A significant portion of violent crimes are committed by individuals meeting criteria for antisocial personality disorder (ASPD), with approximately one-third of these individuals also exhibiting psychopathy (ASPD + P). These individuals display callous-unemotional traits, begin offending earlier, and engage in more extensive criminal behavior compared to those with ASPD but without psychopathy (ASPD – P). Current treatment options are limited, with no established pharmacological interventions. Understanding the underlying neurobiological mechanisms, specifically deficits in emotional and empathic processing, is crucial for developing effective treatments. Abnormalities in reinforcement-based decision-making and emotional responsiveness contribute to the behaviors observed in these individuals. Previous research has highlighted differences in neural responses to punishment between those with and without psychopathy. Deficits in empathic processing, particularly in recognizing and responding to fear and distress in others, seem more pronounced in ASPD + P individuals. This reduced ability to recognize distress may be linked to their use of goal-directed instrumental aggression, driven less by concern for the victim's suffering and fear of punishment. While studies have examined explicit emotion recognition and neural responses to empathy-inducing stimuli in individuals with psychopathy, the implicit neural responses to fearful facial expressions—a crucial aspect of empathic processing—have been under-explored, particularly in a controlled comparison between ASPD + P and ASPD – P individuals. Healthy individuals exhibit distinct neural systems for processing specific emotions, with the amygdala, insula, and anterior/mid-cingulate cortex playing significant roles in processing fearful expressions. Studies in antisocial youth have shown reduced amygdala activity in response to fearful faces in children with high callous-unemotional traits (a precursor to ASPD + P) but increased activity in those with low callous-unemotional traits (a precursor to ASPD – P). Existing adult studies on implicit neural processing of fearful expressions in violent antisocial men are limited by small sample sizes, lack of control groups, or unclear ASPD diagnoses. No prior research has examined the potential of pharmacological agents, such as oxytocin, to modify these neural differences. Oxytocin, a neuropeptide crucial for social behavior regulation, interacts with receptors in brain regions implicated in ASPD (amygdala and cingulate cortex). In healthy individuals, oxytocin enhances both explicit recognition of fearful faces and activity within fear-processing brain regions. Limited behavioral evidence suggests oxytocin may improve fearful expression recognition in antisocial adults. This study aimed to investigate the impact of oxytocin on implicit neural responses to varying intensities of fearful facial expressions in violent male offenders with ASPD + P, ASPD – P, and healthy controls. The hypotheses were: 1) Violent offenders with ASPD + P would show reduced modulation by fearful expression intensity within the amygdala, anterior insula, and bilateral anterior/mid-cingulate cortices compared to both ASPD – P offenders and healthy controls under placebo; and 2) Intranasal oxytocin administration would reduce group differences in neural responding to fearful expression intensity within these regions.

The literature review section thoroughly examines prior research on the neurobiological underpinnings of antisocial behavior, particularly in individuals with ASPD and psychopathy. It discusses studies focusing on reinforcement learning deficits, emotional responsiveness abnormalities, and specifically, impairments in empathic processing. The review highlights the discrepancies in amygdala activity observed in response to fearful faces in antisocial youth and adults, noting the inconsistencies and limitations of prior fMRI studies on implicit neural processing of fearful expressions in violent offenders with varying degrees of psychopathy. The critical role of oxytocin in social cognition and its potential therapeutic effects on emotion recognition is explored, highlighting the lack of prior research on the neural effects of oxytocin in this specific population.

