Machine learning approaches for parsing comorbidity/heterogeneity in antisociality and substance use disorders: A primer.

By some accounts, as many as 93% of individuals diagnosed with antisocial personality disorder (ASPD) or psychopathy also meet criteria for some form of substance use disorder (SUD). This high level of comorbidity, combined with an overlapping biopsychosocial profile, and potentially interacting features, has made it difficult to delineate the shared/unique characteristics of each disorder. Moreover, while rarely acknowledged, both SUD and antisociality exist as highly heterogeneous disorders in need of more targeted parcellation. While emerging data-driven nosology for psychiatric disorders (e.g., Research Domain Criteria (RDoC), Hierarchical Taxonomy of Psychopathology (HiTOP)) offers the opportunity for a more systematic delineation of the externalizing spectrum, the interrogation of large, complex neuroimaging-based datasets may require data-driven approaches that are not yet widely employed in psychiatric neuroscience. With this in mind, the proposed article sets out to provide an introduction into machine learning methods for neuroimaging that can help parse comorbid, heterogeneous externalizing samples. The modest machine learning work conducted to date within the externalizing domain demonstrates the potential utility of the approach but remains highly nascent. Within the paper, we make suggestions for how future work can make use of machine learning methods, in combination with emerging psychiatric nosology systems, to further diagnostic and etiological understandings of the externalizing spectrum. Finally, we briefly consider some challenges that will need to be overcome to encourage further progress in the field.

Altered power spectra in antisocial males during rest as a function of cocaine dependence: A network analysis.

Abnormalities in the spectral power of offenders' neural oscillations have been noted within select Resting-State Networks (RSNs); however, no study has yet evaluated the influence of cocaine dependence, drug use severity, and psychopathic traits on these abnormalities. To this end, the present study compared rest-related power spectral characteristics between two groups of offenders (with and without a DSM-IV-TR cocaine-dependence diagnosis) and a non-offender control group. Results indicated that both offender groups presented with lower low frequency power ratio (LFPR) scores (i.e. across all RSNs) than non-offenders. These differences in LFPR scores were due to both higher high-frequency power (0.15-0.25 Hz; within seven (in non-dependent offenders) and five (in cocaine-dependent offenders) of eight investigated networks) and decreased low-frequency power (0.01-0.10 Hz; within six (in non-dependent offenders) and one (in cocaine-dependent offenders) of eight investigated networks) compared to non-offenders. Thus, both cocaine-dependent and non-dependent offenders displayed abnormal neural oscillations, suggesting that these oscillatory abnormalities could exist as neurobiological features associated with offender status. Offenders' LFPR levels correlated with lifetime years of cocaine use, but not with the level of psychopathic traits. These findings supplement our knowledge regarding the influence of substance use on resting-state activity in offenders; moreover, they provide further indication of the importance of evaluating shared/unique variance associated with drug use and pyschopathic personality traits.

History of withdrawal modulates drug- and food-cue reactivity in cocaine dependent participants.

While the centrality of withdrawal in the diagnosis of addiction has been decreasing with each successive edition of the Diagnostic and Statistical Manual of Mental Disorders, psychometric and neurobiological evidence provides withdrawal a central role in the development and maintenance of addiction. The current study offers insight into these conflicting positions by using secondary analyses to assess how a history of DSM-assessed withdrawal influences the magnitude of bias in neural reactivity to drug- and/or food-related reward cues. To this end, we separated an existing sample of cocaine-dependent participants (Denomme et al., 2018) into those with (WD) and without (N-WD) a history of withdrawal, and compared food- and drug-cue reactivity between these groups, and to a non-dependent control group (ND). Analyses indicated that biases in neural reactivity towards drug- versus food-related cues only occurred among the WD participants (within: left dorsomedial prefrontal cortex, left anterior cingulate cortex, left orbitofrontal cortex, left caudate nucleus, and right ventrolateral prefrontal cortex). Thus, withdrawal status may be an important factor to consider when interpreting dependence-related biases in neural reactivity following reward-related cues. Interestingly, while N-WD participants did not show these broad biases in neural reactivity, the magnitude of their bias correlated positively with years of lifetime substance use history, particularly when psychopathic traits were low. It may be that for individuals who's addiction has not yet reached a compulsive state (see Wise and Koob, 2014), the magnitude of their drug > food bias could serve as a valuable biomarker of addiction severity.

Neuroimaging Metrics of Drug and Food Processing in Cocaine-Dependence, as a Function of Psychopathic Traits and Substance Use Severity.

