_page-0001.jpg)
.png)
INTRODUCTION: Aggression is one of most enduring, complex, and problematic forms of human social interaction. The consequences of human aggression exact a substantial toll on public health and criminal justice systems, communities, and individuals. Epidemiological and experimental data show that chronic alcohol dependence is related to an increased risk for assault and aggressive behavior. By some estimates, as much as 50% of all violent crimes, and greater than 60% of intimate partner violence, involve alcohol. A review of the neurobiology of personality disorders concluded that impulsive aggression was characterized by abnormal functioning in amygdala, OFC, DLPFC, and anterior cingulate cortex (ACC)4 . In the present study, we employed a well-validated laboratory task the Point Subtraction Aggression Paradigm (PSAP; 1) that was adapted for use during fMRI. The PSAP allows for control and manipulation of independent variables, including the frequency of provocation. The timing and frequency of experimental events can be precisely controlled, allowing for examination of neural activity when individuals are provoked and during bouts of aggressive behavior. Based on previous work in the neurobiology of aggression and brain imaging studies of alcohol-dependent subjects, we hypothesized that compared to control subjects alcohol-dependent subjects would demonstrate (a) more aggressive responding on the PSAP; (b) reduced BOLD activation in frontal cortex (notably, OFC) and the limbic system (reflecting diminished activation of emotional regulatory circuitry); and (c) greater ROI BOLD activation in amygdala following provocation and during aggressive responding.
METHODS:
Subjects: This study was approved by the local IRB (at UTHSC Houston) and in accordance with the Declaration of Helsinki. Participants were recruited through local classified newspaper advertisements. Exclusionary criteria included (a) current or past medical problems (e.g. seizures, diabetes, high blood pressure, renal or cardiovascular disease), (b) current use of any medications, (c) current illicit drug use or alcohol use (measured by daily urinalysis and breath alcohol testing), and (d) current of past history of an Axis I mood or psychotic disorder, as determined by the Structured Clinical Interview for the DSM-4 (SCID-I, version 2.0, First et al., 1996). All subjects with past alcohol dependence met DSM-4 criteria for alcohol dependence within the past 24 months, and were in early full remission, early partial remission, or sustained full remission. At intake, subjects read and signed an informed consent document. Subjects were provided information about urine drug testing, breath alcohol testing, psychiatric evaluation, experimental procedures and compensation. After consent, subjects provided urine samples for drug screen analysis using a one-step drug screen test card (Innovacon, Inc.), which tested for cocaine, stimulants, opiates, benzodiazepines and marijuana. Temperature monitoring and creatinine level determinations were used to detect attempts to alter urine samples. Subjects also provided breath alcohol samples using an AlcoSensor III (Intoximeters, Inc.), which required subjects to expire air for 10 seconds to measure alcohol content. No differences were observed in subject demographics, including gender [Fisher’s exact=0.41, ns]; age [t (24)=1.29, ns]; education level [t (24)=0.51, ns]; number of smokers [6 in each group]; level of tobacco use [Mann-Whitney U, z=0.78, ns]; Shipley scale cognitive aptitude (Zachary, 1986) [t (24)=0.75, ns]; or lifetime use of other drugs [Fisher’s exact=0.24, ns]. Demographic information on the two groups is provided in Table 1. Subjects came to the lab for 3 days. They provided breath and urine samples each day upon arrival. Subjects were removed from the study if they provided two consecutive alcohol positive breath or drug-positive urine samples. Two subjects were excluded from the study for consecutive positive THC samples. All other subjects were free of illicit drugs and alcohol on all testing days. On the first test day, subjects were instructed on the PSAP and completed 3 practice PSAP sessions in a mock-scanner (Philips) to familiarize them with the protocol, habituate them with the scanner environment and stabilize aggressive responding. Behavioral Assessments: Subjects performed a version of the Point Subtraction Aggression Paradigm (PSAP, 2), a well-validated laboratory measure of human aggression that was adapted for fMRI. The paradigm utilized a computer-simulated social interaction in which subjects were paired with a fictitious other person, as established by instructional deception. Before the first test session, subjects were shown a diagram of the computer monitor and response panel and were read instructions. There was no use of terms such as aggression, game, competition, or anything that might indicate the behavior of interest. During the task, subjects had two