Protocol description for a randomized controlled trial of fMRI neurofeedback for tics in adolescents with Tourette Syndrome.

This article describes the protocol for a randomized, controlled clinical trial of a neurofeedback (NF) intervention for Tourette Syndrome (TS) and chronic tic disorder. The intervention involves using functional magnetic resonance imaging (fMRI) to provide feedback regarding activity in the supplementary motor area: participants practice controlling this brain area while using the feedback as a training signal. The previous version of this NF protocol was tested in a small study (n = 21) training adolescents with TS that yielded clinically promising results. Therefore, we plan a larger trial. Here we describe the background literature that motivated this work, the design of our original neurofeedback study protocol, and adaptations of the research study protocol for the new trial. We focus on those ideas incorporated into our protocol that may be of interest to others designing and running NF studies. For example, we highlight our approach for defining an unrelated brain region to be trained in the control group that is based on identifying a region with low functional connectivity to the target area. Consistent with a desire for transparency and open science, the new protocol is described in detail here prior to conducting the trial.

Aggression Is Associated With Social Adaptive Functioning in Children With ASD and Anxiety.

Social adaptive functioning is notably compromised and may be further impaired by aggressive behavior in children with autism spectrum disorder (ASD). This study examined the association between aggressive behavior and social adaptive skills in children with ASD and the contribution of aggressive behavior to social adaptive skills in a combined sample of children with and without ASD. Participants consisted of children, ages 8 to 15 years, with ASD (n = 52) and who were typically developing (n = 29). Results indicate that aggressive behavior is negatively associated with social adaptive skills in children with ASD and that it contributes to reduced social adaptive functioning above and beyond ASD diagnosis. Findings underscore the importance of considering the role of aggressive behavior when evaluating and promoting social functioning in children with ASD.

Amygdala-prefrontal connectivity in children with maladaptive aggression is modulated by social impairment.

Aggressive behavior is common across childhood-onset psychiatric disorders and is associated with impairments in social cognition and communication. The present study examined whether amygdala connectivity and reactivity during face emotion processing in children with maladaptive aggression are moderated by social impairment. This cross-sectional study included a well-characterized transdiagnostic sample of 101 children of age 8-16 years old with clinically significant levels of aggressive behavior and 32 typically developing children without aggressive behavior. Children completed a face emotion perception task of fearful and calm faces during functional magnetic resonance imaging. Aggressive behavior and social functioning were measured by standardized parent ratings. Relative to controls, children with aggressive behavior showed reduced connectivity between the amygdala and the dorsolateral prefrontal cortex (PFC) during implicit emotion processing. In children with aggressive behavior, the association between reduced amygdala-ventrolateral PFC connectivity and greater severity of aggression was moderated by greater social impairment. Amygdala reactivity to fearful faces was also associated with severity of aggressive behavior for children without social deficits but not for children with social deficits. Social impairments entail difficulties in interpreting social cues and enacting socially appropriate responses to frustration or provocation, which increase the propensity for an aggressive response via diminished connectivity between the amygdala and the ventral PFC.

Increased amygdala and decreased frontolimbic r esting- s tate functional connectivity in children with aggressive behavior.

Childhood maladaptive aggression is associated with disrupted functional connectivity within amygdala-prefrontal circuitry. In this study, neural correlates of childhood aggression were probed using the intrinsic connectivity distribution, a voxel-wise metric of global resting-state brain connectivity. This sample included 38 children with aggressive behavior (26 boys, 12 girls) ages 8-16 years and 21 healthy controls (14 boys, 6 girls) matched for age and IQ. Functional MRI data were acquired during resting state, and differential patterns of intrinsic functional connectivity were tested in a priori regions of interest implicated in the pathophysiology of aggressive behavior. Next, correlational analyses tested for associations between functional connectivity and severity of aggression measured by the Reactive-Proactive Aggression Questionnaire in children with aggression. Children with aggressive behavior showed increased global connectivity in the bilateral amygdala relative to controls. Greater severity of aggressive behavior was associated with decreasing global connectivity in the dorsal anterior cingulate and ventromedial prefrontal cortex. Follow-up seed analysis revealed that aggression was also positively correlated with left amygdala connectivity with the dorsal anterior cingulate, ventromedial and dorsolateral prefrontal cortical regions. These results highlight the potential role of connectivity of the amygdala and medial prefrontal and anterior cingulate cortices in modulating the severity of aggressive behavior in treatment-seeking children.

