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Compulsive Addiction-like Aggressive Behavior in Mice.
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Compulsive Addiction-like Aggressive Behavior in Mice.

Biol Psychiatry. 2017 Aug 15;82(4):239-248

Authors: Golden SA, Heins C, Venniro M, Caprioli D, Zhang M, Epstein DH, Shaham Y

Abstract
BACKGROUND: Some people are highly motivated to seek aggressive encounters, and among those who have been incarcerated for such behavior, recidivism rates are high. These observations echo two core features of drug addiction: high motivation to seek addictive substances, despite adverse consequences, and high relapse rates. Here we used established rodent models of drug addiction to determine whether they would be sensitive to "addiction-like" features of aggression in CD-1 mice.
METHODS: In experiments 1 and 2, we trained older CD-1 mice to lever press for opportunities to attack younger C57BL6/J mice. We then tested them for relapse to aggression seeking after forced abstinence or punishment-induced suppression of aggression self-administration. In experiment 3, we trained a large cohort of CD-1 mice and tested them for choice-based voluntary suppression of aggression seeking, relapse to aggression seeking, progressive ratio responding, and punishment-induced suppression of aggression self-administration. We then used cluster analysis to identify patterns of individual differences in compulsive "addiction-like" aggressive behavior.
RESULTS: In experiments 1 and 2, we observed strong motivation to acquire operant self-administration of opportunities to aggress and relapse vulnerability during abstinence. In experiment 3, cluster analysis of the aggression-related measures identified a subset of "addicted" mice (∼19%) that exhibited intense operant-reinforced attack behavior, decreased likelihood to select an alternative reinforcer over aggression, heightened relapse vulnerability and progressive ratio responding, and resilience to punishment-induced suppression of aggressive behavior.
CONCLUSIONS: Using procedures established to model drug addiction, we showed that a subpopulation of CD-1 mice demonstrate "addiction-like" aggressive behavior, suggesting an evolutionary origin for compulsive aggression.

PMID: 28434654 [PubMed - indexed for MEDLINE]




Brain Mechanisms Underlying Reactive Aggression in Borderline Personality Disorder-Sex Matters.
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Brain Mechanisms Underlying Reactive Aggression in Borderline Personality Disorder-Sex Matters.

Biol Psychiatry. 2017 Aug 15;82(4):257-266

Authors: Herpertz SC, Nagy K, Ueltzhöffer K, Schmitt R, Mancke F, Schmahl C, Bertsch K

Abstract
BACKGROUND: Aggression in borderline personality disorder (BPD) is thought to be mediated through emotion dysregulation via high trait anger. Until now, data comparing anger and aggression in female and male patients with BPD have been widely missing on the behavioral and particularly the brain levels.
METHODS: Thirty-three female and 23 male patients with BPD and 30 healthy women and 26 healthy men participated in this functional magnetic resonance imaging study. We used a script-driven imagery task consisting of narratives of both interpersonal rejection and directing physical aggression toward others.
RESULTS: While imagining both interpersonal rejection and acting out aggressively, a sex × group interaction was found in which male BPD patients revealed higher activity in the left amygdala than female patients. In the aggression phase, men with BPD exhibited higher activity in the lateral orbitofrontal and dorsolateral prefrontal cortices compared with healthy men and female patients. Positive connectivity between amygdala and posterior middle cingulate cortex was found in female patients but negative connectivity was found in male patients with BPD. Negative modulatory effects of trait anger on amygdala-dorsolateral prefrontal cortex and amygdala-lateral orbitofrontal cortex coupling were shown in male BPD patients, while in female patients trait anger positively modulated dorsolateral prefrontal cortex-amygdala coupling. Trait aggression was found to positively modulate connectivity of the left amygdala to the posterior thalamus in male but not female patients.
CONCLUSIONS: Data suggest poor top-down adjustment of behavior in male patients with BPD despite their efforts at control. Female patients appear to be less aroused through rejection and to successfully dampen aggressive tension during the imagination of aggressive behavior.

PMID: 28388995 [PubMed - indexed for MEDLINE]




Structural Brain Imaging of Long-Term Anabolic-Androgenic Steroid Users and Nonusing Weightlifters.
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Structural Brain Imaging of Long-Term Anabolic-Androgenic Steroid Users and Nonusing Weightlifters.

