Neurodevelopmental Pathways to Aggression: A Model to Understand and Target Treatment in Youth
2006; American Psychiatric Association Publishing; Volume: 18; Issue: 3 Linguagem: Inglês
10.1176/appi.neuropsych.18.3.302
ISSN1545-7222
AutoresS. G. Sugden, S. J. Kile, R. L. Hendren,
Tópico(s)Child and Adolescent Psychosocial and Emotional Development
ResumoBack to table of contents Previous article Next article SPECIALFull AccessNeurodevelopmental Pathways to Aggression: A Model to Understand and Target Treatment in YouthSteven G. Sugden M.D.Shawn J. Kile M.D.Robert L. Hendren D.O.Steven G. Sugden M.D.Shawn J. Kile M.D.Robert L. Hendren D.O.Published Online:1 Jul 2006AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail A ggression is one of the most common symptoms mental health professionals are asked to treat, yet it is also one of the most complex. Aggression can lead to great difficulty for the child and family's ability to function. Furthermore, behavior programs and/or psychotropic medications are only variably helpful in treating aggressive behaviors, and designing effective treatments often involves time-consuming, educated trial and error procedures. Because aggression is a multidetermined behavior, we propose that it will be best treated by identifying specific characteristics and, most importantly, by identifying the underlying "primary symptoms" that can then be targeted by more specific interventions. We identify and characterize primary symptoms of aggressive behavior, propose possible neurodevelopmental etiologies for each of these, and finally describe how to use these symptom domains to choose effective treatments. Aggressive behavior, ranging from self-directed to other-directed destructive behavior, originates in multiple sources and can be associated with numerous Diagnostic and Statistical Manual IV-TR (DSM-IV-TR) defined mental disorders. 1 The impulsivity, hyperactivity, and distractible inattention associated with attention deficit hyperactivity disorder (ADHD) can lead to greater than expected accidents and injuries. The affective instability in bipolar disorder, borderline personality disorder, and intermittent explosive disorder can lead to emotionally charged aggressive behavior. The irritability associated with major depressive disorder and dysthymia can lead to aggressive and self-destructive behavior, including "acting out" aggression and suicide. Excessive anxiety associated with posttraumatic stress disorder (PTSD), autism spectrum disorders, and other developmental disabilities can result in low frustration tolerance and "striking out" aggressive behavior. Substance abuse and thought disorder (psychosis, schizophrenia) can impair judgment leading to inadvertent aggression and exposure to danger. Youth with conduct disorder and oppositional defiant disorder may seek the arousal, novelty, and stimulation of aggressive behavior, often with a predatory quality. While these DSM-IV-TR diagnoses may help guide interventions for associated aggression, the diagnosis by itself is often not sufficient to lead directly to effective treatment due to the multidetermined etiology of the aggression and comorbidity. 2 Until we understand the origins or etiologies of these episodes of aggression, we are limited in our ability to develop effective treatments for them. Symptom Domains This article is organized around symptom domains that can be understood through a neurodevelopmental model from the presenting or surface, primary symptom to underlying, related brain structures and functions. Early reports identified at least seven subtypes of aggression that were linked to neuroanatomical origins within the animal literature: predatory, intermale, territorial, maternal, irritable, fear-induced, and instrumental. 3 Traditionally, these aggressive behavior subtypes have been reduced to binary domains when dealing with humans: for example, hostile versus instrumental, overt versus covert, reactive versus proactive, defensive versus offensive, affective versus predatory, or impulsive versus controlled (for a complete review see Vitiello and Stoff, 1997). 