Parent Emotion Socialization in Children with Autism Spectrum Disorder and Co-Occurring Anxiety.

Although parents' socialization of children's emotional experiences and expression has been widely studied in typically developing (TD) populations, these processes have been largely unexplored in families of children with autism spectrum disorder (ASD). The present study examined parent emotion socialization in a well-characterized sample of verbally fluent children with ASD and comorbid anxiety disorders. Participants included 64 children, aged 8-15 years, who had ASD and co-occurring anxiety and 24 matched TD children without psychiatric disorders. Parents completed ratings of their responses to their children's emotional experiences using the Coping with Children's Negative Emotions Scale (CCNES), and both parents and children completed ratings of child anxiety using the Multidimensional Anxiety Rating Scale (MASC). Parents of children with ASD and anxiety did not differ from parents of TD children without psychiatric disorders in their endorsement of different emotion socialization practices. However, among children with ASD and anxiety, greater anxiety was associated with more emotion-focused responses from parents, and for children with less ASD symptom severity, lower levels of anxiety were associated with more punitive responses from parents. Results suggest that certain types of more directive emotion socialization approaches may be associated with lower anxiety in children with ASD, whereas emotion socialization approaches focused on altering the child's emotional experiences may be associated with greater anxiety in this population. While it is likely that parent emotion socialization practices impact children's emotional experiences of anxiety, it is also likely that children with distinct profiles of anxiety and ASD symptomology elicit specific styles of emotion socialization from parents.

Conducting CBT for Anxiety in Children with Autism Spectrum Disorder During COVID-19 Pandemic.

This commentary describes the transition to remote delivery of cognitive-behavioral therapy (CBT) for anxiety in children with autism spectrum disorder (ASD) who participates in a clinical trial during the COVID-19 pandemic. The effects of COVID-19 on children's anxiety and on the family functioning are discussed. Modifications to CBT necessitated by telehealth delivery were aimed at maximizing engagement of children and their parents while maintaining treatment fidelity and adhering to the research protocol. Treatment targets were updated to address new sources of anxiety and CBT exposure exercises were modified to accommodate the new reality of quarantine restrictions. If the COVID-19 pandemic continues to affect treatment delivery it may require a widespread utilization of telehealth for treating anxiety in children with ASD.

Sex differences in medial prefrontal and parietal cortex structure in children with disruptive behavior.

Sex differences in brain structure in children with disruptive behavior disorders (DBD) remain poorly understood. This study examined sex differences in gray matter volume in children with DBD in a priori regions-of-interest implicated in the pathophysiology of disruptive behavior. We then conducted a whole-brain analysis of cortical thickness to examine sex differences in regions not included in our hypothesis. Exploratory analyses investigated unique associations between structure, and dimensional measures of severity of disruptive behavior and callous-unemotional traits. This cross-sectional study included 88 children with DBD (30 females) aged 8-16 years and 50 healthy controls (20 females). Structural MRI data were analyzed using surface-based morphometry to test for interactions between sex and group. Multiple-regression analyses tested for sex-specific associations between structure, callous-unemotional traits, and disruptive behavior severity. Boys with DBD showed reduced gray matter volume in the left ventromedial prefrontal cortex (vmPFC) and reduced cortical thickness in the supramarginal gyrus, but not girls compared to respective controls. Dimensional analyses revealed associations between sex, callous-unemotional traits, and disruptive behavior for amygdala and vmPFC volume, and ventrolateral prefrontal cortex cortical thickness. Sex-specific differences in prefrontal structures involved in emotion regulation may support identification of neural biomarkers of disruptive behavior to inform target-based treatments.

