Self-injuring adolescent girls exhibit insular cortex volumetric abnormalities that are similar to those seen in adults with borderline personality disorder.

Self-inflicted injury (SII) in adolescence is a serious public health concern that portends prospective vulnerability to internalizing and externalizing psychopathology, borderline personality development, suicide attempts, and suicide. To date, however, our understanding of neurobiological vulnerabilities to SII is limited. Behaviorally, affect dysregulation is common among those who self-injure. This suggests ineffective cortical modulation of emotion, as observed among adults with borderline personality disorder. In borderline samples, structural and functional abnormalities are observed in several frontal regions that subserve emotion regulation (e.g., anterior cingulate, insula, dorsolateral prefrontal cortex). However, no volumetric analyses of cortical brain regions have been conducted among self-injuring adolescents. We used voxel-based morphometry to compare cortical gray matter volumes between self-injuring adolescent girls, ages 13-19 years (n = 20), and controls (n = 20). Whole-brain analyses revealed reduced gray matter volumes among self-injurers in the insular cortex bilaterally, and in the right inferior frontal gyrus, an adjacent neural structure also implicated in emotion and self-regulation. Insular and inferior frontal gyrus gray matter volumes correlated inversely with self-reported emotion dysregulation, over-and-above effects of psychopathology. Findings are consistent with an emotion dysregulation construal of SII, and indicate structural abnormalities in some but not all cortical brain regions implicated in borderline personality disorder among adults.

Robust is not necessarily reliable: From within-subjects fMRI contrasts to between-subjects comparisons.

Advances in cognitive and affective neuroscience come largely from within-subjects comparisons, in which the functional significance of neural activity is determined by contrasting two or more experimental conditions. Clinical and social neuroscience studies have attempted to leverage between-subject variability in such condition differences to better understand psychopathology and other individual differences. Shifting from within-to between-subjects comparisons requires that measures have adequate internal consistency to function as individual difference variables. This is particularly relevant for difference scores-which have lower reliability. The field has assumed reasonable internal consistency of neural measures based on consistent findings across studies (i.e., if a within-subject difference in neural activity is robust, then it must be reliable). Using one of the most common fMRI paradigms in the clinical neuroscience literature (i.e., a face- and shape-matching task), in a large sample of adolescents (N = 139) we replicate a robust finding: amygdala activation is greater for faces than shapes. Moreover, we demonstrate that the internal consistency of the amygdala in face and shape blocks was excellent (Spearman-Brown corrected reliability [SB] > .94). However, the internal consistency of the activation difference between faces and shapes was nearly zero (SB = -.06). This reflected the fact that the amygdala response to faces and shapes was highly correlated (r = .97) across individuals. Increased neural activation to faces versus shapes could not possibly function as an individual difference measure in these data-illustrating how neural activation can be robust within subjects, but unreliable as an individual difference measure. Strong and reproducible condition differences in neural activity are not necessarily well-suited for individual differences research-and neuroimaging studies should always report the internal consistency of, and correlations between, activations used in individual differences research.

Trait Impulsivity and the Externalizing Spectrum.

This article reviews evidence that trait impulsivity-expressed early in life as the hyperactive-impulsive and combined presentations of attention-deficit/hyperactivity disorder (ADHD)-is a bottom-up, subcortically mediated vulnerability to all externalizing disorders. This vulnerability arises from deficient mesolimbic dopamine responding, which imbues psychological states (irritability, discontentment) that motivate excessive approach behavior (hyperactivity, impulsivity). Through complex interactions with (a) aversive motivational states that arise from largely independent subcortical systems, (b) emotion regulatory mechanisms that arise from top-down, cortical modulation of subcortical neural function, and (c) environmental risk factors that shape and maintain emotion dysregulation, trait impulsivity confers vulnerability to increasingly severe externalizing behaviors across development. This perspective highlights the importance of identifying transdiagnostic neural vulnerabilities to psychopathology; dovetails with the hierarchical, latent structure of psychopathology; and suggests that progression along the externalizing spectrum is an ontogenic process whereby a common, multifactorially inherited trait interacts with endogenous and exogenous influences to yield increasingly intractable externalizing behaviors across development.

Neural responses to monetary incentives among self-injuring adolescent girls.