4 Though helpful as a conceptual model, these binary constructs offer little for treatment options since many of the subtypes of aggression often present in a similar affective, impulsive manner. Therefore, based on the human and animal aggression literature as well as clinical experience using pharmacological and psychological target symptoms, we are proposing five primary symptom domains of aggressive behavior: impulsivity (rapid, thoughtless aggressive acts), affective instability (affectively charged attacks with seemingly little provocation), anxiety/hyperarousal (overwhelming anxiety and frustration leading to aggressive outbursts), cognitive disorganization (poorly organized and confused aggressive acts), and predatory/planned aggression (goal-directed preying on others). The neurodevelopmental model proposes that brain development is a continuous process that is influenced by genetics, brain structure and function, and environmental interaction. All social influences affect brain development and all psychological constructs are implemented by brain mechanisms. Neurodevelopmental models trace healthy and pathological neurodevelopmental etiologies through brain mechanisms to surface symptoms. 5 In children and adolescents we see neurodevelopmental maturity leading to control of impulse, affect, anxiety, and cognition with individual differences based on individual and environmental factors. Thus, controlling aggression is a neurodevelopmental process that is increasingly understood using neuroscience research and will be used as the underpinning of support throughout this article. Future longitudinal research will determine if these targeted interventions for aggression enhance neurodevelopment. Identification of these potential targets and their biomarkers outlined in this article is a working model. The brain regions that are of particular interest in understanding aggression are listed in Table 1 . Each primary symptom section will be identified clinically and linked to the neuroanatomical regions that are relevant to the origin of the target, primary symptom. Neuromodulators and functional circuits involving these regions will also be integrated. TABLE 1. Brain Regions Involved in Aggressive BehaviorTABLE 1. Brain Regions Involved in Aggressive BehaviorEnlarge tableTherefore, this model-building paper will begin with the identification of key behavioral symptoms that lend themselves to treatment interventions, and then describe the neurostructural and neurofunctional underpinnings of these primary symptoms and relate these to treatment choice and response. Eventually, as the literature becomes available, the neuroendocrine system (testosterone, cortisol, cholesterol, etc.), which modulates many of the mentioned brain regions and has been implicated in aggressive behavior, and genetics, which confers both susceptibility (vulnerability) and resilience (resistance) to aggressive behavior, will be integrated into this model.ImpulsivityClinical Description Impulsivity is the failure to resist an impulse, drive, or temptation, resulting in rapid, unplanned reactions to internal or external stimuli. It involves the inability to delay reward where the individual is unable to modify his or her behavior according to the context of the situation or to reflect on the consequences of the behavior, thus impairing judgment. With impulsivity there is an associated underestimated sense of harm and lack of regard for the negative consequences. 6 Impulsive aggression disorder has been defined as recurrent incidents of physical or verbal aggression that are out of proportion to the circumstances, occur at least twice a week for more than 1 month and lead to marked distress or impairment. 7 Subjects who demonstrate impulsive choice choose small or poor rewards that are immediately available over larger but delayed rewards. They are unable to calculate future risks or consequences and unable to delay acting on impulse, indicating impaired executive functioning. This type of aggression was shown to develop in almost 40% of children who sustained traumatic brain injury. 8 Impulsive aggression also appears to have a familial transmission. 9 Novelty or sensation seeking often is associated with impulsivity, but there are differences. Novelty seeking seems more likely to occur in youth who are seeking a means of stimulation rather than the "out-of-the-blue" impulsive behavior. 10 Novelty seeking can also occur in youth who are experiencing stress or are overstimulated, and are seeking distractions from their stress. This might occur with PTSD, depression, and/or substance abuse. Impulsive behavior is not sought, even indirectly, but it happens with no forethought. Although certain vulnerabilities (e.g., substance dependence or heightened anxiety) may occur in tandem with the impulsive act, it is not the preceding affect that seems to drive the impulsive act. Case Example"Mr. A" is a 14-year-old boy with a long history of ADHD and erratic school performance, but no serious behavior problems or depression. There is a family history of alcoholism on both sides, but no other disorders in his upper-middle class family. Mr. A has not been physically aggressive toward others but is known to do things without thinking and is quick to respond to any challenge. While drinking a few beers with a group of mixed sex peers, he impulsively responds to a dare and jumps off a bridge into the water below, breaking one of his legs.Brain Structure & Function Behavioral inhibition is linked to four executive neuropsychological functions. These are working memory, self-regulation, internalization of speech, and reconstruction (behavioral analysis and synthesis). 