at home twice daily for 4 weeks. At the end of 4 weeks, participants will have the post-taVNS MRI scanning and behavioral evaluation. Additionally, participants will also complete the behavioral evaluation virtually right after the 2-week treatment, and follow-up 1 and 4 weeks after the completion of treatment. Aim 1. Identify dynamic imaging biomarkers capable of tracking the brain state changes of ASD throughout a one-month taVNS treatment at home. Aim 2. Explore whether dynamic brain state measures derived from baseline can predict symptom improvement and response to taVNS treatment. Results from this study may help to further optimize this taVNS therapy and lead to more effective treatment for ASD, as well as identify dynamic imaging biomarkers that can quantify and track symptom recovery in this unique population.

Imaging - Clinical Evaluation of Altered Nervous System Drainage

Among the various indirect markers of altered drainage of neuroglial waste metabolites, there is the widening of the perivascular spaces (PVS) and the presence of white matter signal alterations. An increase in the number of PVS and their enlargement could represent an indirect marker of obstruction to the drainage of fluids and solutes along the arterial wall at the level of the white matter. This obstruction would also be the basis of tissue hypoxia resulting in the formation of areas of signal hyperintensity in the white matter (White Matter Hyperintensities, WMH) often observed in patients with neurodegenerative diseases and small vessel disease. It is currently unclear what the main drainage route of brain waste metabolites is. Surely there are at least two. The glymphatic theory proposes the entry of the cerebrospinal fluid (CSF) from the subarachnoid space towards the brain parenchyma in a centripetal direction and exit of the metabolic waste along the perivenous spaces. The drainage of metabolic waste could also be explained by the more recent "intramural periarterial drainage" (IPAD) theory which shows elimination along the arterial walls in a centrifugal direction. In magnetic resonance imaging (MRI), the study of solute drainage requires a dynamic evaluation, which is able to evaluate the temporal movement of a tracer. There are several MRI techniques, already described in the literature, which can be used to obtain information relating to perfusion processes and the coupling of neuronal and vascular activity in different brain areas. The circulation of CSF is well known, which is produced largely at the level of the choroid plexuses and is then partly reabsorbed by the arachnoid granulations at the level of the subarachnoid space. Recent studies demonstrate that the CSF re-enters the brain parenchyma in a centripetal manner, crossing the thickness of the gray matter and then the white matter. This movement is regulated by various factors, and in particular by the activity of the smooth muscle cells of the arterial walls, the aquaporin 4 receptors (water channels) and by the chemical-physical properties of the extracellular matrix in the extracellular space.

Iterative Redesign of a Multifaceted Implementation Strategy for a School-based Behavioral Skills Intervention (RUBI)

Specifically, this study will test the effects of the newly redesigned Research Units in Behavioral Intervention in Educational Settings (RUBIES) Implementation Strategy in comparison with the unadapted Research Units in Behavioral Intervention (RUBI) Implementation Strategy on DDBT mechanisms (engagement, usability, appropriateness), proximal implementation outcomes (adoption, fidelity, adaptation, reach) and child outcomes (disruptive behavior, functioning, top problems). Compared with the un-adapted RUBI IS, the newly designed implementation strategy RUBIES-Team will lead to: H3-1: greater RUBIES usability, engagement, and appropriateness; H3-2: greater RUBIES adoption, fidelity, and reach, with fewer reactive adaptations to the RUBIES IS; H3-3: noninferiority on student disruptive behavior in autistic children; and H3-4: more students with improved behavioral outcomes than deterioration or unchanged outcomes across conditions.

Family-school Partnership Intervention for Early Childhood Education

Hybrid Effectiveness-Implementation Trial of an Executive Functioning Intervention for Children's Mental Health Services

Autism is a highly prevalent neurodevelopmental condition, affecting 1 in 36 youth. The annual cost in the U.S. of autism was $223 billion in 2020 and is estimated to rise to $589 billion by 2030. Outcomes are poor and care disparities and high rates of unmet service needs are common. Mental health services play a key role in caring for autistic youth. There have been efforts to develop evidence-based interventions (EBIs) with the potential to lessen the public health burden of autism. Yet, research indicates limited community EBI penetration. Several work gaps remain, including a focus on EBIs designed for community implementation and those addressing multilevel barriers impeding EBI use. There is an urgent need to focus on EBIs that improve mental health services for autism and optimize outcomes for this priority, complex population. Executive functioning (EF) is a potent mechanism underlying autism and commonly co-occurring mental health conditions. EF impairments (e.g., inflexibility, poor goal setting, poor planning) contribute to negative outcomes spanning multiple areas (e.g., academic, vocational, health). Our work underscores the impact of EF deficits on mental health services, including its transdiagnostic impact on the majority of children served in this setting and its role as a barrier to psychotherapy engagement and progress. EF is responsive to treatment, and mental health therapists cite a significant need and motivation for EF treatments, making EF EBIs highly relevant for community mental health settings. However, EF EBIs have not been widely used and tested in such settings. Autism EBIs, or those developed or adapted for autistic youth, have the potential to enhance mental health services, in addition to improving service quality for the populations targeted (e.g., autism). This is due to the specific components and strategies incorporated into the EBI to enhance its impact and fit. We propose a Hybrid Type 2 randomized trial examining the effectiveness and implementation of an autism EF EBI (Unstuck and On Target) in community mental health settings. Unstuck and On Target is a cognitive-behavioral EF intervention effective for autism. With NIMH funding (K23MH115100;), Unstuck and On Target were systematically adapted for and tested in mental health settings, with a pilot test suggesting its preliminary effectiveness, high fidelity, and use beyond autism. Findings have the potential to transform implementation and service quality for the high-priority population of autistic youth as well as youth generally. Aim 1. Evaluate the effectiveness and implementation of an autism EBI (Unstuck and On Target), relative to a non-autism transdiagnostic intervention (Unified Protocol for Children) for autistic youth. Aim 2. Evaluate mediators of EBI training effects to confirm engaged change mechanisms of clinical and implementation outcomes. Aim 3. Explore the generalized effects of EBI training on reach and improved psychotherapy quality with non-autistic youth.