This double-blind, placebo-controlled, randomized crossover study involved 58 male participants aged 20-58 years with an IQ > 70. Participants were divided into three groups: 24 healthy non-offenders (NO), 15 violent offenders with ASPD without psychopathy (ASPD – P), and 19 violent offenders with ASPD and psychopathy (ASPD + P). Psychopathy was determined using the Psychopathy Checklist-Revised (PCL-R), with a cut-off score of 25. Participants completed diagnostic interviews and authorized access to criminal records. The Reactive-Proactive Aggression Questionnaire (RPQ) assessed aggression levels. In a randomized crossover design, each participant received 40 IU of intranasal oxytocin (IN-OT) or a placebo in two separate sessions, with a functional MRI (fMRI) scan after each administration. During fMRI scanning, participants performed a morphed faces task, rating the gender of faces with varying intensities (40%, 60%, 80%, 100%) of fearful expressions. Urine samples were collected to assess for substance misuse. The fMRI data were analyzed using a three-group (NO, ASPD – P, ASPD + P) by two-condition (placebo, oxytocin) 3dMVM model to investigate the modulation of neural activity by fear intensity. Regions of interest (ROIs) included the amygdala, anterior insula, and mid-cingulate cortex. Statistical analysis included repeated-measures analysis of variance for behavioral data (accuracy and response latency) and 3dMVM for fMRI data. Multiple comparison corrections were applied to account for the multiple brain regions examined.

Behavioral data showed no significant differences in accuracy or response latency across groups or conditions. fMRI results revealed significant activation in the visual cortex and fusiform gyrus related to fearful expression modulation. Key findings from the ROI analyses are summarized below: * **Placebo Condition:** Violent offenders with ASPD + P showed significantly reduced modulation of blood-oxygen-level-dependent (BOLD) response by fearful expression intensity in the bilateral mid-cingulate cortex and right anterior insula compared to ASPD – P offenders. * **Oxytocin Condition:** Violent offenders with ASPD + P showed significant increases in modulation by fearful expression intensity in bilateral mid-cingulate cortex and left anterior insula under oxytocin compared to placebo. * **Interaction Effect:** Oxytocin abolished the group differences (ASPD + P vs. ASPD – P) observed under placebo conditions in the left mid-cingulate cortex. No significant main effects or group differences were found in the amygdala. Table 1 provides a detailed breakdown of the significant BOLD responses, including brain regions, Brodmann areas, voxel counts, coordinates, and statistical values. Figure 1 illustrates the group differences in the placebo condition, showing reduced modulation in the mid-cingulate cortex and right anterior insula for ASPD + P individuals. Figure 2 shows the increased modulation in these regions following oxytocin administration in the ASPD + P group.

The findings support the hypothesis that individuals with ASPD + P exhibit reduced reactivity in brain regions associated with fear processing compared to ASPD – P individuals. This reduced reactivity in the anterior insula (involved in stimulus salience) and mid-cingulate cortex (crucial for reactive fear circuitry and coordinating emotional responses) is consistent with existing literature, suggesting impaired processing of distress cues in ASPD + P, potentially contributing to their aggressive behavior. The novel finding of oxytocin abolishing these group differences in the mid-cingulate cortex provides the first evidence, to the authors' knowledge, that neurochemical interventions can modulate these core deficits. The increased modulation of fearful expression intensity in the mid-cingulate cortex and insula following oxytocin administration suggests that oxytocin enhances the salience of fearful faces, potentially leading to altered behavioral responses. These results highlight the potential of oxytocin as a therapeutic agent for addressing core deficits in psychopathy.

This study demonstrates significant differences in the implicit processing of fearful facial expressions between violent male offenders with and without psychopathy. Oxytocin effectively normalized these group differences in the mid-cingulate cortex. This provides compelling evidence for neurochemical modulation of empathic processing deficits in psychopathy, opening promising avenues for developing targeted treatments for this disorder. Future research should explore the long-term effects of oxytocin and investigate potential behavioral changes associated with these neural modulations.

Some limitations should be considered. The reduced anterior insula reactivity in ASPD + P under placebo did not survive strict multiple comparison corrections, requiring replication in a larger sample. Inconsistencies regarding the hemispheric laterality of oxytocin effects in fMRI studies warrant cautious interpretation of the unilateral effects observed. The findings in the mid-cingulate cortex included some white matter, though steps were taken to mitigate potential noise. While significant differences were observed between the ASPD + P and ASPD – P groups, differences relative to the healthy control group were not always significant, potentially due to underpowered samples. The lack of significant findings in the amygdala and the limited assessment of behavioral impact also warrant caution. Despite controlling for substance misuse, some differences remained, which could have influenced the findings.