Pediatrics & Neonatology- Juniper Publishers Abstract The aim of this randomized controlled trial with an intention-to-treat analysis was to evaluate the effectiveness, efficacy, and safety of the Acute Stress Syndrome Stabilization Individual (ASSYST-I) treatment intervention in reducing posttraumatic stress disorder (PTSD) symptoms in female children polytraumatized by adverse childhood experiences, neglect, and maltreatment. A total of 40 female children met the inclusion criteria and participated in the study. Participants’ ages ranged from 8 to 17 years old (M =14.67 years). A two-arm randomized controlled trial (RCT) design was applied. PTSD symptoms were measured in three-time points for all participants in the study. Results showed that the intervention had a significant effect for time on PTSD symptoms (F (2,76) = 36.92 p <.000, η² = .493). A significant effect for group was also found (F (1, 38 = 32.7, p<.005, η² = .896) with a large effect, and a significant interaction between time and group, (F (2, 76) = 56.00, p <.000, η² = .600). Means comparison using t test between groups showed significant differences between the Treatment Group (TG) and the Control Group (CG) in the three-time points comparisons showing a large effect on Time 2 (Post-treatment assessment) which was maintained on Time 3 (Follow-up assessment). Results on the Reliable Change Index (RCI) and the Clinically Significant Change (CSC) Margin showed that the ASSYST-I treatment intervention exhibited reliable change on PTSD symptom reduction and clinically significant change, indicating that the treatment group participants are more likely to belong to the non-PTSD population after the intervention. Conversely, the control group participants are more likely to belong to the PTSD population. No adverse effects or events were reported by the participants during the treatment procedure administration or at follow-up. None of the participants showed clinically significant worsening/exacerbation of symptoms after treatment. Participants in the control group received the intervention treatment after the follow-up assessment, fulfilling our ethical criteria. Keywords: Acute Stress Syndrome Stabilization; ASSYST; Posttraumatic stress disorder (PTSD), Female Children; Adverse Childhood Experiences; Neglect and Maltreatment Go to Introduction Childhood abuse, neglect, and maltreatment, and especially polytraumatization, are known contributing factors to long-term insidious detrimental health defects. While definitions of abuse, neglect, and maltreatment vary and have evolved, the consensus in the scientific literature is that child maltreatment refers to acts of both commission (abuse) and omission or deprivation (neglect) that result in harm, potential harm, or threat of harm to a child and encompasses a variety of lived experiences [1]. These health defects in adults, such as diabetes, heart attack, obesity, cardiovascular and respiratory diseases, cancer, higher mortality rate, drug abuse, depression, anxiety, have been correlated with those who have lived adverse childhood experiences or ACEs, which include child abuse, neglect, and maltreatment, and are partially due to homeostatic changes to physiology and epigenetic processes during critical developmental periods [2-9]. Specifically, ages 3–5 have been associated with hippocampus development and exposure to abuse, neglect, and maltreatment may result in heightened vulnerability to later dissociation and posttraumatic stress disorder (PTSD), with ages 11–13 a key period affecting hippocampal development if exposed to abuse and neglect, age 10-11 affecting amygdala development, and ages 14-16 affecting prefrontal cortex development [10]. The neural processes affected in those who have experienced child abuse, neglect, and maltreatment are mainly in fronto-limbic networks including the medial prefrontal cortex, orbitofrontal cortex, anterior cingulate cortex, hippocampus, and amygdala, with neglect related to developmental changes in insula activation during risk processing and abuse related to developmental changes in fronto-parietal activation during cognitive control [11]. Studies also show that a smaller volume and altered activity patterns in the ventromedial region of the prefrontal cortex (vmPFC) have been observed in children with PTSD, suggesting the implication of frontal lobe circuitry in altered fear extinction features, affecting fear conditioning and learning, having important treatment implications [12]. The prevalence of child abuse, neglect, and maltreatment is alarming. On April 6, 2022, the United States Center for Disease Control and Prevention (CDC) reported that 1,750 children died of abuse and neglect in the year 2020 and that of the 74.2 million children in the US 10.6 million, or 1 out of 7, has experienced maltreatment in the previous year, which is likely underestimated due to lack of reporting [13]. Therefore, the need for prevention of child abuse, neglect, and