Rates of self-inflicted injury among adolescents have risen in recent years, yet much remains to be learned about the pathophysiology of such conduct. Self-injuring adolescents report high levels of both impulsivity and depression behaviorally. Aberrant neural responding to incentives, particularly in striatal and prefrontal regions, is observed among both impulsive and depressed adolescents, and may mark common vulnerability to symptoms of anhedonia, irritability, and low positive affectivity. To date, however, no studies have examined associations between central nervous system reward responding and self-injury. In the current study, self-injuring (n = 19) and control (n = 19) adolescent females, ages 13-19 years, participated in a monetary incentive delay task in which rewards were obtained on some trials and losses were incurred on others. Consistent with previous findings from impulsive and depressed samples, self-injuring adolescents exhibited less activation in both striatal and orbitofrontal cortex regions during anticipation of reward than did controls. Self-injuring adolescents also exhibited reduced bilateral amygdala activation during reward anticipation. Although few studies to date have examined amygdala activity during reward tasks, such findings are common among adults with mood disorders and borderline personality disorder. Implications for neural models of impulsivity, depression, heterotypic comorbidity, and development of both self-injury and borderline personality traits are discussed.

Reward dysfunction in major depression: multimodal neuroimaging evidence for refining the melancholic phenotype.

Reward dysfunction is thought to play a core role in the pathophysiology of major depressive disorder (MDD). Event-related potential (ERP) and functional magnetic resonance imaging (fMRI) studies have identified reward processing deficits in MDD, but these methods have yet to be applied together in a single MDD sample. We utilized multimodal neuroimaging evidence to examine reward dysfunction in MDD. Further, we explored how neurobiological reward dysfunction would map onto subtypes of MDD. The feedback negativity (FN), an ERP index of reward evaluation, was recorded in 34 unmedicated depressed individuals and 42 never-depressed controls during a laboratory gambling task. Ventral striatal (VS) activation to reward was recorded in a separate fMRI session, using an identical task, among a subgroup of 24 depressed individuals and a comparison group of 18 non-depressed controls. FN amplitude was blunted in MDD. This effect was driven by a MDD subgroup characterized by impaired mood reactivity to positive events, a core feature of melancholic MDD. A similar pattern was observed for VS activation, which was also blunted among the MDD subgroup with impaired mood reactivity. Neither FN amplitude nor VS activation was related to the full, DSM-defined melancholic or atypical MDD subtypes. Across the MDD sample, FN amplitude and VS activation were correlated, indicating convergence across methods. These results indicate that not all MDD is characterized by reward dysfunction, and that there is meaningful heterogeneity in reward processing within MDD. The current study offers neurobiological evidence that impaired mood reactivity is a key phenotypic distinction for subtyping MDD, and further suggests that the existing melancholic phenotype may require further refinement.

Neuroanatomical correlates of heterotypic comorbidity in externalizing male adolescents.

Children and adolescents with externalizing behavior disorders including attention-deficit/hyperactivity disorder (ADHD) and conduct disorder (CD) often present with symptoms of comorbid internalizing psychopathology. However, few studies have examined central nervous system correlates of such comorbidity. We evaluated interactions between externalizing and internalizing symptoms in predicting mesolimbic, septo-hippocampal, and anterior cingulate volumes among 12- to 16-year-old boys with either ADHD, ADHD and CD, or no psychiatric condition (n = 35). These regions were chosen given established links to trait impulsivity, trait anxiety, and behavior regulation, respectively. Collapsed across groups, Externalizing × Internalizing symptom interactions accounted for individual differences in gray matter densities in each region. Externalizing youth with comorbid internalizing symptoms showed smaller reductions in gray matter than individuals with externalizing psychopathology alone. These results suggest that internalizing symptoms are associated with less severe structural compromises in brain regions subserving motivation and behavior regulation among externalizing boys.

Effectiveness of KarXT (xanomeline-trospium) for cognitive impairment in schizophrenia: post hoc analyses from a randomised, double-blind, placebo-controlled phase 2 study.