response options available, labeled A or B on the computer screen. The money-earning option (A) added $2.00 to the subject’s earnings counter (shown near the top of the screen) after a fixed response ratio of 40 responses was completed. The aggressive option (B) ostensibly subtracted $2.00 from the “other” person, at no gain to the subject, after a fixed ratio of 10 responses. Throughout the task, subjects were periodically provoked via $2.00 subtractions from their earnings, and instructed that when the “other” person chose the B option s/he kept the $2.00 subtraction (providing an ostensible reason for subtractions). No provocations occurred when the counter was at $0. All provocations occurred at randomly scheduled intervals that occurred on average every 90 sec, and were scheduled only during bouts of pressing on the A (monetary) option; this allowed independent assessment of neural activation patterns (a) during provocation prior to the initiation of aggressive responding, and (b) during aggressive responding. Switching to option B (aggressive) was only permitted after the completion of a ratio. However, there were no restrictions on the initiation of consecutive A ratios or B ratios. fMRI Protocol: All subjects underwent scanning on a Philips 3.0 T Intera system with SENSE head coil (Philips Medical Systems, Best, Netherlands). Spin-echo Echo Planar Imaging (EPI) fMRI with a pulse sequence sensitive to BOLD effect at 3.0 T was utilized to eliminate signal dropout in the medial orbitofrontal region, a key region of interest. The fMRI images were acquired in the transverse plane using single shot spin-echo EPI with SENSE acceleration factor of 2.0, repetition time (TR) of 2200 ms, echo time (TE) of 75 ms, flip angle of 90 degree, number of slices=22, in-plane resolution of 3.75 mm x 3.75 mm, slice thickness of 3.75 mm; gap between slices 1.25 mm, 290 whole brain dynamic volumes per run Transverse plane acquisition, and a run duration of 10 min 38 s. Each subject completed 3 runs in separated by approximately 5 minutes. A high-resolution T-1 weighted 3D-MPRAGE structural scan (0.94 mm x 0.94 mm x 0.94 mm) was acquired for co-registration with the fMRI scans. Statistical analysis of the fMRI data was conducted using SPM8. Statistical analyses utilized SPM8 Random Effects models, with two-tailed corrected cluster-level p<0.05.
RESULTS AND DISCUSSION: Here we utilized the PSAP with fMRI to better understand the neural correlates of reactive aggression in individuals with past alcohol dependence. Alcohol-dependent subjects produced more aggressive responses per provocation than control subjects, but also made significantly more monetary responses. Rates of monetary earnings and subtractions were similar even though alcohol-dependent subjects made more overall responses on both the monetary and aggressive options. This could reflect diminished inhibitory control over responding, greater problems organizing patterned motor movements, poor adherence to instructional control, or some combination thereof. Analysis of BOLD activation during aggressive responding and following provocation revealed between-group differences cortically in postcentral gyrus, middle frontal gyrus, and precentral gyrus, and subcortically in the basal ganglia (primarily dorsal striatum). In all regions, subjects with past alcohol dependence showed less activation than controls. Broadly, these regions most well established functions include visual motor processing, and planning and coordinating complex movements. Chronic alcohol use may disrupt activation of the collective emotional/inhibitory circuitry and manifest as a general inhibitory control deficit . When all 26 subjects were combined across groups and aggressive responding (B_response) was regressed on the contrast of postprovocation to non-provocation responding (PA), we observed one statistically significant positive regression slope located in a contiguous cluster comprising the fusiform gyrus, parahippocampal gyrus, and postcentral gyrus. These regions are most well established in subserving sensorimotor functions, including visual and tactile information processing and coordination of motor movements. Multiple clusters were observed in the significant negative regression slopes. These multiple clusters involved orbitofrontal cortex, prefrontal cortex, and caudate and putamen. The negative relationships suggest that aggressive behavior on the PSAP was related to decreased activation in these regions. The present data suggest that the dorsal striatum may play a role in modulating response to aversive stimuli. More broadly, current theories propose that it is the interconnected network between the limbic, OFC, and DLPFC regions that primarily subserve the processing of emotional and goal driven behavior, and that damage or dysfunction in this network results in problems with the regulation of emotion and subsequent difficulties with response inhibition, decision making, and aggressive behavior5 .