Neuroimaging Approaches to Understanding Youth Antisocial Behavior

Neuroimaging Approaches to Understanding Youth Antisocial Behavior R Waller, L Murray, HL Dotterer, and LW Hyde, University of Michigan, Ann Arbor, MI, USA ã 2015 Elsevier Inc. All rights reserved.

Glossary Amygdala An almond-shaped group of nuclei located subcortically in the medial temporal lobes of the brain. The amygdala is involved in many cognitive and emotional processes, including emotional learning, fear response and classical conditioning, memory consolidation, and general arousal (Cardinal, Parkinson, Hall, & Everitt, 2002; LeDoux, 2000). Anterior cingulate cortex (ACC) The ACC is implicated in error detection and correction and regulation of cognitive and emotional processing (Botvinick, Cohen, & Carter, 2004; Devinsky, Morrell, & Vogt, 1995) and is often divided into both ventral ‘affect’ and anterior/rostral ‘cognitive’ components (Bush, Lee, & Posner, 2000). Antisocial behavior A broad term encompassing a range of behaviors that are harmful, including rule breaking, aggression, illegal activities, and risky behaviors (e.g., drug use). Attention-deficit/hyperactivity disorder (ADHD) A behavioral disorder defined by the DSM-5 as comprising symptoms of inattention, hyperactivity, and impulsivity. Callous–unemotional (CU) traits CU traits comprise behaviors such as shallow affect and lack of empathy and represent a downward extension of the affective and interpersonal components of adult psychopathy (Burke, Loeber, & Lahey, 2007). The presence of CU traits has recently been added as a specifier (subgrouping scheme) in the diagnosis of AB disorders in the DSM-5, categorized as a ‘limited prosocial emotions’ (Frick & Moffitt, 2010). Caudate A portion of the striatum and basal ganglia, located medially in the brain, that is involved in voluntary movement, goal-directed action, and learning and memory, among many other functions (Delgado, 2007). Conduct disorder A behavioral disorder in children and adolescents defined by the DSM-5 as encompassing antisocial and rule-breaking behaviors such as aggression, destruction of property, and lying. Delinquency The legal definition of antisocial behavior in youth that refers to behavior that breaks the law and is self-destructive or harmful to society. Diagnostic and statistical manual of mental disorders version 5 (DSM-5) A diagnostic manual published by the American Psychiatric Association (APA) in 2013 that contains a listing of mental, behavioral, and psychiatric disorders and their symptoms including many listed here such as conduct disorder and ADHD. Diffusion tension imaging (DTI) A neuroimaging technique that uses magnetic resonance imaging to measure the diffusion of water molecules in brain tissue. This technique provides a measure of the microstructure of white matter connections and integrity of white matter tracts in the brain (Assaf & Pasternak, 2008).

Brain Mapping: An Encyclopedic Reference

Dorsolateral prefrontal cortex (dlPFC) The dorsal and lateral portions of the prefrontal cortex. The dlPFC has been implicated in a variety of functions, including executive functioning tasks such as working memory, cognitive flexibility, motor planning, and decision making (Cardinal et al., 2002; Fuster, 2001; Kringelbach, 2005; Wood & Grafman, 2003). Executive functioning A broad term that encompasses a number of higher-order cognitive functions including attention, cognitive control, working memory, inhibition, flexibility, and planning. Fractional anisotropy (FA) FA is the most commonly used measure in DTI. Fractional anisotropy provides a map of the level of diffusion of water molecules that occurs parallel and perpendicular to cell membranes in the brain and has been interpreted as a measure of white matter tract integrity (Assaf & Pasternak, 2008). Functional connectivity An estimate of the temporal correlation of activity in spatially distinct regions of the brain during fMRI (Kelly & Castellanos, 2014). Functional magnetic resonance imaging (fMRI) A technique used to measure and image brain activity that uses alternating magnetic fields to detect activity-related changes in blood flow in the brain. fMRI measures the changing magnetic properties of the blood using the blood oxygenation level-dependent (BOLD) signal. By measuring changes in blood flow, the BOLD signal provides an indirect estimate of the neural activity in a region of the brain. Gray matter The part of the brain and broader central nervous system that consists of the cell bodies, dendrites, and unmyelinated axons of the brain’s neurons. The gray matter contains most of the brain’s neuronal cell bodies. Insula A brain region located deep within the lateral sulcus. The insula receives inputs from sensory association areas and socioemotional regions and has many functions including interoception, the representation of pain, the integration of sensory and emotional information, and conscious feelings (Craig, 2002; Decety & Jackson, 2006; Naqvi & Bechara, 2009). Limbic system A system of cortical and subcortical structures in the ventromedial temporal and frontal lobes, broadly responsible for processing socioemotional information and motivation. While the specific structures that comprise the limbic system have been debated (LeDoux, 2000), the limbic system includes a number of regions of the brain associated with socioemotional processing and motivation such as the amygdala, hippocampus, and parahippocampal gyrus (Sokolowski & Corbin, 2012). Orbitofrontal cortex (OFC) The ventral and medial portion of the prefrontal cortex that has been implicated in sensory integration, representing affective values of reinforcers, decision making, and executive function