The muscarinic receptor agonist xanomeline improved cognition in phase 2 trials in Alzheimer's disease and schizophrenia. We present data on the effect of KarXT (xanomeline-trospium) on cognition in schizophrenia from the 5-week, randomised, double-blind, placebo-controlled EMERGENT-1 trial (NCT03697252). Analyses included 125 patients with computerised Cogstate Brief Battery (CBB) subtest scores at baseline and endpoint. A post hoc subgroup analysis evaluated the effects of KarXT on cognitive performance in patients with or without clinically meaningful cognitive impairment at baseline, and a separate outlier analysis excluded patients with excessive intraindividual variability (IIV) across cognitive subdomains. ANCOVA models assessed treatment effects for completers and impairment subgroups, with or without removal of outliers. Sample-wide, cognitive improvement was numerically but not statistically greater with KarXT (n = 60) than placebo (n = 65), p = 0.16. However, post hoc analyses showed 65 patients did not exhibit clinically meaningful cognitive impairment at baseline, while eight patients had implausibly high IIV at one or both timepoints. Significant treatment effects were observed after removing outliers (KarXT n = 54, placebo n = 63; p = 0.04). Despite the small sample size, a robust (d = 0.50) and significant effect was observed among patients with cognitive impairment (KarXT n = 23, placebo n = 37; p = 0.03). These effects did not appear to be related to improvement in PANSS total scores (linear regression, R2 = 0.03). Collectively, these findings suggest that KarXT may have a separable and meaningful impact on cognition, particularly among patients with cognitive impairment.

Ecological momentary assessment as a measurement tool in depression trials.

We used ecological momentary assessment (EMA) to track symptoms during a clinical trial. Thirty-six participants with major depressive disorder (MDD) and MADRS scores ≥20 were enrolled in a nonrandomized 6-week open-label trial of commercially available antidepressants. Twice daily, a mobile device prompted participants to self-report the 6 items of the HamD6 sub-scale derived from the Hamilton rating scale for depression (HamD17). Morning EMA reports asked "how do you feel now" whereas evening reports gathered a full-day impression. Clinicians who were blinded to the EMA data rated the MADRS, HamD17 and HamD6 at screen, baseline and weeks 2,4, and 6. Hierarchical linear modeling (HLM) examined the course of the EMA assessments and convergence between EMA scores and clinician ratings. HLM analyses revealed strong correlations between AM and PM EMA derived HamD6 scores and revealed significant improvements over time. EMA improvements were significantly correlated with the clinician rated HamD6 scores at endpoint and predicted clinician rated HamD6 score changes from baseline to endpoint (p < .001). There was a large correlation between EMA and clinician derived HamD6 scores at each in-person assessment after baseline. Treatment response defined by EMA matched the clinician rated HamD6 treatment responses in 33 of 36 cases (91.7%). EMA derived symptom scores appear to be efficient and valid measures to track daily symptomatic change in clinical trials and may provide more accurate measures of symptom severity than the episodic "snapshots" that are currently used as clinical outcomes. These findings support further investigation of EMA for assessment in clinical trials.

Remote Digital Measurement of Facial and Vocal Markers of Major Depressive Disorder Severity and Treatment Response: A Pilot Study.

Objectives: Multiple machine learning-based visual and auditory digital markers have demonstrated associations between major depressive disorder (MDD) status and severity. The current study examines if such measurements can quantify response to antidepressant treatment (ADT) with selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine uptake inhibitors (SNRIs). Methods: Visual and auditory markers were acquired through an automated smartphone task that measures facial, vocal, and head movement characteristics across 4 weeks of treatment (with time points at baseline, 2 weeks, and 4 weeks) on ADT (n = 18). MDD diagnosis was confirmed using the Mini-International Neuropsychiatric Interview (MINI), and the Montgomery-Åsberg Depression Rating Scale (MADRS) was collected concordantly to assess changes in MDD severity. Results: Patient responses to ADT demonstrated clinically and statistically significant changes in the MADRS [F (2, 34) = 51.62, p < 0.0001]. Additionally, patients demonstrated significant increases in multiple digital markers including facial expressivity, head movement, and amount of speech. Finally, patients demonstrated significantly decreased frequency of fear and anger facial expressions. Conclusion: Digital markers associated with MDD demonstrate validity as measures of treatment response.

Stepped Treatment for Attention-Deficit/Hyperactivity Disorder and Aggressive Behavior: A Randomized, Controlled Trial of Adjunctive Risperidone, Divalproex Sodium, or Placebo After Stimulant Medication Optimization.