STRW-T Intervention for Autistic Adolescents in 11th and 12th Grade

Individuals with high functioning autism spectrum disorder (ASD) are not developing the skills necessary to successfully transition from adolescence to college, employment, and independent living. Daily living skills (DLS) have been linked to positive adult outcome in individuals with ASD. Despite the importance of daily living skills to adult outcome, adolescents with high functioning ASD have impaired daily living skills. A complex set of environmental, individual, and family factors likely affect the ability of adolescents with high functioning ASD to acquire critical daily living skills. There are currently no evidence-based daily living skills intervention packages for adolescents with high functioning ASD that would prepare them for independence in adulthood. A total of 192 autistic adolescents between the ages of 15-21 who are in their last 2 years of high school will be randomized to the STRW-T group (n=96) or the PEERS-T control group (n=96). Outcome measures will be assessed at baseline, post-treatment, 6-month follow-up, and 6-month post-high school graduation assessments. Adolescents will meet the following inclusion criteria: (1) a diagnosis of ASD; (2) enrolled in 11th or 12th grade; (3) Intelligence Quotient of greater than or equal to 70; and (4) a DLS deficit on the Vineland-3 interview as reported by caregivers. Aim 1: Examine the efficacy of STRW-T on DLS compared to a control group (PEERS-T). Hypothesis 1: STRW-T youth will have greater gains on the primary DLS assessment (VABS-3) compared to PEERS-T youth at post-treatment; Hypothesis 2: STRW-T youth will have greater gains on secondary DLS assessments (Adaptive Behavior Assessment System, 3rd Edition, DLS-Goal Attainment Scale, daily phone diaries) compared to PEERS-T at post-treatment. Aim 2: Evaluate whether the improvement on DLS outcomes by STRW-T are sustained beyond the intervention period. Hypothesis 3: The impact of STRW-T on DLS gains (as assessed by primary and secondary DLS assessments) will be sustained at 6-months post-treatment. Aim 3: Examine the effects of the STRW-T intervention on outcomes in college, employment, and Quality of Life after high school graduation. Hypothesis 4: STRW-T youth will have better college, employment, and Quality of Life outcomes compared to PEERS-T youth at 6-months post-high school graduation.

Pilot Trial of the RUBI Program for Autistic Adults

Over the past decade, across three large-scale, NIH-funded trials, the Research Unit in Behavioral Interventions (RUBI) Autism Network developed and systematically tested a low-intensity manualized parenting intervention for autistic children ages 3-14 with challenging behaviors.8-10 RUBI teaches families how to foster home environments that support their autistic child, including teaching parents how to understand their child's behaviors as forms of communication, respond and adapt to their child's unique needs, and personalize strategies for their child's needs and preferences (e.g. utilizing visual supports to align with information processing needs; attuning to the negative impact of unpredictable expectations; accommodating sensory needs). RUBI also may be a promising approach to support families as they provide care and support to their autistic adult dependents. RUBI has been found to be acceptable to families, reliably delivered by trained therapists, and effective in reducing challenging behaviors and increasing adaptive skills in children.8-10 In response to the shortage of efficacious interventions for autistic adults, RUBI could serve to be systematically redesigned to better support collaboration between family members and their autistic adult dependents, thereby helping autistic adults lead more meaningful and independent lives. To this end, RUBI was recently redesigned utilizing the Discover, Design/Build, Test (DDBT) Framework,11 which leverages user-centered design, participatory action research, and implementation science to ensure that a modified intervention meets the needs of end users (parents, autistic adults, community providers) and is viable across contexts (home, community). Redesign targets included (1) changes in text examples, in-session activities, and language to be more acceptable and relevant to the autistic adult population, (2) content modifications to align focus on supporting communication and dyad co-regulation, (3) improvement in inclusionary and collaborative engagement strategies, and (4) promotion of the autistic adult's engagement, autonomy, and agency during sessions and when implementing strategies. With the Discover, Design/Build phases successfully completed, a two-year pilot randomized trial will extend our work to the Test phase in order to evaluate the feasibility, acceptability, and efficacy of the newly redesigned RUBI intervention compared to an active control - Introduction to the Science and Lived Experience of Autism (ISLEA). Eighty autistic adults with co-occurring challenging behaviors and their parents will be randomized 1:1 to either RUBI or ISLEA and followed for 20 weeks in order to evaluate key outcomes, including feasibility and acceptability of the redesigned RUBI intervention. This study will also explore the impact of RUBI on autistic adults' challenging behaviors, adaptive skills, and quality of life as well as parent self-efficacy. Successful completion of this proposed pilot study will allow for a future large-scale effectiveness trial of RUBI with autistic adults and their parents.