11 These functions are processed in a network between the prefrontal cortex and the basal ganglia in the fronto-striatal region. The orbitofrontal cortex constrains impulsive outbursts, 12 and the ventromedial prefrontal cortex is involved with the delay of gratification 13 but is not directly involved in impulsive choice. In addition to the key role of the orbitofrontal cortex in restraining impulsive aggression, 7 , 14 the nucleus accumbens (reward and reinforcement) and the amygdala (identification of negative emotion) 15 are involved in impulsive behavior and the restraint of it. The amygdala is not involved in the regulation or mediation of impulsive and aggressive behavior but is involved in the acquisition of emotional memories used for decision-making based on experience. 16 Though it does not appear that the anterior cingulate is directly involved in impulsivity, it recruits other brain regions to contain impulsivity. 17 The usefulness of differentiating executive inhibition, thought to be frontal/fronto-striatal and dopaminergic, from motivational inhibition, thought to be noradrenergic/serotoninergic and limbic in nature, is proposed as an important way of subtyping aggression in youth. 18Neuromodulators Serotonin plays a central role in impulsivity 19 , 20 with the greatest effects in the orbitofrontal and cingulate cortex, 7 but serotonin neurotransmission is complex. 21 Impulsivity is also influenced by interconnections with the noradrenergic (irritable), dopaminergic (reward), glutaminergic and gamma-aminobutyric acid (GABA) systems. 22 Specific serotonin receptors and genes 23 are likely more involved with impulsive aggression than are others. For instance, knockout mice lacking the serotonin receptor 5-HT1B exhibited increased impulsive aggression. 24 Thus, the 5-HT1B receptors are suggested as a promising pharmacological target for reducing impulsive aggressive behavior in humans. TreatmentIntervention is targeted at prolonging thinking before action, either with cognitive behavior techniques, removal from high-risk situations and overstimulation, or pharmacological intervention. Pharmacological interventions that have been shown to decrease impulsive aggression include stimulants, SSRIs, and mood stabilizers ( Table 2 ), but often with different populations. 6 For instance, stimulants may be of greater benefit to individuals with distractible inattention leading to their impulsivity than to individuals without distractible inattention, even if they do not meet the criteria for ADHD. TABLE 2. Summary of Evidence for Treatment Effects in AggressionTABLE 2. Summary of Evidence for Treatment Effects in AggressionEnlarge tablePsychosocial treatments for impulsivity usually begin with an educational and behavioral focus, progress to a cognitive focus, and conclude with a focus on relapse prevention. The major themes in intervention are practicing delay and improving response inhibition and reflection deficit.Intervention is also directed toward strengthening the "cultural container," the cultural protection offered by a strong culture surrounding the youngster and the youth's identification with it. This is related to interventions that increase "reward dependence," or the seeking of the positive aspects of approval. Other environmental interventions include changes in peer group and public education. After an initial evaluation of Mr. A, described above, effective treatment included substance abuse counseling, an SSRI, and therapy directed at impulse delay through anticipation, rehearsal, and modeling.Affective InstabilityClinical Description Affective instability is emotional dysregulation expressed as exaggerated reactions to negative or frustrating stimuli, 25 which may result in rage and aggression. In children and adolescents, affective instability usually occurs rapidly and is highly reactive. Emotional regulation is described as the ability to manage arousal or to modulate the intensity of emotional reactions. 