http://dx.doi.org/10.1016/B978-0-12-397025-1.00125-1

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INTRODUCTION TO CLINICAL BRAIN MAPPING | Neuroimaging Approaches to Understanding Youth Antisocial Behavior

(Cardinal et al., 2002; Forbes & Grafman, 2010; Fuster, 2001; Kringelbach, 2005). Person-centered An approach to data analysis that focuses on grouping individuals into categories based on their similarity to each other on a given variable or variables. Many neuropsychiatric studies are person-centered in that they compare a group of patients to controls. Prefrontal cortex (PFC) The anterior part of the frontal lobes of the brain. The prefrontal cortex has been implicated in a variety of tasks including those involved in cognitive and executive functioning and encompasses many distinct regions defined here including the dlPFC and OFC, among other subdivisions. Proactive aggression Planned, goal-directed, or instrumental forms of aggressive behavior that are typically accompanied by low arousal. Psychopathy A personality disorder characterized by affective and interpersonal deficits such as a lack of empathy, manipulation, deceitfulness, narcissism, superficial charm, and antisocial behavior and an impulsive and parasitic lifestyle. Reactive aggression A form of unplanned, impulsive, aggressive behavior that occurs in response to a perceived threat to the individual.

Antisocial Behavior Antisocial behavior (AB) refers to a range of behaviors, including rule breaking, aggression, and other dangerous activities, which are harmful and costly to individuals, communities, and the society as a whole. Beyond criminal outcomes, youth with AB are at risk of developing a range of other adverse mental and physical health problems in adulthood, including substance use and depression (see Odgers et al. (2008)). AB also represents the main reason for youth referral to mental health treatment (Kazdin, Whitley, & Marciano, 2006). Thus, research employing brain imaging techniques aims to identify neural correlates of AB to improve understanding of the etiology of these behaviors and inform more effective and personalized treatments.

Subtypes of AB AB is a heterogeneous term referring to behaviors that differ in timing of onset, cause, and course. Research has focused on ways to identify subgroups of youth that are more homogenous in behavior or etiology with focus on two subtyping approaches that are prominent within the DSM-5: (1) earlyversus late-onset AB and (2) presence or absence of callous– unemotional (CU) traits.

Age of onset Early-onset AB (before age 10) is associated with greater early risk and worse long-term outcomes such as early neurocognitive deficits, harsh parenting, and difficult temperament, as well as a more chronic and escalating trajectory of AB over time (Moffitt, Caspi, Dickson, Silva, & Stanton, 1996).

Striatum A component of the basal ganglia that contains the caudate, putamen, olfactory tubercle, and nucleus accumbens. The striatum receives input from many socioemotional processing regions including the amygdala, hippocampus, thalamus, OFC, and insula and also receives dense projections of the neurotransmitter dopamine from the midbrain. The ventral portion of the striatum (i.e., the nucleus accumbens) has been linked to reward and motivation, particularly reward wanting and anticipation (Berridge & Robinson, 2003; Haber, 2011). Structural magnetic resonance imaging (sMRI) A magnetic resonance imaging technique that uses magnetic fields to measure composition of tissue that provides a measure of the structural anatomy of the brain. Uncinate fasciculus The uncinate fasciculus is a white matter tract that connects limbic structures such as the amygdala and hippocampus to the frontal lobe structures such as the OFC (Von Der Heide, Skipper, Klobusicky, & Olson, 2013). White matter A part of the brain and broader central nervous system that consists mainly of glial cells and the myelinated axons. Thus, the white matter is composed largely of tissue that transmits signals across the brain.