Assessing Irritability in Children with Autism Spectrum Disorder Using the Affective Reactivity Index.

Irritability is an impairing problem in children with ASD that may be associated with other behavioral and emotional concerns. The Affective Reactivity Index (ARI) is a parent-rated measure of irritability widely used in children with mood disorders, however, its utility in children with ASD remains unclear. In this study, we examined ARI parent ratings in children with ASD and contributions of parent-rated anxiety and noncompliance to irritability measured by the ARI. Participants included 81 children with ASD, aged 8-16 years. Results suggest that both anxiety and noncompliance contribute to irritability, but that anxiety only contributes to irritability in the absence of noncompliance. Further, the ARI is likely to be a useful measure of irritability in children with ASD.

Fixel-Based Diffusion Magnetic Resonance Imaging Reveals Novel Associations Between White Matter Microstructure and Childhood Aggressive Behavior.

BACKGROUND: Childhood aggression has been linked to white matter abnormalities, but research has been inconsistent with regard to both regions of alterations and directionality of the associations. We examined white matter microstructure correlates of aggression using a novel diffusion imaging analysis technique, fixel-based analysis, which leverages connectivity and crossing-fiber information to assess fiber bundle density. METHODS: The sample included 70 children with aggressive behavior and 25 healthy control children without aggressive behavior. Aggression was measured by the parent-rated Aggressive Behavior scale of the Child Behavior Checklist. Fixel-based analysis was conducted at the whole-brain and region-of-interest levels, including the uncinate fasciculus, inferior longitudinal fasciculus, fornix, cingulum bundle, and genu, body, isthmus, and splenium of the corpus callosum. RESULTS: Whole-brain analysis of covariance revealed that children with aggressive behavior, relative to control children, had lower fiber density in a cluster of limbic and cortical pathways, including the inferior fronto-occipital fasciculus, fornix, middle cerebellar peduncle, and superior thalamic radiations (familywise error-corrected p < .01), and had higher fiber density in the corpus callosum (body and splenium) (familywise error-corrected p < .05). Region-of-interest analyses showed decreased fiber density in cingulum bundles associated with aggression. These effects were independent of age, sex, IQ, symptoms of attention-deficit/hyperactivity disorder, medications, and head motion. In children with aggressive behavior, co-occurring callous-unemotional traits and anxiety did not moderate the association between aggression and white matter density. CONCLUSIONS: Diminished white matter density in pathways connecting limbic and cortical regions is associated with childhood aggression. Abnormal interhemispheric connectivity via corpus callosum may also reflect a potential neural mechanism involved in aggression.

Anxiety in 3- to 7-year-old children with autism spectrum disorder seeking treatment for disruptive behavior.

Anxiety is a common and impairing problem in children with autism spectrum disorder, but little is known about it in preschool children with autism spectrum disorder. This article reports on the characteristics of anxiety symptoms in young children with autism spectrum disorder using a parent-completed rating scale. One hundred and eighty children (age 3-7 years) participated in a clinical trial of parent training for disruptive behaviors. Anxiety was measured as part of pre-treatment subject characterization with 16 items from the Early Childhood Inventory, a parent-completed scale on child psychiatric symptoms. Parents also completed other measures of behavioral problems. Sixty-seven percent of children were rated by their parents as having two or more clinically significant symptoms of anxiety. There were no differences in the Early Childhood Inventory anxiety severity scores of children with IQ < 70 and those with ⩾70. Higher levels of anxiety were associated with severity of oppositional defiant behavior and social disability. Anxiety symptoms are common in preschoolers with autism spectrum disorder. These findings are consistent with earlier work in school-age children with autism spectrum disorder. There were no differences in anxiety between children with IQ below 70 and those with IQ of 70 and above. Social withdrawal and oppositional behavior were associated with anxiety in young children with autism spectrum disorder.

Discrepancies between parent and child ratings of anxiety in children with autism spectrum disorder.