Biol Psychiatry. 2017 Aug 15;82(4):294-302

Authors: Bjørnebekk A, Walhovd KB, Jørstad ML, Due-Tønnessen P, Hullstein IR, Fjell AM

Abstract
BACKGROUND: Prolonged high-dose anabolic-androgenic steroid (AAS) use has been associated with psychiatric symptoms and cognitive deficits, yet we have almost no knowledge of the long-term consequences of AAS use on the brain. The purpose of this study is to investigate the association between long-term AAS exposure and brain morphometry, including subcortical neuroanatomical volumes and regional cortical thickness.
METHODS: Male AAS users and weightlifters with no experience with AASs or any other equivalent doping substances underwent structural magnetic resonance imaging scans of the brain. The current paper is based upon high-resolution structural T1-weighted images from 82 current or past AAS users exceeding 1 year of cumulative AAS use and 68 non-AAS-using weightlifters. Images were processed with the FreeSurfer software to compare neuroanatomical volumes and cerebral cortical thickness between the groups.
RESULTS: Compared to non-AAS-using weightlifters, the AAS group had thinner cortex in widespread regions and significantly smaller neuroanatomical volumes, including total gray matter, cerebral cortex, and putamen. Both volumetric and thickness effects remained relatively stable across different AAS subsamples comprising various degrees of exposure to AASs and also when excluding participants with previous and current non-AAS drug abuse. The effects could not be explained by differences in verbal IQ, intracranial volume, anxiety/depression, or attention or behavioral problems.
CONCLUSIONS: This large-scale systematic investigation of AAS use on brain structure shows negative correlations between AAS use and brain volume and cortical thickness. Although the findings are correlational, they may serve to raise concern about the long-term consequences of AAS use on structural features of the brain.

PMID: 27616036 [PubMed - indexed for MEDLINE]




Exogenous Testosterone Rapidly Increases Aggressive Behavior in Dominant and Impulsive Men.
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Exogenous Testosterone Rapidly Increases Aggressive Behavior in Dominant and Impulsive Men.

Biol Psychiatry. 2017 Aug 15;82(4):249-256

Authors: Carré JM, Geniole SN, Ortiz TL, Bird BM, Videto A, Bonin PL

Abstract
BACKGROUND: Although traditional wisdom suggests that baseline levels of testosterone (T) promote aggressive behavior, decades of research have produced findings that have been largely weak and inconsistent. However, more recent experimental work suggests that exogenous administration of T rapidly potentiates amygdala and hypothalamus responses to angry facial expressions. Notably, these brain regions are rich in androgen receptors and play a key role in modulating aggressive behavior in animal models.
METHODS: The present experiment extends this work by examining whether acutely increasing T potentiates aggressive behavior in men. In a double-blind, placebo-controlled, between-subject design, healthy adult men (n = 121) were administered either T or placebo, and subsequently engaged in a well-validated decision-making game that measures aggressive behavior in response to social provocation. In light of prior correlational research, we also assessed the extent to which T's effects on aggressive behavior would depend on variability in trait dominance and/or trait self-control.
RESULTS: Exogenous T on its own did not modulate aggressive behavior. However, T's effects on aggression were strongly influenced by variation in trait dominance and trait self-control. Specifically, T caused an increase in aggressive behavior, but only among men scoring relatively high in trait dominance or low in trait self-control.
CONCLUSIONS: These findings are the first to demonstrate that T can rapidly (within 60 minutes) potentiate aggressive behavior, but only among men with dominant or impulsive personality styles.

PMID: 27524498 [PubMed - indexed for MEDLINE]




Disorganized Amygdala Networks in Conduct-Disordered Juvenile Offenders With Callous-Unemotional Traits.
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Disorganized Amygdala Networks in Conduct-Disordered Juvenile Offenders With Callous-Unemotional Traits.

Biol Psychiatry. 2017 Aug 15;82(4):283-293

Authors: Aghajani M, Klapwijk ET, van der Wee NJ, Veer IM, Rombouts SARB, Boon AE, van Beelen P, Popma A, Vermeiren RRJM, Colins OF

Abstract
BACKGROUND: The developmental trajectory of psychopathy seemingly begins early in life and includes the presence of callous-unemotional (CU) traits (e.g., deficient emotional reactivity, callousness) in conduct-disordered (CD) youth. Though subregion-specific anomalies in amygdala function have been suggested in CU pathophysiology among antisocial populations, system-level studies of CU traits have typically examined the amygdala as a unitary structure. Hence, nothing is yet known of how amygdala subregional network function may contribute to callous-unemotionality in severely antisocial people.
METHODS: We addressed this important issue by uniquely examining the intrinsic functional connectivity of basolateral amygdala (BLA) and centromedial amygdala (CMA) networks across three matched groups of juveniles: CD offenders with CU traits (CD/CU+; n = 25), CD offenders without CU traits (CD/CU-; n = 25), and healthy control subjects (n = 24). We additionally examined whether perturbed amygdala subregional connectivity coincides with altered volume and shape of the amygdaloid complex.
RESULTS: Relative to CD/CU- and healthy control youths, CD/CU+ youths showed abnormally increased BLA connectivity with a cluster that included both dorsal and ventral portions of the anterior cingulate and medial prefrontal cortices, along with posterior cingulate, sensory associative, and striatal regions. In contrast, compared with CD/CU- and healthy control youths, CD/CU+ youths showed diminished CMA connectivity with ventromedial/orbitofrontal regions. Critically, these connectivity changes coincided with local hypotrophy of BLA and CMA subregions (without being statistically correlated) and were associated to more severe CU symptoms.
CONCLUSIONS: These findings provide unique insights into a putative mechanism for perturbed attention-emotion interactions, which could bias salience processing and associative learning in youth with CD/CU+.