26 According to Bhangoo and Leibenluft, 27 this ability develops biologically and its dysregulation is common to several disorders, including bipolar disorder and developmental disabilities like autism spectrum disorders. Affective instability may be combined with impulsivity to result in risky and aggressive behavior, 4 but the two do not describe the same phenomenon; a person can be impulsive with or without an affective component. Purely impulsive aggression has no identifiable precedent, seemingly coming "out of the blue." Affective aggression usually happens rapidly and may seem impulsive, but is differentiated by the preceding rush of affect, resulting in "hot tempered" aggression. Both affective instability and impulsivity are related to poor attention, attention shifting, and verbal self-control. 25 Affective instability, rages, euphoria, and rapid cycling or mixed moods are increasingly diagnosed as bipolar disorder in youth. 28 However, children with a number of psychiatric disorders manifest emotional dysregulation. 27 They may not meet the full criteria for bipolar disorder because they do not have grandiosity, decreased need for sleep, increased goal-directed activity, but do have hyperarousal, abnormal baseline mood, and extreme responses to frustration. Leibenluft et al. 25 suggest the phenotype in juvenile mania ranges from the narrow phenotype with all the classic bipolar symptoms to a broader phenotype that does not include all of the hallmark symptoms but shares symptoms of irritability and hyperarousal that are also commonly described in the narrower phenotype. Affective instability is clearly associated with this "broader" phenotype. In a recent study of the personality changes due to brain injury, affective instability was noted to be the most common sequelae of traumatic brain injury in children, occurring in nearly 50% of the sample. 8 This affective dysregulation was most frequently characterized by very rapid shifts to pathological irritability. Depression and irritability can lead to risk-taking and aggressive behavior that can be directed toward others or toward the self. 9 Factors that increase impulsivity, such as substance abuse or the availability of weapons, can increase the risk of harm, but treatment needs to be directed not only toward these factors but also to the underlying depression. Case Example"Ms. B" was a 12-year-old girl who had a history of severe temper tantrums and, over the past year, an aggression of increasing destructiveness. Ms. B would have episodes lasting 45 to 120 minutes in which she would seem beyond herself with rage and physical aggression. Episodes happened several times a week for several weeks, and then went away for a few weeks. They occurred more frequently in the late afternoon. She remembered the episodes when they were over but did not feel remorse. Ms. B had been diagnosed with ADHD and had benefited modestly from a regimen of amphetamine/dextroamphetamine, 10 mg, each weekday morning, especially at school. She was distractible, very impulsive, easily frustrated, mildly depressed at times, had no marked anxiety or tics, did well academically, and had poor social skills, although other kids "followed her." A family history of mental disorder was denied. While Ms. B's symptoms met the criteria for a diagnosis of attention deficit hyperactivity disorder–combined type, her additional symptoms of affective instability demonstrated by her moody, impulsive, and episodically aggressive behavior suggested bipolar disorder II, but she did not meet all the criteria for this disorder.Brain Structure & Function Emotional regulation involves complex neural circuitry, including the orbital frontal cortex, amygdala, anterior cingulate, and cerebellum. In addition, emotional regulation also plays a role in functional involvement of the autonomic nervous system and neurotransmitters, particularly serotonin. 17 This neurobiology of emotion has been further divided into the ventral system, including the amygdala, insula, ventral striatum, ventral anterior cingulate, and the prefrontal cortex for the identification of the emotional significance of a stimulus and the automatic regulation of emotional responses. The dorsal system has also been included as well, demonstrating effortful regulation of affective states and subsequent behavior in structures including the hippocampus, dorsal anterior cingulate and prefrontal cortex. 29 Affective aggression is commonly found in temporal lobe epilepsy. 30 A recent well-executed study with bipolar adolescents and adults who were aggressive found significant amygdala volume reductions of 15.6% compared to healthy subjects. 31 Additional studies suggesting a link between temporal lobe structures and affective aggression include studies of anger in healthy men which link aggression with the bilateral temporal poles as well as with the left frontal cortex and right anterior cingulate. 