OBJECTIVE: Stimulant medications are the most prevalent first-line pharmacotherapy for attention-deficit/hyperactivity disorder, but children with aggressive behavior often receive multiagent treatment. There is sparse evidence for the benefits of adjunctive medications when stimulant monotherapy provides inadequate benefit for aggressive behavior, yet the adverse effects of common adjuncts are well established. This study compared the efficacy in reducing aggressive behavior of risperidone (RISP), divalproex sodium (DVPX), and placebo (PBO) added to stimulant medication among childrenwhose symptoms persisted after individually optimized stimulant treatment. METHOD: This trial enrolled 6- to 12-year-old with attention-deficit/hyperactivity disorder, a disruptive disorder, significant aggressive behavior, and prior stimulant treatment. Open, systematically titrated stimulant treatment identified patients with inadequate reductions in aggressive behavior, who were then randomly assigned to receive adjunctive RISP, DVPX, or PBO under double-blinded conditions for 8 weeks. Family-based behavioral treatment was offered throughout the trial. The primary outcome was the parent-completed Retrospective Modified Overt Aggression Scale. RESULTS: Participants included 175 children (mean [SD] age 9.48 [2.04] years, 19% female). Of participants, 151 completed the stimulant optimization phase, with aggression remitting among 96 (63%), and 45 were randomly assigned to adjunctive treatment groups. The adjunctive RISP group showed greater reductions in aggression ratings than the PBO group (least squares means difference [ΔLSM], -2.33; 95% CI, -3.83 to -0.82; effect size [ES], -1.32), as did the DVPX group (ΔLSM, -1.60; 95% CI, -3.18 to -0.03; ES, -0.91). Mean standardized body mass index scores increased more among RISP-treated participants than participants receiving PBO (ΔLSM, 1.54; 95% CI, 0.68 to 2.40; ES, 0.58). CONCLUSION: High response rate during the trial's open stimulant optimization phase suggests that rigorous titration of stimulant medication and concurrent behavioral therapy may avert the need for additional medications. Among nonremitters, RISP and DVPX were efficacious adjunctive treatments, although RISP was associated with weight gain. CLINICAL TRIAL REGISTRATION INFORMATION: Effectiveness of Combined Medication Treatment for Aggression in Children With Attention Deficit With Hyperactivity Disorder (The SPICY Study); https://www.clinicaltrials.gov; NCT00794625.

Consistency checks to improve measurement with the Montgomery-Asberg Depression Rating Scale (MADRS).

International Society for CNS Clinical Trials and Methodology convened an expert Working Group that assembled consistency/inconsistency flags for the Montgomery-Asberg Depression Rating Scale (MADRS). Twenty-two flags were identified. Seven flags are believed to be strong flags that suggest that a thorough review of rating is warranted. The flags were applied to assessments derived from the NEWMEDS data repository. Almost 65% of ratings had at least one inconsistency flag raised and 22% had two or more. Application of flags to clinical ratings may improve reliability of ratings and validity of trials.

Ventral Striatal Function Interacts With Positive and Negative Life Events to Predict Concurrent Youth Depressive Symptoms.

BACKGROUND: Life events and reward-system functioning contribute to resilience and risk for depression. However, interactions between life events and neural responses to reward and loss have not been previously investigated in relation to depression symptoms in child and adolescent populations. METHODS: An unselected sample (N = 130) of 8- to 14-year-old girls (mean = 12.6 years) completed the Child Depression Inventory and a functional magnetic resonance imaging guessing task in which they won or lost money on each trial. Parents completed a measure of life events experienced by the child. Life events were separated by positive versus negative and whether they were likely related or unrelated to the daughter's behavior (i.e., dependent vs. independent, respectively). Multiple regressions tested whether the interaction between ventral striatal (VS) response to wins or losses and recent life events were associated with child-reported depressive symptoms. RESULTS: A greater number of dependent positive life events related to decreased total depression symptoms when VS response to wins was robust. Conversely, a greater number of independent negative life events related to increased negative mood depression symptoms when VS response to losses was robust; this relationship was in the opposite direction when VS response to loss was low. CONCLUSIONS: VS response to reward and loss were independent moderators of the relationship between recent life events (positive and negative, respectively) and depressive symptoms. Findings suggest that targeting neural responses (i.e., increasing responses to winning or decreasing responses to losing) may be important for both improving resilience and reducing risk in different environmental contexts.

Internal Consistency of Functional Magnetic Resonance Imaging and Electroencephalography Measures of Reward in Late Childhood and Early Adolescence.