In contrast, adolescent-onset AB is linked to deviant peer affiliation (Dishion, Patterson, Stoolmiller, & Skinner, 1991) but fewer family risks and a less severe trajectory of AB, though still with greater impairment in adulthood compared to non-AB youth (Moffitt et al., 1996).

CU Traits A newer approach focuses on whether antisocial youth display CU traits, indexed by diminished empathy, affect, and a lack of guilt. CU traits identify antisocial youth with a more severe, chronic, and heritable AB (Frick, Ray, Thornton, & Kahn, 2014).

Functional Neuroimaging Studies Overview Behavioral and psychophysiological research has demonstrated that youth with AB exhibit a range of behavioral impairments that have, in turn, guided the targets of neuroimaging research. For example, youth with AB demonstrate impairments in affective processing (e.g., poor recognition of emotional faces and reduced empathic concern for others; e.g., Marsh & Blair, 2008; Shirtcliff et al., 2009) and distinct physiological differences in response to startle and affective tasks (e.g., Gao, Raine, Venables, Dawson, & Mednick, 2010; Raine, 2002; Scarpa & Raine, 2006), which has led researchers to hypothesize that deficits in the limbic system are important in the etiology of youth AB, particularly among youth with high CU traits. In addition, youth with AB exhibit generally disinhibited behavior (e.g., Lahey, Waldman, & McBurnett, 1999) and impairments in cognitive functioning to specific tasks (e.g., poor behavioral inhibition and cognitive control) that have implicated dysfunction in

INTRODUCTION TO CLINICAL BRAIN MAPPING | Neuroimaging Approaches to Understanding Youth Antisocial Behavior

frontocortical structures (Blair, 2013). Finally, antisocial youth show oversensitivity to reward, including difficulties in switching their behavior once a previously rewarded response is punished, which has further implicated reward-related neural regions as important to the development of AB (Byrd, Loeber, & Pardini, 2014) Thus, behavioral and psychophysiological studies highlight that neuroimaging studies of youth AB should focus on brain areas implicated in affective processing, cognitive control, and reward.

Amygdala The amygdala is as a primary focus for neuroimaging studies examining youth AB for several reasons. First, youth AB is characterized by impairments that are linked to amygdala functioning, including deficits in emotional learning and fear response (Glenn & Raine 2008). Second, children and adults with AB display psychophysiological differences that are similar to patients with amygdala lesions (Blair, Peschardt, Budhani, Mitchell, & Pine, 2006; Gao et al., 2010). Finally, neuroimaging studies of antisocial adults have demonstrated that differences in amygdala reactivity to emotional paradigms are correlated with AB (Kiehl, 2006). Consistent with these studies, recent functional MRI (fMRI) studies have shown that antisocial youth display reduced amygdala reactivity to negative emotional stimuli (e.g., Jones, Laurens, Herba, Gareth, & Viding, 2009; Kalnin et al., 2011; Passamonti et al., 2010). However, in other studies, youth with AB have been shown to display increased amygdala reactivity to negative emotional stimuli, including animations of other people experiencing pain (Decety, Michalska, Akitsuki, & Lahey, 2009) or comparing amygdala reactivity to negative versus neutral International Affective Picture System (IAPS) pictures (Herpertz et al., 2008). While this literature appears somewhat mixed, early studies may have ignored the importance of subgroups within samples of antisocial youth. Indeed, one line of work that has investigated the different directions of findings has focused on the presence or absence of CU traits. Antisocial youth with high CU traits show hyporesponsivity, particularly to fearful faces (i.e., reduced amygdala reactivity), appear underaroused by emotion or threat, exhibit both proactive aggression and reactive aggression, and display reduced empathy (e.g., Lozier, Cardinale, VanMeter, & Marsh, 2014; Viding et al., 2012). In contrast, antisocial youth with low CU traits appear hypersensitive to emotional faces (i.e., greater amygdala reactivity), demonstrate emotional dysregulation to threat, and display primarily reactive aggression (e.g., Sebastian et al., 2014; Viding et al., 2012). Thus, there appears to be utility for neuroimaging studies to subgroup antisocial youth according to presence of CU traits, which converges with their behavioral characteristics and may explain discrepant findings. Beyond explaining discrepant findings, emerging research is beginning to explore mechanisms to elucidate why youth high on CU traits show decreased amygdala reactivity to negative emotional faces with studies suggesting that the level of attentional load required by fMRI tasks (Baskin-Sommers, Curtin, & Newman, 2011; White et al., 2012) and youth’s attention to the eyes in face-processing tasks (e.g., Dadds, Jambrak, Pasalich, Hawes, & Brennan, 2011; Han, Alders, Greening, Neufeld, & Mitchell, 2012) may