32 It is possible that the prefrontal cortex and the anterior cingulate control the expression of angry aggression in healthy men. 33Neuromodulators The neuromodulators involved in affect regulation overlap with those involved in other symptom domains, which may account for the improvement in affective instability when using agents such as antidepressants also used for impulse control and atypical neuroleptics used for cognitive disorganization. For instance, serotonin is involved in both impulse control and in affect regulation. 21 , 32 In addition, the GABA system seems to be heavily involved in affective stabilization from anticonvulsants. 21Treatment Pharmacological treatments for affective instability are primarily atypical neuroleptics (e.g., risperidone) and mood stabilizers (e.g., divalproex) ( Table 2 ). 34 There are suggestions in the literature that those medications that improve affective instability have their primary action in those brain regions associated with affective instability, the temporal lobes, and the cerebellum. Psychosocial treatments are similar to those used for impulsivity, but focus on strengthening the cognitive path from the perception of emotion to action. As described earlier, the path to emotional action is through the superior temporal lobe, so to modify this rapid rage response, the pathways through the cortex, including the prefrontal cortex, need to be strengthened through cognitive practice. This includes identification of emotion and pairing it with a pro-social response through practice with cognitive behavior and dialectic therapies. Sublimation of affective aggression through sports and martial arts may also be helpful for selected youth. For Ms. B in the example above, divalproex was added to stimulant treatment. This along with 10 sessions of cognitive behavior therapy resulted in relatively stable mood and behavior during an 18-month period.Anxiety/HyperarousalClinical DescriptionFear is an adaptive response to a threatening stimulus that may lead to a protective response, whereas anxiety is an emotional response linked to a threatening stimulus, even in the absence of direct danger. Anxiety may be considered part of a normal response until it becomes excessive or difficult to tolerate, resulting in overstimulation. As coping tolerance is exceeded, the anxious hyperarousal may precipitate decompensation and disorganization, resulting in poorly directed aggression toward the self or others, sleep disturbances, irritability, difficulty concentrating, hypervigilance, and an exaggerated startle response. Oftentimes the aggressive act relieves the precipitating anxious hyperarousal sensations. These symptoms are commonly seen in children with PTSD, Cluster B disorders, depression-related anxiety, autism spectrum disorders, neurodevelopmental disorders, and other forms of mental retardation.Case Example"Ms. C," a 13-year-old girl, came to the inpatient unit because of her unpredictable behavior. Her family had difficulty dealing with the random aggressive behavior Ms. C displayed toward her stepfather and younger siblings. Ms. C's mother described her as a "difficult child" who was physically abused by her biological father. When Ms. C's mother remarried, her behavior worsened, and eventually she spent 1 year in a group home where she was frequently abused physically, sexually, and verbally. During the hospitalization, Ms. C was guarded and often lashed out unexpectedly when she encountered an anxiety-evoking situation (i.e., in a group setting talking about her gender identity). She mentioned feelings of relief that often accompanied her aggressive behavior. Though she tried to minimize the impact of the abuse, when she actually talked about her abuse, she often became tearful. Ms. C was diagnosed with PTSD.Brain Structure & Function The limbic-hypothalamic-pituitary-adrenal (HPA) axis plays a vital role within the stress response. When stress is perceived at the level of the limbic system, the hypothalamus secretes corticotropin-releasing factor (CRF), which, in turn, stimulates the release of the adrenocorticotropin hormone (ACTH) from the pituitary. This, in turn, stimulates the release of glucocorticoid from the adrenal, which has a negative feedback effect on the axis of the limbic system (e.g., hippocampus and amygdala) and the hypothalamus, and the pituitary CRF stimulates other neurochemical responses in the brain, including the noradrenergic system within the locus coeruleus within the posterior pons. 35 The hippocampus typically has an inhibitory effect on the HPA. However, it is an area that is particularly sensitive to stress because of the high density of glucocorticoid receptors. Hypercortisolemia has been shown to decrease dendritic branching and neuronal loss in the CA3 region of the hippocampus, 36 and it has been associated with deficits in new learning. 