Co-occurring anxiety is common in children with autism spectrum disorder (ASD). However, inconsistencies across parent and child reports of anxiety may complicate the assessment of anxiety in this population. The present study examined parent and child anxiety ratings in children with ASD with and without anxiety disorders and tested the association between parent-child anxiety rating discrepancy and ASD symptom severity. Participants included children aged 8-16 years in three diagnostic groups: ASD with co-occurring anxiety disorders (ASD + Anxiety; n = 34), ASD without co-occurring anxiety disorders (ASD; n = 18), and typically developing healthy controls (TD; n = 50). Parents and children completed ratings of child anxiety using the Multidimensional Anxiety Rating Scale. Patterns of parent and child anxiety ratings differed among the three groups, with parent ratings exceeding child ratings only in the ASD + Anxiety group. Parents reported higher levels of child anxiety in the ASD + Anxiety versus ASD group, whereas children reported comparable levels of anxiety in the two groups. Among children with ASD, ASD symptom severity was positively associated with the degree to which parent ratings exceeded child ratings. Results suggest that children with ASD and co-occurring anxiety disorders endorse some anxiety symptoms but may underreport overall levels of anxiety. In addition, ASD symptom severity might increase discrepancies in parent-child anxiety ratings. These findings suggest a unique and valuable role of child anxiety ratings and suggest that both parent and child anxiety ratings should be considered in light of children's ASD symptom severity and used to guide further assessment. Autism Res 2020, 13: 93-103. © 2019 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Children with autism spectrum disorder (ASD) commonly experience anxiety; yet, their perceptions of their anxiety might differ from their parents' perceptions. This study found that, while children with ASD and anxiety disorders acknowledge some anxiety, their parents report them as having higher levels of anxiety. Also, child and parent perceptions of anxiety may differ more for children with more severe ASD symptoms. How these findings may guide research and clinical practice is discussed.

Anger Rumination is Associated with Restricted and Repetitive Behaviors in Children with Autism Spectrum Disorder.

Children with autism spectrum disorder (ASD) are reported to have greater levels of anger rumination than typically developing children. This study examined anger rumination in children with ASD in comparison to children with disruptive behavior disorder without ASD. We also tested if anger rumination is associated with aggression and the core ASD symptoms of restricted and repetitive behaviors (RRBs). This study included three groups of children aged 8-16 years: 63 had ASD (ASD group), 79 had disruptive behavior disorder (DB group), and 40 healthy controls (HC). ASD and DB groups showed greater anger rumination relative to the HC group. Anger rumination was associated with RRBs in children with ASD, suggesting the link to core ASD symptoms.

Child and adolescent risk factors that differentially predict violent versus nonviolent crime.

While most research on the development of antisocial and criminal behavior has considered nonviolent and violent crime together, some evidence points to differential risk factors for these separate types of crime. The present study explored differential risk for nonviolent and violent crime by investigating the longitudinal associations between three key child risk factors (aggression, emotion dysregulation, and social isolation) and two key adolescent risk factors (parent detachment and deviant peer affiliation) predicting violent and nonviolent crime outcomes in early adulthood. Data on 754 participants (46% African American, 50% European American, 4% other; 58% male) oversampled for aggressive-disruptive behavior were collected across three time points. Parents and teachers rated aggression, emotion dysregulation, and social isolation in fifth grade (middle childhood, age 10-11); parents and youth rated parent detachment and deviant peer affiliation in seventh and eighth grade (early adolescence, age 12-14) and arrest data were collected when participants were 22-23 years old (early adulthood). Different pathways to violent and nonviolent crime emerged. The severity of child dysfunction in late childhood, including aggression, emotion dysregulation, and social isolation, was a powerful and direct predictor of violent crime. Although child dysfunction also predicted nonviolent crime, the direct pathway accounted for half as much variance as the direct pathway to violent crime. Significant indirect pathways through adolescent socialization experiences (peer deviancy) emerged for nonviolent crime, but not for violent crime, suggesting adolescent socialization plays a more distinctive role in predicting nonviolent than violent crime. The clinical implications of these findings are discussed.