BACKGROUND: Abnormal neural response to reward is increasingly thought to function as a biological correlate of emerging psychopathology during adolescence. However, this view assumes such responses have good psychometric properties-especially internal consistency-an assumption that is rarely tested. METHODS: Internal consistency (i.e., spilt-half reliability) was calculated for event-related potentials (ERPs) and Blood Oxygen Level Dependent (BOLD) responses to monetary gain and loss feedback from the same sample of 8-14 year-old females (n=177). Internal consistency for ERPs (i.e. feedback negativity) and BOLD responses within the ventral striatum and medial/lateral prefrontal cortex to gain, loss, difference scores (gain-loss), and residual scores (gain controlling for loss) were compared. Moderation analyses were conducted to investigate whether internal consistency differed by age. RESULTS: ERP and BOLD responses to gain and loss feedback showed high internal consistency in all regions (Spearman Brown Coefficients (SB) ≥ 0.70). When considering difference and residual scores, however, responses showed lower internal consistency (SBs ≤ 0.50), with particularly low internal consistency for subtraction-based scores (SB ≤ 0.36). Age was not a significant moderator of split-half relationships, indicating similar internal consistency across late childhood to early adolescence. CONCLUSIONS: Within the same subjects, high internal consistency was observed for both ERP and fMRI measures of response to gains and losses, which did not vary as a function of age. Moreover, excellent psychometric properties were evident even within the first half of the experiment. Difference scores were characterized by lower internal consistency, although regression-based approaches outperformed subtraction-based difference scores.

Prevalence and Treatment Outcomes of Persistent Negative Mood Among Children with Attention-Deficit/Hyperactivity Disorder and Aggressive Behavior.

OBJECTIVE: Diagnostic criteria for disruptive mood dysregulation disorder (DMDD) require 1) periodic rageful outbursts and 2) disturbed mood (anger or irritability) that persists most of the time in between outbursts. Stimulant monotherapy, methodically titrated, often culminates in remission of severe aggressive behavior, but it is unclear whether those with persistent mood symptoms benefit less.This study examined the association between the presence of persistent mood disturbances and treatment outcomes among children with attention-deficit/hyperactivity disorder (ADHD) and periodic aggressive, rageful outbursts. METHODS: Within a cohort of children with ADHD and aggressive behavior (n = 156), the prevalence of persistent mood symptoms was evaluated at baseline and after completion of a treatment protocol that provided stimulant monotherapy and family-based behavioral treatment (duration mean [SD] = 70.04 [37.83] days). The relationship of persistent mood symptoms on posttreatment aggressive behavior was assessed, as well as changes in mood symptoms. RESULTS: Aggressive behavior and periodic rageful outbursts remitted among 51% of the participants. Persistent mood symptoms at baseline did not affect the odds that aggressive behavior would remit during treatment. Reductions in symptoms of sustained mood disturbance accompanied reductions in periodic outbursts. Children who at baseline had high irritability but low depression ratings showed elevated aggression scores at baseline and after treatment; however, they still displayed large reductions in aggression. CONCLUSIONS: Among aggressive children with ADHD, aggressive behaviors are just as likely to decrease following stimulant monotherapy and behavioral treatment among those with sustained mood symptoms and those without. Improvements in mood problems are evident as well. Therefore, the abnormalities in persistent mood described by DMDD's criteria do not contraindicate stimulant therapy as initial treatment among those with comorbid ADHD. Rather, substantial improvements may be anticipated, and remission of both behavioral and mood symptoms seems achievable for a proportion of patients. TRIAL REGISTRATION: ClinicalTrials.gov (U.S.); IDs: NCT00228046 and NCT00794625; www.clinicaltrials.gov.

Intrusions in episodic recall: age differences in editing of overt responses.

Two experiments compared episodic word-list recall of young and older adults. In Experiment 1, using standard free-recall procedures, older adults recalled significantly fewer correct items and made significantly more intrusions (recall of items that had not appeared on the target list) than younger adults. In Experiment 2, we introduced a new method, called externalized free recall, in which participants were asked to recall any items that came to mind during the recall period but to indicate with an immediate key press those items they could identify as intrusions. Both age groups generated a large number of intrusions, but older adults were significantly less likely than young adults to identify these as nonlist items. Results suggest that an editing deficit may be a contributor to age differences in episodic recall and that externalized free recall may be a useful tool for testing computationally explicit models of episodic recall.

