Evidence for a dysfunctional prefrontal circuit in patients with an impulsive aggressive disorder

Intermittent explosive disorder (IED), as described in DSM-5, is the categorical expression of pathological impulsive aggression. Previous work has identified neurobiological correlates of the disorder in patterns of frontal-limbic brain activity and dysregulation of serotonergic neurotransmission. Given the importance of short-and-long range white matter connections of the brain in social and emotional behavior, studies of white matter connectivity in impulsive aggression are warranted. Diffusion tensor imaging (DTI) studies in the related conditions of antisocial and borderline personality disorder have produced preliminary evidence of disturbed white matter connectivity in these disorders, but to date there have been no DTI studies in IED. A total of 132 male and female adults between the ages of 18 and 55 years underwent Turboprop-DTI on a 3-Tesla MRI scanner. Of these, 42 subjects had IED, 40 were normal controls, and 50 were clinical psychiatric controls with psychiatric disorders without IED. All subjects were free of alcohol, psychotropic medications, or drugs of abuse. The diffusion tensor was calculated in each voxel and maps of fractional anisotropy (FA) were generated. Tract-based spatial statistics (TBSS) were used to compare FA along the white matter skeleton among the three subject groups. IED was associated with lower FA in two clusters located in the superior longitudinal fasciculus (SLF) when compared with the psychiatric and healthy controls. Impulsive aggression and borderline personality disorder, but not psychopathy or antisocial personality disorder, was associated with lower FA in the two clusters within the SLF. In conclusion, IED was associated with lower white matter integrity in long-range connections between the frontal and temporoparietal regions.

Section: Introductionmentioning

confidence: 66%

White Matter Integrity Reductions in Intermittent Explosive Disorder

Lee

Arfanakis

Evia

et al. 2016

“…Statistical parametric maps (SPMs) were produced from linear contrasts of interest: each face category versus baseline (eg, angry4fixation) and all faces4fixation. We opted for this latter contrast to use in the group-level analyses for several reasons: (1) because of the application of high-pass filtering, condition (face expression)-specific effects are partly removed; (2) amygdala activation to the 'neutral' expressionless faces have been shown to also activate the amygdala to the same extent as emotional faces (Fitzgerald et al, 2006); and (3) IED subjects have been shown to mislabel 'neutral' faces as conveying negative emotions (Best et al, 2002). To test whole-brain voxel-wise effects, a full-factorial model was set up in SPM.…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, IED patients showed less amygdala-orbitofrontal cortex connectivity than controls, suggesting reduced regulatory control of the prefrontal cortex. Previous work already showed that IED patients make disadvantageous choices on the Iowa gambling task, hinting at the possibility of disrupted prefrontal functioning (Best et al, 2002). The limited available research on the neural systems underlying IED so far thus points at a disrupted amygdala-prefrontal circuitry, yet a complex disorder like IED undoubtedly involves an even broader network of brain regions.…”

Section: Introductionmentioning

confidence: 99%

Effects of Escitalopram Administration on Face Processing in Intermittent Explosive Disorder: An fMRI Study

Cremers

Lee

Keedy

et al. 2015

The neurobiological underpinnings of intermittent explosive disorder (IED) are traditionally linked to deficiencies in the serotonergic system. In this study, we investigated the effects of escitalopram, a selective serotonin reuptake inhibitor (SSRI), on brain activation during face processing. We expected that escitalopram would reduce amygdala activity in IED and in addition, we explored the effect in other social-emotional-related brain regions. A total of 17 subjects with current IED and 14 healthy controls participated in a randomized, double-blind, placebo-controlled, counterbalanced fMRI face processing study. The analysis focused on the faces compared to a fixation baseline contrast, and a factorial model with Group as between-subject and Drug as within-subject factor was tested. Group × Drug interaction effects were found in the amygdala (small volume corrected) and the left temporal parietal junction (TPJ; whole-brain corrected). Escitalopram increased amygdala activation in controls, but surprisingly not in IED. However, the TPJ showed increased activity in IED on escitalopram compared with placebo. The TPJ is associated with social-cognitive processes, such as perspective taking and empathy. The TPJ findings suggest that SSRI administration may reduce aggressive tendencies towards other people by enhancing these social-cognitive processes. Future research should further elucidate the long-term effects of SSRIs on various social-emotional tasks in IED.

“…5-HT neurons project from the dorsal raphé (DRN) to the PFC and there has been increasing evidence that dysfunctions in these neurons may underlie impulsive behavior and aggression (Grafman et al, 1996;Bechara et al, 2000;Brower and Price, 2001;Chudasama et al, 2003;Best et al, 2002;Spinella, 2004). For these reasons, presynaptic 5-HT 1B receptors located in this region might be important modulators of Alc-heightened aggression.…”

Section: Introductionmentioning

confidence: 99%

Escalated Aggression after Alcohol Drinking in Male Mice: Dorsal Raphé and Prefrontal Cortex Serotonin and 5-HT1B Receptors

Faccidomo

Bannai

Miczek

2008

A significant minority of individuals engages in escalated levels of aggression after consuming moderate doses of alcohol (Alc). Neural modulation of escalated aggression involves altered levels of serotonin (5-HT) and the activity of 5-HT 1B receptors. The aim of these studies was to determine whether 5-HT 1B receptors in the dorsal raphé (DRN), orbitofrontal (OFC), and medial prefrontal (mPFC) cortex attenuate heightened aggression and regulate extracellular levels of 5-HT. Male mice were trained to self-administer Alc by performing an operant response that was reinforced with a delivery of 6% Alc. To identify Alc-heightened aggressors, each mouse was repeatedly tested for aggression after consuming either 1.0 g/kg Alc or H 2 O. Next, a cannula was implanted into either the DRN, OFC, or mPFC, and subsets of mice were tested for aggression after drinking either Alc or H 2 O prior to a microinjection of the 5-HT 1B agonist, CP-94,253. Additional mice were implanted with a microdialysis probe into the mPFC, through which CP-94,253 was perfused and samples were collected for 5-HT measurement. Approximately 60% of the mice were more aggressive after drinking Alc, confirming the aggression-heightening effects of 1.0 g/kg Alc. Infusion of 1 mg CP-94,253 into the DRN reduced both aggressive and motor behaviors. However, infusion of 1 mg CP-94,253 into the mPFC, but not the OFC, after Alc drinking, increased aggressive behavior. In the mPFC, reverse microdialysis of CP-94,253 increased extracellular levels of 5-HT; levels decreased immediately after the perfusion. This 5-HT increase was attenuated in self-administering mice. These results suggest that 5-HT 1B receptors in the mPFC may serve to selectively disinhibit aggressive behavior in mice with a history of Alc self-administration.