Emotional Reactivity, Behavior Problems, and Social Adjustment at School Entry in a High-risk Sample.

Prior research suggests that heightened emotional reactivity to emotionally distressing stimuli may be associated with elevated internalizing and externalizing behaviors, and contribute to impaired social functioning. These links were explored in a sample of 169 economically-disadvantaged kindergarteners (66 % male; 68 % African American, 22 % Hispanic, 10 % Caucasian) oversampled for elevated aggression. Physiological measures of emotional reactivity (respiratory sinus arrhythmia [RSA], heart rate [HR], and cardiac pre-ejection period [PEP]) were collected, and teachers and peers provided ratings of externalizing and internalizing behavior, prosocial competence, and peer rejection. RSA withdrawal, HR reactivity, and PEP shortening (indicating increased arousal) were correlated with reduced prosocial competence, and RSA withdrawal and HR reactivity were correlated with elevated internalizing problems. HR reactivity was also correlated with elevated externalizing problems and peer rejection. Linear regressions controlling for age, sex, race, verbal proficiency, and resting physiology showed that HR reactivity explained unique variance in both teacher-rated prosocial competence and peer rejection, and contributed indirectly to these outcomes through pathways mediated by internalizing and externalizing problems. A trend also emerged for the unique contribution of PEP reactivity to peer-rated prosocial competence. These findings support the contribution of emotional reactivity to behavior problems and social adjustment among children living in disadvantaged urban contexts, and further suggest that elevated reactivity may confer risk for social difficulties in ways that overlap only partially with internalizing and externalizing behavior problems.

Developmental trajectories of clinically significant attention-deficit/hyperactivity disorder (ADHD) symptoms from grade 3 through 12 in a high-risk sample: Predictors and outcomes.

Developmental trajectories of clinically significant attention-deficit/hyperactivity (ADHD) symptoms were explored in a sample of 413 children identified as high risk because of elevated kindergarten conduct problems. Symptoms of inattention and hyperactivity-impulsivity were modeled simultaneously in a longitudinal latent class analyses, using parent reports collected in Grades 3, 6, 9, and 12. Three developmental trajectories emerged: (1) low levels of inattention and hyperactivity (low), (2) initially high but then declining symptoms (declining), and (3) continuously high symptoms that featured hyperactivity in childhood and early adolescence and inattention in adolescence (high). Multinomial logistic regressions examined child characteristics and family risk factors as predictors of ADHD trajectories. Relative to the low class, children in the high and declining classes displayed similar elevations of inattention and hyperactivity in early childhood. The high class was distinguished from the declining class by higher rates of aggression and hyperactivity at school and emotion dysregulation at home. In contrast, the declining class displayed more social isolation at home and school, relative to the low class. Families of children in both high and declining trajectory classes experienced elevated life stressors, and parents of children in the high class were also more inconsistent in their discipline practices relative to the low class. By late adolescence, children in the high class were significantly more antisocial than those in the low class, with higher rates of arrests, school dropout, and unemployment, whereas children in the declining class did not differ from those in the low trajectory class. The developmental and clinical implications of these findings are discussed.

Early childhood precursors and adolescent sequelae of grade school peer rejection and victimization.

This study examined the early childhood precursors and adolescent outcomes associated with grade school peer rejection and victimization among children oversampled for aggressive-disruptive behaviors. A central goal was to better understand the common and unique developmental correlates associated with these two types of peer adversity. There were 754 participants (46% African American, 50% European American, 4% other; 58% male; average age=5.65 at kindergarten entry) followed into seventh grade. Six waves of data were included in structural models focused on three developmental periods. Parents and teachers rated aggressive behavior, emotion dysregulation, and internalizing problems in kindergarten and Grade 1 (Waves 1-2); peer sociometric nominations tracked "least liked" and victimization in Grades 2, 3, and 4 (Waves 3-5); and youth reported on social problems, depressed mood, school adjustment difficulties, and delinquent activities in early adolescence (Grade 7, Wave 6). Structural models revealed that early aggression and emotion dysregulation (but not internalizing behavior) made unique contributions to grade school peer rejection; only emotion dysregulation made unique contributions to grade school victimization. Early internalizing problems and grade school victimization uniquely predicted adolescent social problems and depressed mood. Early aggression and grade school peer rejection uniquely predicted adolescent school adjustment difficulties and delinquent activities. Aggression and emotion dysregulation at school entry increased risk for peer rejection and victimization, and these two types of peer adversity had distinct as well as shared risk and adjustment correlates. Results suggest that the emotional functioning and peer experiences of aggressive-disruptive children deserve further attention in developmental and clinical research.