maltreatment is crucial. In instances where prevention is not occurring, effective, efficient, and safe evidence-based PTSD treatment interventions for polytraumatized children is essential for the health, growth, and functioning of individuals, families, and communities. AIP Theoretical Model According to the Adaptive Information Processing (AIP) theoretical model memory networks of stored experiences are the basis of both human mental health and human pathology across the clinical spectrum. AIP disruptions due to high arousal states from adverse life experiences result in pathogenic memories that are inadequately processed and dysfunctionally stored in the brain. The information stored in these neurophysiological memory networks generates the present suffering, difficulties, and symptoms across the clinical spectrum [14,15]. PTSD and Intrusion Symptoms According to the Diagnostic and Statistical Manual of Mental Disorders (5th Edition; DSM-5) posttraumatic stress disorder (PTSD) is a trauma- and stressor-related disorder occurring after exposure to one or more traumatic events (Criterion A). These Criterion A events include, but are not limited to, threatened or actual physical assault (e.g., childhood physical abuse, physical attack), threatened or actual sexual violence (e.g., forced sexual penetration, alcohol/drug-facilitated sexual penetration, abusive sexual contact, noncontact sexual abuse, sexual trafficking) (p. 274) [16]. PTSD Intrusion Symptoms associated with the traumatic event(s), beginning after the traumatic event occurred, are 1. Recurrent, involuntary, and intrusive distressing memories of the traumatic event(s). 2. Recurrent distressing dreams in which the content and/or affect of the dream are related to the traumatic event(s). 3. Dissociative reactions (e.g., flashbacks) in which the individual feels or acts as if the traumatic event(s) were recurring. 4. Intense or prolonged psychological distress at exposure to internal or external cues that symbolize or resemble an aspect of the traumatic event(s). 5. Marked physiological reactions to internal or external clues that symbolize or resemble an aspect of the traumatic event(s). “These intrusive memories often include sensory (e.g., sensing the intense heat that was perceived in a house fire), emotional (e.g., experiencing the fear of believing that one was about to be stabbed), or physiological (e.g., experiencing the shortness of breath that one suffered during a near-drowning) components.Some individuals with the disorder do not have intrusive memories of the event itself, but instead experience intense psychological distress or physiological reactivity when they are exposed to triggering events that resemble or symbolize an aspect of the traumatic event” (p. 271, 282-283) [16]. Acute Stress Syndrome Stabilization Individual Treatment Intervention The Acute Stress Syndrome Stabilization (ASSYST) Individual treatment intervention was born during humanitarian fieldwork and is an AIP-informed, evidence-based, carefully field-tested, and user-friendly psychophysiological algorithmic approach, whose reference is the EMDR Protocol for Recent Critical Incidents and Ongoing Traumatic Stress (EMDR-PRECI) [17-25]. This treatment intervention is specifically designed to provide in-person or online support to clients who present Acute Stress Disorder (ASD) or Posttraumatic Stress Disorder (PTSD) intense psychological distress and/or physiological reactivity caused by the disorders’ intrusion symptoms associated with the memories of the adverse experience(s). The objective of this treatment intervention is focused on the patient’s Autonomic Nervous System sympathetic branch hyperactivation regulation through the reduction or removal of the activation produced by the sensory, emotional, or physiological components of the pathogenic memories of the adverse experience(s) to achieve optimal levels of Autonomic Nervous System activation, stop the three major stress hormones [adrenaline (epinephrine), noradrenaline (norepinephrine), and cortisol] secretion, and reestablish the Prefrontal Cortex functions (e.g., processing of information); thus, facilitating the AIP-system and the subsequent adaptive processing of information [26]. Previous ASSYST Treatment Intervention Studies: Seven previous studies on the ASSYST treatment interventions have proven their efficacy and safety with different populations: (I) General population in lockdown and with ongoing traumatic stress during the COVID-19 Pandemic. (II) TeleMental Health counseling to the general population after adverse experiences. (III) Mental Health Professionals working during the COVID-19 Pandemic with patients suffering from trauma-related disorders and stressors. (IV) General population with non-recent pathogenic memories. (V) Adult Syrian refugees living in Lebanon. (VI) Adult Females with Adverse Childhood Experiences. (VII) Public sector workers during the COVID-19 pandemic [27-33]. Reliable