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drive differences in findings for amygdala reactivity for antisocial youth with high versus low levels of CU traits.

Orbitofrontal Cortex The orbitofrontal cortex (OFC) remains a prime candidate for understanding youth AB because it is implicated in representing the affective values of reinforcers, decision making, and executive function (Damasio, 1994; Kringelbach, 2005), which are tasks that antisocial youth exhibit difficulties on (Blair et al., 2006). In particular, the OFC is theorized to integrate signals and modulate the activity of other brain regions, including the amygdala, which may be a key mechanism in trying to understand the development of AB (Blair, 2004). In fMRI studies, antisocial youth have been shown to demonstrate reduced OFC reactivity, including during decisionmaking tasks in the context of reward (Crowley et al., 2010) and rewarded continuous performance tasks (Rubia, Smith, et al., 2009) and particularly in those with high CU traits (Finger et al., 2011). Further, decreased functional connectivity has been reported between the amygdala and ventromedial prefrontal cortex (vmPFC) in response to fearful faces among antisocial youth (Marsh et al., 2008). Overall, these findings are consistent with the notion that dysfunction of OFC is related to the behavioral deficits seen in youth AB, including their poor representation of the expected value of outcomes (Blair, 2004, 2013; Finger et al., 2011).

Anterior Cingulate Cortex Antisocial youth demonstrate deficits in learning, detecting errors, and reward processing (Fairchild et al., 2009), implicating the anterior cingulate cortex (ACC) because of its role in networks key to error detection and avoidance learning. In general, studies of antisocial youth have reported decreased activation in the ACC during tasks assessing the processing of negative pictures (Sterzer, Stadler, Krebs, Kleinschmidt, & Poustka, 2005), attention (Rubia, Smith, et al., 2009), emotional words (Kalnin et al., 2011), and after both nonrewarded (Gatzke-Kopp et al., 2009) and rewarded trials (Crowley et al., 2010). Thus, the ACC appears disrupted in youth AB during cognitive (i.e., error monitoring and attention) and affective tasks (i.e., negative pictures and emotional words). However, empirical evidence supports separable dorsal ‘cognitive’ and rostral–ventral ‘affective’ divisions of the ACC (Bush et al., 2000), yet few studies of youth AB have distinguished between these subregions.

Caudate and Ventral Striatum These regions are of particular interest because of impairments displayed by antisocial youth in stimulus–reinforcement and response–outcome learning (Gatzke-Kopp et al., 2009). Youth with AB and CU traits are hypothesized to show reduced recruitment of the regions that guide behavioral choices based on expected value information (see Blair (2013)). In support of this notion, youth with AB showed continued activation of the caudate when previously rewarded behavior was no longer rewarded. In contrast, control youth showed a shift to decreased caudate activation and increased ACC activation (Gatzke-Kopp

