Colin L. Sauder

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.

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.

Disrupted Effective Connectivity Between the Medial Frontal Cortex and the Caudate in Adolescent Boys With Externalizing Behavior Disorders

Studies addressing the neural correlates of criminal behavior have focused primarily on the prefrontal cortex and the amygdala. However, few studies have examined dopaminergic inputs to these or other brain regions, despite the fact that central dopamine (DA) dysfunction is associated with both trait impulsivity and novelty seeking. Given long-standing associations between both of these personality traits and externalizing psychopathology, the authors examined effective connectivity between the caudate nucleus and the anterior cingulate cortex, two areas that rely on DA input to facilitate associative learning and goal directed behavior. Dysfunction in top-down and bottom-up processing within this dopaminergically mediated frontostriatal circuit may be an important biological vulnerability that increases one’s likelihood of engaging in delinquent and criminal behavior. When compared with controls, reduced effective connectivity between these regions among adolescents with externalizing psychopathology was found, suggesting deficiencies in frontostriatal circuitry.

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 studys 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.

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.

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.

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 DMDDs 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.