Change Index and Clinically Significant Change Margin To know whether PTSD symptoms change does indeed indicate reliable and clinical significant change in this study, we used the Reliable Change Index (RCI) and the Clinically Significant Change (CSC) Margin. The RCI is used to determine if the magnitude of observed change over time on a given measure is beyond what should be attributed to measurement error. The CSC is used to determine if an observed end score on a measure of symptomatology indicates that respondent is more likely to belong to the non-disordered population than the disordered population. For the Posttraumatic Stress Disorder Checklist for DSM-5 (PCL- 5), the more conservative value of the RCI is 18-points and ≤ 28 end score for the CSC margin [34]. Go to Objective The objective of this randomized controlled trial with intention-to-treat analysis was to evaluate the effectiveness, efficacy, and safety of the Acute Stress Syndrome Stabilization Individual (ASSYST-I) treatment intervention in reducing posttraumatic stress disorder (PTSD) symptoms in female children polytraumatized by adverse childhood experiences, neglect, and maltreatment. Go to Method Study design To measure the effectiveness of the ASSYST-I on the dependent variable PTSD symptoms, this study with an intention-to-treat analysis used a two-arm randomized controlled trial (RCT) with a waitlist no-treatment control group design. PTSD symptoms were measured at three time points for all participants in the study: Time 1. Pre-treatment assessment; Time 2. Post-treatment assessment; and Time 3. Follow-up assessment. For ethical reasons, all participants in the control group received the intervention treatment after the follow-up assessment was competed. Ethics and research quality The research protocol was reviewed and approved by the EMDR Mexico International Research Ethics Review Board (also known in the United States of America as an Institutional Review Board) in compliance with the International Committee of Medical Journal Editors recommendations, the Guidelines for Good Clinical Practice of the European Medicines Agency (version 1 December 2016), and the Helsinki Declaration as revised in 2013. The research quality of this study was based on the Consolidated Standards of Reporting Trials (CONSORT) 2010 Statement and the Standard Protocol Items Recommendation for Interventional Trials (SPIRIT) 2013 checklist [35,36]. Participants This study was conducted in Toluca City, Mexico, from May to July 2023, with the Mexican (Latina) female child population with pathogenic memories from adverse childhood experiences (ACEs), neglect, and maltreatment living in a center under the Mexican Government’s protection. Forty-seven potential participants were recruited. Inclusion criteria was: (a) being a female child, (b) having pathogenic memories from ACEs, neglect, and maltreatment causing current distress, (c) voluntarily participating in the study, (d) not receiving specialized trauma therapy, (e) not receiving drug therapy for PTSD symptoms, (f) having a PCL-5 total score of 33 points or more. Exclusion criteria was: (a) ongoing self-harm/suicidal or homicidal ideation, (b) diagnosis of schizophrenia, psychotic, or bipolar disorder, (c) diagnosis of a dissociative disorder, (d) organic mental disorder, (e) a current, active chemical dependency problem, (f) significant cognitive impairment (e.g., severe intellectual disability, dementia), (g) presence of uncontrolled symptoms due to a medical illness. Seven of the 47 potential participants were excluded due to having PCL-5 scores under 33 points (subclinical symptoms). These seven participants have been living in the center since they were very young and were not exposed to prolonged adverse experiences like the other participants. A total of 40 females children met the inclusion criteria and participated in the study. Participants’ ages ranged from 8 to 17 years old (M =14.67 years). Participation was voluntary with the participants’ and their legal guardians signed informed consent in accordance with the Mental Capacity Act 2005. Instruments for Psychometric Evaluation a) We used the Trauma Screen Checklist from the Child PTSD Symptom Scale for DSM-5 for trauma-exposed children and adolescents for the study participants to choose the traumatic events they have lived prior to being rescued by the Mexican Government. This list contains 15 frightening or stressful events that can happen to children and all of them fulfill DSM-5 PTSD Criterion A. Participants chose the event that bothered them the most to answer the PCL-5 during the three assessment times [37,38]. b) To measure PTSD symptom severity and treatment response, we used the Posttraumatic Stress Disorder Checklist for DSM-5 (PCL-5) provided by the National Center for PTSD (NCPTSD) with the time interval for symptoms to be the past week. The instrument was translated and back-translated to Spanish. It contains 20 items, including