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INTRODUCTION TO CLINICAL BRAIN MAPPING | Neuroimaging Approaches to Understanding Youth Antisocial Behavior

et al., 2009). This finding suggests continued reward activation rather than a switch to error monitoring in antisocial youth, consistent with behavioral studies demonstrating their tendency to continue to respond in ways that were previously, but no longer, rewarded (Fonesca & Yule, 1995). Studies have also demonstrated increased activation of the caudate among antisocial youth viewing animations of others in pain (Decety et al., 2009), while other studies have reported decreased caudate activation among youth with AB during early-stimulus– reinforcement exposures (Finger et al., 2011) and during vignettes portraying interpersonal interactions (Sharp, Burton, & Ha, 2011), suggesting that the direction of findings may differ according to the nature of the task (i.e., timing of stimulus presentation or affective component of stimulus). Finally, the ventral striatum has a major role in processing the motivational salience of stimuli (Berridge & Robinson, 2003). Thus, the ventral striatum is likely to be important for understanding youth AB, which is characterized by deficits in reward-related behavior, including the pursuit of behaviors with high risk and reward. Work with adult populations has linked ventral striatum reactivity to AB, particularly in relation to the anticipation of reward (e.g., increased activity; Buckholtz et al., 2010) and affective memory (reduced functioning; Kiehl et al., 2001), and one study that found increased reactivity of the ventral striatum when antisocial youth viewed animations of others in pain (Decety et al., 2009).

Other Regions Beyond the areas reviewed in the preceding text, studies are beginning to link the dorsolateral prefrontal cortex (dlPFC) to youth AB. These emerging findings are not surprising given well-documented deficits in decision making and executive functioning/working memory among antisocial youth and the role of the dlPFC in these respective processes (e.g., Naqvi & Bechara, 2009; Wood & Grafman, 2003). In fMRI studies, youth with AB exhibited decreased activation in the dlPFC when viewing animations of others in pain (Decety et al., 2009) and during tasks that assessed attention (e.g., Fairchild et al., 2013; Rubia, Halari, et al., 2009), supporting the notion that dysfunction in this region may underpin behavioral deficits associated with youth AB. Finally, there has been a mixed pattern of findings for implicating the insula in AB, with one study reporting decreased activation during an attention task (Rubia, Smith, et al., 2009) but other studies reporting increased activation during tasks with both affective (e.g., Passamonti et al., 2010) and reward (Cservenka, Herting, Seghete, Hudson, & Nagel, 2013) components. The different patterns of findings for insula reactivity are interesting in relation to AB, given some work implicating the insula in empathy (e.g., Craig, 2009; Naqvi & Bechara, 2009) and its role in interoception, subjective feelings, and behaviors such as addiction.

Structural Neuroimaging Findings Findings from studies that have examined structural MRI (sMRI) highlight many of the same brain structures emphasized in the functional literature (see Figure 1).

Volume sMRI studies of youth AB have demonstrated reduced volume of the insula, amygdala, and striatum (e.g., Sterzer, Stadler, Poustka, & Kleinschmidt, 2007; Wallace et al., 2014), though not in all studies (e.g., Fairchild et al., 2011). Among incarcerated antisocial youth, psychopathic traits were correlated with decreased OFC volume among males (Ermer, Cope, Nyalakanti, Calhoun, & Kiehl, 2013) and females (Cope, Ermer, Nyalakanti, Calhoun, & Kiehl, 2014). However, increased gray matter concentration in medial OFC and ACC regions was found among antisocial boys with high CU traits, which may be a marker of delayed cortical maturation (see De Brito et al. (2009)).

Connectivity Studies have examined connectivity between brain regions implicated in youth AB (i.e., OFC and amygdala) using diffusion tensor imaging (DTI) to assess fractional anisotropy (FA) values in the uncinate fasciculus (UF), a key fiber tract connecting the amygdala and OFC. To date, findings have been somewhat inconsistent with studies reporting increased (Passamonti et al., 2012; Sarkar et al., 2013), no difference (Finger et al., 2012), and decreased FA in the UF (Wang et al., 2012). Given the relatively robust functional and structural findings implicating the OFC and amygdala in youth AB (particularly for those with CU traits), research on the UF may be critical to our understanding of youth AB. Moreover, other studies have reported reduced functional connectivity between prefrontal and limbic structures, particularly for youth with high CU traits (e.g., Ameis et al., 2014; Finger et al., 2012), suggesting that connections between these areas may explain functional findings.