In our own voice-family companion: reducing self-stigma of family members of persons with serious mental illness.

OBJECTIVE: This article reports preliminary findings from a novel, family peer-based intervention designed to reduce self-stigma among family members of people with serious mental illness. METHODS: A total of 158 primary caregivers of patients with schizophrenia were recruited from a large urban mental health facility (93 caregivers) or from a family and consumer advocacy organization (65 caregivers). Caregivers (N=122) who reported they perceived at least a moderate level of mental illness-related stigma were evaluated on measures of self-stigma, withdrawal, secrecy, anxiety, and social comparison and randomly assigned to receive one of two, one-session group interventions: a peer-led intervention (In Our Own Voice-Family Companion [IOOV-FC]) designed to stimulate group discussion or a clinician-led family education session, which delivered information about mental illness in a structured, didactic format. IOOV-FC consisted of playing a videotape of family members who describe their experiences coping with stigma, which was followed by a discussion led by two family peers who modeled sharing their own experiences and facilitated group sharing. RESULTS: Of 24 family members and ten consumers, 96% rated the videotape above a predetermined acceptability threshold on a 19-item scale assessing cultural sensitivity, respect for different stakeholders, relevance of content, and technical quality (α=.92). Caregivers receiving IOOV-FC with low to moderate pretreatment anxiety reported a substantial reduction in self-stigma (effect size=.50) relative to those receiving clinician-led family education (p=.017) as well as significant reductions in secrecy (p=.031). CONCLUSIONS: Peer-led group interventions may be more effective in reducing family self-stigma than clinician-led education, at least for persons reporting experiencing low to moderate anxiety levels on a standard questionnaire

Family-focused treatment for caregivers of patients with bipolar disorder.

OBJECTIVES: Family members of patients with bipolar disorder experience high rates of subjective and objective burden which place them at risk for adverse physical health and mental health outcomes. We present preliminary efficacy data from a novel variation of Family Focused Treatment [Miklowitz DJ. Bipolar Disorder: A Family-Focused Treatment Approach (2(nd) ed.). New York: The Guilford Press, 2008] that aimed to reduce symptoms of bipolar disorder by working with caregivers to enhance illness management skills and self-care. METHODS: The primary family caregivers of 46 patients with bipolar I (n = 40) or II (n = 6) disorder, diagnosed by the Structured Clinical Interview for DSM-IV Axis I Disorders, were assigned randomly to receive either: (i) a 12-15-session family-focused, cognitive-behavioral intervention designed to provide the caregiver with skills for managing the relative's illness, attaining self-care goals, and reducing strain, depression, and health risk behavior [Family-Focused Treatment-Health Promoting Intervention (FFT-HPI)]; or (ii) an 8- to 12-session health education (HE) intervention delivered via videotapes. We assessed patients pre- and post-treatment on levels of depression and mania and caregivers on levels of burden, health behavior, and coping. RESULTS: Randomization to FFT-HPI was associated with significant decreases in caregiver depressive symptoms and health risk behavior. Greater reductions in depressive symptoms among patients were also observed in the FFT-HPI group. Reduction in patients' depression was partially mediated by reductions in caregivers' depression levels. Decreases in caregivers' depression were partially mediated by reductions in caregivers' levels of avoidance coping. CONCLUSIONS: Families coping with bipolar disorder may benefit from family interventions as a result of changes in the caregivers' ability to manage stress and regulate their moods, even when the patient is not available for treatment.