three new PTSD symptoms (compared with the PTSD Checklist for DSM-IV) [39,40]: blame, negative emotions, and reckless or self-destructive behavior. Respondents indicated how much they have been bothered by each PTSD symptom over the past week (rather than the past month), using a 5-point Likert scale ranging from 0=not at all, 1=a little bit, 2=moderately, 3=quite a bit, and 4=extremely. A total symptom score of zero to 80 can be obtained by summing the items. The sum of the scores yields a continuous measure of PTSD symptom severity for symptom clusters and the whole disorder. Psychometrics for the PCL-5, validated against the Clinician- Administered PTSD Scale-5 (CAPS-5) diagnosis, suggest that a score of 31-33 is optimal to determine probable PTSD diagnosis, and a score of 33 is recommended for use at present [38-40]. Go to Procedure Randomization, Allocation Concealment Mechanism, and Blinding Procedure A computer-generated simple randomization with a 1:1 allocation ratio was used. Two independent assessors blind to treatment conditions conducted the randomization process to avoid allocation influence. The treatment random allocation sequence was concealed using sequentially numbered, opaque, sealed, and stapled envelopes who were open only after they were irreversibly assigned to the participants. The safekeeping of the envelopes and the assignment of participants to each arm of the trial (implementation of the random allocation sequence) was overseen by a person not involved in the research study and independent of the enrollment personnel. The treatment allocation of the participants was blinded for the research assistants who conducted the intake interview, initial assessment, and enrollment, and also for the independent assessors who conducted the followup assessments. Participants were instructed to not reveal their treatment allocation to the persons conducting the assessments. Twenty participants were allocated in the treatment group (TG) and twenty participants in the control group (CG). See Figure 1. Flow Diagram. Enrollment, Assessments Times, Blind Data Collection, and Confidentiality of Data Treatment group (TG) and control group (CG) participants completed the instruments in person and on an individual basis during distinct assessment moments. During Time 1, research assistants formally trained in all of the instruments’ administration, who were not blind to the study, but blind to the participant’s treatment allocation, conducted the intake interview, collected demographic data (e.g., name, age, gender, and contact information), assessed potential participants for eligibility based on the inclusion/exclusion criteria, obtained signed informed consent from the participants and their legal guardians, conducted the pre-treatment application of instruments, enrolled participants in the study, and randomly assigned each treatment group participant to one of the four clinicians formally trained in the ASSYST-I that participated in this study. The research assistants also assisted the participants in identifying the pathogenic memory of their worst adverse experience from the Trauma Screen Checklist to be treated with the ASSYST-I. Each identified memory was written down by the research assistants on the Memory Record Sheets that were utilized by the clinicians during the ASSYST-I treatment intervention and utilized by participants during the three assessments times to ensure participants were focusing on the same memory when they received the treatment intervention, as well as the specific assessment time when they completed the assessment tools. To obtain maximally interpretable PCL-5 scores, research assistants and independent assessors a) discussed with each participant the purpose of the instrument in detail, b) encouraged attentive and specific responding, c) invited participants to read each question carefully before responding and to select the correct answer, d) clarified their questions about some the symptoms, such as differentiating between intrusive memories and flashbacks, e) reworded conceptually complex symptoms (i.e., symptoms in the reexperiencing cluster) when necessary, f) reminded participants of the last-week symptom’s time frame, as well as, g) to only report symptoms related to the pathogenic memory of their worst adverse experience and not based on their everyday general distress. During Time 2 (post-treatment assessment 7 days after treatment), and Time 3 (follow-up assessment 30 days after treatment), assessments were conducted for all participants by blind to treatment allocation independent assessors with formal training in administration of the instruments. The data safe keeper independent assessor received the participant’s assessment instruments that were answered during Times 1, 2, and 3. All data was collected, stored, and handled in full compliance with the EMDR Mexico International Research Ethics Review Board requirements to ensure confidentiality. Ea