Relevant Research from Adult Literature Studies from adults displaying symptoms of psychopathy and AB help to inform theory and research on youth AB. Studies have primarily focused on the amygdala and prefrontal regions (see reviews by Gao and Raine (2010) and Kiehl (2006)).

Amygdala Decreased amygdala activity has been reported among adult criminal psychopaths during tasks involving aversive classical conditioning (e.g., Birbaumer et al., 2005), contrasting emotional to neutral phrases (Kiehl et al., 2001), fear responsivity (Marsh & Cardinale, 2014), and moral decision making (Glenn, Raine, & Schug, 2009). However, similar to findings in youth, studies have demonstrated that impulsive or reactive forms of AB are linked to different patterns of neural reactivity compared with AB in the context of psychopathy. For example, greater amygdala reactivity was seen in a patient group that was high on impulsive aggression compared to controls (Coccaro, McCloskey, Fitzgerald, & Phan, 2007). Two recent studies from community samples imply that these relationships may generalize to more normative dimensions of AB, reporting a positive association between AB and amygdala reactivity and a negative

INTRODUCTION TO CLINICAL BRAIN MAPPING | Neuroimaging Approaches to Understanding Youth Antisocial Behavior

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Dorsolateral prefrontal cortex Execution of movement, planned behaviors, executing long-term goals, working memory, integration of sensory information

Orbitofrontal cortex

Caudate and ventral striatum

Integrates information from areas of emotion (amygdala) and memory (hippocampus), and high order sensory processing

Anterior cingulate cortex

Error detection and correction, cognitive processing, salience of emotion, and motivational information

Reward and motivation

Amygdala

Regulates arousal and emotion, response to threat, learning from the environment

Primary sensory and visceromotor inputs

Insula

Interoceptive states (particularly disgust), consciousness, decisionmaking, empathy and pain recognition in others

Figure 1 Areas implicated in youth AB as they connect anatomically and functionally. Adapted from Hyde, L. W., Shaw, D. S., & Hariri, A. R. (2013). Understanding youth antisocial behavior using neuroscience through a developmental psychopathology lens: Review, integration, and directions for research. Developmental Review: DR, 33(3), 168–223, with permission.

association between psychopathy and amygdala reactivity (Carre´, Hyde, Neumann, Viding, & Hariri, 2013; Hyde, Byrd, Votruba-Drzal, Hariri, & Manuck, 2014). These findings mirror statistical suppressor effects noted for amygdala reactivity among antisocial youth with high CU traits (Lozier et al., 2014; Sebastian et al., 2014).

Other Regions Functional differences have also been noted in areas of the PFC. In particular, decreased OFC functioning has been found in psychopaths versus healthy controls during aversive classical conditioning tasks (e.g., Birbaumer et al., 2005). Two studies have also reported decreased dlPFC functioning among college students high on psychopathic traits during cooperation tasks (Rilling et al., 2007) and among criminal psychopaths during aversive classical conditioning tasks (Veit et al., 2002). Differences in activation have also been noted in other regions in adult psychopaths. For example, decreased ACC and

insula activation was reported during conditioning paradigms (e.g., Veit et al., 2002), and the ACC and ventral striatum showed decreased activation to an affective lexical task (Kiehl et al., 2001). Finally, increased activation in the ventral striatum was reported during reward processing among aggressive/ antisocial psychopathic traits among healthy volunteers (Bjork, Chen, & Hommer, 2012) and college students (Carre´ et al., 2013).

Summary The literature from adults converges with neuroimaging studies of youth AB by implicating many overlapping regions. For example, reduced activity has been observed in limbic and paralimbic areas, including the amygdala, ACC, ventral striatum, and insula, particularly in response to affective tasks. However, as with studies examining youth, diverging patterns of activity emerge depending on task content and attentional load (e.g., Baskin-Sommers et al., 2011) (Figure 2).