Test-retest reliability of amygdala response to emotional faces.

In the current study, we evaluated the test-retest reliability of amygdala response using an emotional face-matching task that has been widely used to examine pathophysiology and treatment mechanisms in psychiatric populations. Activation within the fusiform face area (FFA) was also examined. Twenty-seven healthy volunteers completed a variation of the face-matching paradigm developed by Hariri et al. (2000) at two time points approximately 90 days apart. Estimates of test-retest reliability of amygdala response to fearful faces were moderate, whereas angry and happy faces showed poor reliability. Test-retest reliability of the FFA was moderate to strong, regardless of facial affect. Collectively, these findings indicate that the reliability of the BOLD MR signal in the amygdala varies substantially by facial affect. Efforts to improve measurement precision, enlarge sample sizes, or increase the number of assessment occasions seem warranted.

Callous-unemotional traits, proactive aggression, and treatment outcomes of aggressive children with attention-deficit/hyperactivity disorder.

OBJECTIVE: Stimulant treatment improves impulse control among children with attention-deficit/hyperactivity disorder (ADHD). Decreased aggression often accompanies stimulant pharmacotherapy, suggesting that impulsiveness is integral to aggressive behavior in these children. However, children with high callous-unemotional (CU) traits and proactive aggression may benefit less from ADHD pharmacotherapy, because their aggressive behavior seems more purposeful and deliberate. This study's objective was to determine whether pretreatment CU traits and proactive aggression affect treatment outcomes among aggressive children with ADHD receiving stimulant monotherapy. METHOD: We implemented a stimulant optimization protocol with 160 children 6 to 13 years of age (mean [SD] age of 9.31 [2.02] years; 78.75% male) with ADHD, oppositional defiant or conduct disorder, and significant aggressive behavior. Family-focused behavioral intervention was provided concurrently. The primary outcome was the Retrospective Modified Overt Aggression Scale. The Antisocial Process Screening Device and the Aggression Scale, also completed by parents, measured CU traits and proactive aggression, respectively. Analyses examined moderating effects of CU traits and proactive aggression on outcomes. RESULTS: In all, 82 children (51%) experienced remission of aggressive behavior. Neither CU traits nor proactive aggression predicted remission (CU traits: odds ratio [OR] = 0.94, 95% CI = 0.80-1.11; proactive aggression, OR = 1.05, 95% CI = 0.86-1.29). Children whose overall aggression remitted showed decreases in CU traits (effect size = -0.379, 95% CI = -0.60 to -0.16) and proactive aggression (effect size = -0.463, 95% CI = -0.69 to -0.23). CONCLUSIONS: Findings suggest that pretreatment CU traits and proactive aggression do not forecast worse outcomes for aggressive children with ADHD receiving optimized stimulant pharmacotherapy. With such treatment, CU traits and proactive aggression may decline alongside other behavioral improvements. Clinical trial registration information--Medication Strategies for Treating Aggressive Behavior in Youth With Attention Deficit Hyperactivity Disorder; http://clinicaltrials.gov/; NCT00228046; and Effectiveness of Combined Medication Treatment for Aggression in Children With Attention Deficit With Hyperactivity Disorder (The SPICY Study); http://clinicaltrials.gov/; NCT00794625.

Tonic immobility in childhood sexual abuse survivors and its relationship to posttraumatic stress symptomatology.

Past research has shown that 37% to 52% of sexual assault survivors report experiencing a set of peritraumatic responses, which include gross motor inhibition, analgesia, and fixed or unfocused staring. This response set closely resembles a set of unconditioned responses, collectively known as Tonic Immobility (TI). This study examined TI among childhood sexual abuse (CSA) survivors and its relation to PTSD symptomatology. Participants were 131 female college undergraduates who completed questionnaires assessing sexual abuse history, TI, and PTSD symptom severity. Results showed that TI partially mediated the relation between peritraumatic fear and overall PTSD symptom severity and completely mediated the relation between fear and the PTSD reexperiencing symptoms. Although peritraumatic fear is associated with TI, the mediation findings provide evidence for the notion that these responses are separate from one another. These results suggest that TI during CSA may play an important role in the subsequent PTSD symptomatology in adulthood.