PMID: 27502216 [PubMed - indexed for MEDLINE]




Serotonin 1B Receptor Binding Is Associated With Trait Anger and Level of Psychopathy in Violent Offenders.
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Serotonin 1B Receptor Binding Is Associated With Trait Anger and Level of Psychopathy in Violent Offenders.

Biol Psychiatry. 2017 Aug 15;82(4):267-274

Authors: da Cunha-Bang S, Hjordt LV, Perfalk E, Beliveau V, Bock C, Lehel S, Thomsen C, Sestoft D, Svarer C, Knudsen GM

Abstract
BACKGROUND: The involvement of serotonin in aggression has traditionally been attributed to impaired prefrontal serotonergic inhibitory control of emotional reactions to provocations in antisocial individuals. However, it is unclear which specific serotonergic receptors are involved in the effects. A large body of preclinical research supports a specific role of serotonin 1B receptors (5-HT1BRs) in aggression and impulsivity, but this has never been evaluated in humans.
METHODS: Nineteen incarcerated violent offenders and 24 healthy control nonoffenders were included and examined with positron emission tomography, using the radioligand [11C]AZ10419369 for quantification of cerebral 5-HT1BR binding in three regions of interest: the anterior cingulate cortex, orbitofrontal cortex, and striatum.
RESULTS: Group status significantly moderated the association between striatal 5-HT1BRs and trait anger (difference in slopes, pcorrected = .04). In the violent offender group, striatal 5-HT1BR binding was positively correlated with self-reported trait anger (p = .0004), trait psychopathy (p = .008), and level of psychopathy according to the Psychopathy Checklist-Revised (p = .02). We found no group differences in 5-HT1BR binding.
CONCLUSIONS: Our data demonstrate for the first time in humans a specific involvement of 5-HT1BR binding in anger and psychopathy. 5-HT1BRs putatively represent a molecular target for development of pharmacologic antiaggressive treatments.

PMID: 27108021 [PubMed - indexed for MEDLINE]




Brain Regions Related to Impulsivity Mediate the Effects of Early Adversity on Antisocial Behavior.
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Brain Regions Related to Impulsivity Mediate the Effects of Early Adversity on Antisocial Behavior.

Biol Psychiatry. 2017 Aug 15;82(4):275-282

Authors: Mackey S, Chaarani B, Kan KJ, Spechler PA, Orr C, Banaschewski T, Barker G, Bokde ALW, Bromberg U, Büchel C, Cattrell A, Conrod PJ, Desrivières S, Flor H, Frouin V, Gallinat J, Gowland P, Heinz A, Ittermann B, Paillère Martinot ML, Artiges E, Nees F, Papadopoulos-Orfanos D, Poustka L, Smolka MN, Jurk S, Walter H, Whelan R, Schumann G, Althoff RR, Garavan H, IMAGEN Consortium

Abstract
BACKGROUND: Individual differences in impulsivity and early adversity are known to be strong predictors of adolescent antisocial behavior. However, the neurobiological bases of impulsivity and their relation to antisocial behavior and adversity are poorly understood.
METHODS: Impulsivity was estimated with a temporal discounting task. Voxel-based morphometry was used to determine the brain structural correlates of temporal discounting in a large cohort (n = 1830) of 14- to 15-year-old children. Mediation analysis was then used to determine whether the volumes of brain regions associated with temporal discounting mediate the relation between adverse life events (e.g., family conflict, serious accidents) and antisocial behaviors (e.g., precocious sexual activity, bullying, illicit substance use).
RESULTS: Greater temporal discounting (more impulsivity) was associated with 1) lower volume in frontomedial cortex and bilateral insula and 2) greater volume in a subcortical region encompassing the ventral striatum, hypothalamus and anterior thalamus. The volume ratio between these cortical and subcortical regions was found to partially mediate the relation between adverse life events and antisocial behavior.
CONCLUSIONS: Temporal discounting is related to regions of the brain involved in reward processing and interoception. The results support a developmental imbalance model of impulsivity and are consistent with the idea that negative environmental factors can alter the developing brain in ways that promote antisocial behavior.

PMID: 26971049 [PubMed - indexed for MEDLINE]