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INTRODUCTION TO CLINICAL BRAIN MAPPING | Neuroimaging Approaches to Understanding Youth Antisocial Behavior

Anterior cingulate cortex fMRI evidence For negative pictures (e.g., Sterzer et al., 2005) and reward tasks (e.g., Gatze-Kopp et al., 2009) sMRI evidence Volume (Boes et al., 2008) Cortical thickness/folding (e.g., Fahim et al., 2011) Gray matter concentration (e.g., De Brito et al., 2008) Adult fMRI evidence For aversive conditioning (e.g., Birbaumer et al., 2005) During reward anticipation (e.g., Kiehl et al., 2001; Bjork et al., 2012)

Caudate and ventral striatum fMRI evidence To others⬘ in pain (Decety et al., 2008) Activation when reward stops (Gatzke-Kopp et al., 2009) Reinforcement, interpersonal interaction vignettes (e.g., Finger et al., 2011; Sharp et al., 2011) sMRI evidence Volume (e.g., Wallace et al., 2013) Adult fMRI evidence For affective lexical tasks/positive versus negative feedback (Kiehl et al., 2001; Carre et al., 2012)

Amygdala

Orbitofrontal cortex/ventromedial prefrontal cortex fMRI evidence Reward tasks (e.g., Crowley et al., 2010; Finger et al., 2011) Functional connectivity with amygdala (Marsh et al., 2008) sMRI evidence Gray matter concentration (e.g., De Brito et al., 2008) Gray matter volume (e.g., Boes et al., 2008) Cortical thicknes and grey matter density/folding (e.g., Fahim et al., 2011; Hyatt et al., 2012) Adult fMRI evidence Aversive conditionong (e.g., Birbaumer et al., 2005) and processing emotional faces (e.g., Riling et al., 2007)

fMRI evidence For angry/sad/fearful faces among high CU traits group (e.g., Marsh et al., 2008; Viding et al., 2012) For fear among low CU traits group (e.g., Viding et al., 2012) sMRI evidence Gray matter volume (e.g., Fairchild et al., 2011) Adult fMRI evidence Activation to emotional/fear faces for high psychopathic group (e.g., Kiehl et al., 2001; Glenn et al., 2009) Activation to anger faces for high antisocial/lifestyle groups (Carre et al., 2013)

Dorsolateral prefrontal cortex fMRI evidence During animations of others in pain/attention task (Decety et al., 2009; Rubia, Halari et al., 2009) sMRI evidence Volume (e.g., Sterzer et al., 2007) Adult fMRI evidence During aversive conditioning (Veit et al., 2002) To emotional faces (Gordon et al., 2004)

Insula fMRI evidence For attention/angry faces/theory of mind tasks (Rubia, Halari, et al., 2009; Passamonti et al., 2010; Sebastian et al., 2014) For others⬘ pain/reward/sharing (Decety et al., 2009; Cservenka et al., 2013; Sharp et al., 2011) sMRI evidence Gray matter (e.g., Fairchild et al., 2011) Cortical thickness/gray matter concentration and folding (e.g., Fahim et al., 2011; Hyatt et al., 2012) Adult fMRI evidence For aversive conditioning (e.g., Birbaumer et al., 2005)

Figure 2 Selected empirical evidence implicating six brain regions in youth AB, based on functional imaging and structural imaging studies of youth and functional imaging studies of adults.

Considerations for Future Research

Multimodal Methods

Subgrouping Approaches

Finally, research is needed that employs multimodal approaches that take into account other aspects of underlying biology (e.g., genes and hormones) and environmental context. In particular, studies are needed that examine the interaction between genes and environment as a predictor of neural differences associated with youth AB while also integrating findings from animal models and other complimentary techniques, such as PET or imaging genetics (see Hyde, Swartz, Waller, and Hariri (2014)). Future research will thus be able to model the underlying molecular mechanisms that give rise to AB.

There is a strong foundation of neuroimaging research for person-centered approaches particularly differentiating between high and low CU traits. However, the behavioral literature of AB highlights multiple other subtyping approaches (e.g., proactive versus reactive aggression) and behavioral constructs (e.g., social information processing) that need to be embraced by future imaging studies. Indeed, just as psychopathy represents only a small percentage of adults with AB, high levels of CU traits occur among only a small percentage of youth with AB (Rowe et al., 2010). Further, very little research has demonstrated continuity between high levels of youth CU traits and adult psychopathy, highlighting the need for future studies to explore other subtyping approaches in conceptualizing AB.