37 Magnetic resonance imaging (MRI) volumetric studies comparing PTSD related to early childhood stress versus matched comparison subjects showed a 12% reduction in the left hippocampus volume, which is similar to results found in individuals with combat-related PTSD and women with early sexual abuse. 38 Hippocampal injury may be significant as it pertains to the amnesic, dissociative, anxiogenic, and disinhibitory symptoms of PTSD. 39 Likewise, the amygdala has been shown to be intimately involved in the regulation of the HPA system. 40 The amygdala in particular has been implicated in the development and retrieval of emotional memory, the learning of nonverbal motor patterns, the trigger of fight-or-flight response, threat detection, and the production of fear and anxiety. 41 Excessive amygdala and nucleus accumbens activity has been implicated in the development of aggressive hyperarousal within PTSD. 42 Similarly, amygdala abnormalities have been linked to heightened anxiety within autism spectrum disorders. 41 In each case, stimulation of the medial and cortical regions of the amygdala elicits additional corticosterone secretion. 43 Long-term exposure to cortisol leads to suppression of serotonin metabolism and down-regulation of the 5-HT1A and 5-HT2 receptors within the limbic system. 44Neuromodulators The serotonin system plays a key regulatory role within the CNS as it modulates internal affective states (anxiety, fear, depression, and aggression), control of sleep, reward circuits that mediate motivation, and hedonic states. 45 As a result of its broad-spectrum activity, serotonin modulation has become a first-line therapy. 46 Additionally, studies have shown increased brain-derived neurotrophic factors in the CA3 and CA1 regions of the hippocampus, which help reverse the effects of stress as well as increase dendritic branching and neurogenesis within the hippocampus when serotonin selective-reuptake inhibitors (SSRIs) are taken. 46 Noradrenergic cell bodies are primarily located in the locus coeruleus and project to the hippocampus, amygdala and other limbic structures within the brain. Exposure to stress increases noradrenergic modulation within these regions, 47 which generates hyperarousal and reexperiencing of symptoms 47 as well as stimulates the release of CRF from the hypothalamus. By targeting autonomic hyperarousal, improvements may be seen in anxiety level, concentration, mood, and behavioral impulsivity. Treatment The symptoms of anxious hyperarousal and spontaneous aggression represent abnormalities within the limbic system and serotonergic and noradrenergic activity, which have resulted in poor coping skills. Interventions aimed at decreasing overall stress and improvement of coping skills through case management, psychoeducation, and psychotherapy (which often combine principles of cognitive and behavior therapies) often combined with serotonergjic and noradrenergic modulation are most likely to be beneficial ( Table 2 ). Ms. C was initially started on an SSRI. Eventually, clonidine was added to her regimen. She received cognitive behavior therapy, and her family participated in weekly family counseling sessions. After 6 weeks of inpatient hospitalization, she returned back to her home and continued to work with her own therapist. Her behavior improved at home, but her relationship with her step-father continues to be strained. Cognitive DisorganizationClinical Description Delusions, psychosis, or substance abuse can result in cognitive disorganization and aggressive behavior. While the behavior may appear impulsive to the casual observer, closer inquiry may reveal more long-standing, distorted perceptions or impaired reasoning as precedents to the aggressive behavior. Paranoia is particularly prominent in recurrently violent adolescents. 48 Delusions and psychosis are associated with schizophrenia, mood disorders, personality disorders, forms of mental retardation (e.g., fetal alcohol syndrome, autism), and brain injury (e.g., epilepsy or traumatic injuries). Often, substance abuse disorders are comorbid with many of the aforementioned categories of severe mental disorders and often exacerbate psychopathology. Recurring psychosis as experienced in schizophrenia has been demonstrated in neurocognitive deficits and worsening behavior. 49 In examining individuals with first-episode psychosis (cognitive disorganization), Foley et al. 50 showed 52 of 157 subjects presented with aggressive behavior (e.g., a hostile or destructive mental attitude, including verbal
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