Need for Longitudinal Designs and Developmental Focus Future longitudinal studies are needed that follow youth from early childhood (Shaw & Gross, 2008) across multiple points using observational measures and self-report data to help determine the direction and timing of these effects.

Conclusion The rapidly growing body of neuroimaging literature examining youth AB is beginning to consistently implicate several brain areas, including the amygdala and OFC, as well as the insula, ACC, caudate, and dlPFC. Further support for the role of these regions in youth AB comes from sMRI studies and findings from adult populations. Studies have broadly connected these different brain areas to impairments seen among antisocial youth, including deficits in emotion processing, empathy, learning and attention, and reward responsivity,

INTRODUCTION TO CLINICAL BRAIN MAPPING | Neuroimaging Approaches to Understanding Youth Antisocial Behavior

each of which appears to have somewhat distinct neural correlates. Differences in the amygdala and related areas (e.g., OFC) among antisocial youth are seen mostly in affective tasks, whereas dlPFC and other prefrontal areas appear to show functional differences in attention, learning, and inhibition tasks, implying possible subdomains of functioning to be explored in future studies. However, many fundamental questions remain, including whether antisocial youth tend to be more hypo- or hyperreactive to emotional or threatening stimuli, whether CU traits or more general severity of AB are driving reported findings, which brain areas would be expected to show greater versus lesser response and to which types of tasks, and whether fMRI can help to uncover other distinct subgroups that vary in both behavior and neural responses (see Hyde, Shaw, and Hariri (2013) for a more detailed discussion of these findings and considerations for future research). Further, in the study of youth AB, an understanding of one area will likely prove less informative than understanding how functioning is linked across regions. As the field evolves, studies are needed that combine task-related functional imaging with methods that assess functional and structural connectivity.

See also: INTRODUCTION TO ACQUISITION METHODS: Anatomical MRI for Human Brain Morphometry; Diffusion MRI; Obtaining Quantitative Information from fMRI; Positron Emission Tomography and Neuroreceptor Mapping In Vivo; INTRODUCTION TO ANATOMY AND PHYSIOLOGY: Amygdala; Basal Ganglia; Cytoarchitectonics, Receptorarchitectonics, and Network Topology of Language; Development of Structural and Functional Connectivity; Development of the Basal Ganglia and the Basal Forebrain; Functional Connectivity; Genoarchitectonic Brain Maps; Insular Cortex; Lateral and Dorsomedial Prefrontal Cortex and the Control of Cognition; INTRODUCTION TO CLINICAL BRAIN MAPPING: Emotion and Stress; Functional Characteristics of Brain Tumor Vascularization; Imaging Genetics of Neuropsychiatric Disease; Imaging Genetics; Structural Abnormalities in Autism Spectrum Disorder; INTRODUCTION TO COGNITIVE NEUROSCIENCE: Attention and Memory; Impulsivity; Interactions between Attention and Emotion; Memory Attribution and Cognitive Control; Neuroimaging Studies of Reinforcement-Learning; Performance Monitoring; Prediction and Expectation; Response Inhibition; Reward Processing; Rule Representation; Value Representation; Working Memory; Working Memory–Attention Interplay; INTRODUCTION TO METHODS AND MODELING: Diffusion Tensor Imaging; Modeling Brain Growth and Development; Resting-State Functional Connectivity; INTRODUCTION TO SOCIAL COGNITIVE NEUROSCIENCE: A Neural Network for Moral Decision Making; Empathy; Observational Fear Learning; Social Decision Making; Social Versus Nonsocial Reasoning; The Default Network and Social Cognition; The Neural Correlates of Social Cognition and Social Interaction; The Social Brain in Childhood and Adolescence; INTRODUCTION TO SYSTEMS: Brain Mapping of Control Processes; Emotion; Face Perception; Memory; Neural Correlates of Motor Deficits in Young Patients with Traumatic Brain Injury; Pain: Acute and Chronic; Reward; Salience Network; Working Memory.

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