Previous studies suggest that psychopathic traits commonly present as comorbid with substance use disorders. Moreover, neuroimaging and psychometric findings suggest that psychopathic traits may predispose individuals to a sensitized reward response to drugs. Given that substance use disorders are characterized by a neurocognitive bias toward drug-reward relative to non-drug reward, it is possible that heightened psychopathic characteristics may further predispose to this processing bias. To evaluate this possibility, we assessed psychopathic traits (measured using the PCL-R; Hare, 2003) in 105 probationers/parolees and evaluated the relationship between PCL-R scores, lifetime duration of drug use, and biases in neural response to drug- compared to food-related videos. Psychopathic traits (potentially driven by interpersonal/affective traits) were positively correlated with drug > food reactivity within the right insula and left amygdala. In addition, psychopathic traits modulated the relationship between drug use and drug > food reactivity within the left dorsomedial prefrontal cortex, right insula, and left caudate nucleus. Specifically, lifetime duration of drug use correlated positively with drug > food reactivity in participants with lower levels of psychopathic traits and correlated negatively with drug > food reactivity in individuals with higher levels of psychopathic traits. These results help reconcile prior studies on psychopathy and drug-stimulus processing and provide neurocognitive support for the notion that psychopathic traits serve as an underlying risk factor for substance use disorders. These results suggest that different treatment regimens for substance abuse for individuals with higher or lower levels of psychopathy may be beneficial and suggest that reduction of neurocognitive biases to drug-related stimuli may offer useful targets for future treatment protocols.

Capacity for upregulation of emotional processing in psychopathy: all you have to do is ask.

Historically, psychopathic individuals have been described as suffering a chronic hyporesponsivity to negatively valent stimuli. However, while a wide body of empirical work indicates that the psychopath does not manifest normal reactivity to emotional stimuli, it does not similarly indicate that they cannot do so. To attempt to differentiate these alternatives, the current functional magnetic resonance imaging (fMRI) study evaluated the extent to which offenders with varying PCL-R scores could up- (or down-) regulate their neural response to negatively valent stimuli. Participants were asked to either watch negatively- and neutrally-valent images naturally (passive-processing), or to try to increase or decrease their emotional response to the images (instructed-processing). During passive processing, high-psychopathy offenders showed reduced activity compared to both low- and mid-psychopathic offenders through a majority of emotion-relevant regions. However, when participants were instructed to try to increase their emotional response all groups showing increased activity throughout relevant regions, including left insula, orbitofrontal cortex and anterior cingulate/medial frontal cortex (ACC/mFC). Comparison of participants' subjective emotion ratings indicated that all groups showed symmetry between their neural/subjective emotion metrics, and the high-psychopathy group may have showed the greatest such symmetry. These findings suggest that psychopathic individuals may be capable of manifesting emotional reactivity to negatively valent stimuli, at least under certain conditions. Relevance for traditional and developing models of psychopathy is discussed in turn.

dACC response to presentation of negative feedback predicts stimulant dependence diagnosis and stimulant use severity.

Error-monitoring abnormalities in stimulant-dependent individuals (SDIs) may be due to reduced awareness of committed errors, or to reduced sensitivity upon such awareness. The distinction between these alternatives remains largely undifferentiated, but may have substantial clinical relevance. We sought to better characterize the nature, and clinical relevance, of SDIs' error-monitoring processes by comparing carefully isolated neural responses during the presentation of negative feedback to a) stimulant dependence status and b) lifetime stimulant use. Forty-eight SDIs and twenty-three non-SDIs performed an fMRI-based time-estimation task specifically designed to isolate neural responses associated with the presentation (versus expectation) of contingent negative feedback. SDIs showed reduced dACC response compared to non-SDIs following the presentation of negative feedback, but only when error expectancies were controlled. Moreover, lifetime stimulant use correlated negatively with magnitude of expectancy-controlled dACC attenuation. While this finding was minimized after controlling for age, these results suggest that SDIs may be characterized by a core reduction in neural activity following error feedback, in the context of intact feedback expectancies. Correlations with lifetime stimulant use suggest that this neural attenuation may hold clinical significance.

Up-regulation of neural indicators of empathic concern in an offender population.

Empathic concern has traditionally been conceived of as a spontaneous reaction to others experiencing pain or distress. As such, the potential role of more deliberate control over empathic responses has frequently been overlooked. The present fMRI study evaluated the role of such deliberate control in empathic concern by examining the extent to which a sample of offenders recruited through probation/parole could voluntarily modulate their neural activity to another person in pain. Offenders were asked to either passively view pictures of other people in painful or non-painful situations, or to actively modulate their level of concern for the person in pain. During passive viewing of painful versus non-painful pictures, offenders showed minimal neural activity in regions previously linked to empathy for pain (e.g., dorsal anterior cingulate cortex and bilateral insula). However, when instructed to try to increase their concern for the person in pain, offenders demonstrated significant increases within these regions. These findings are consistent with recent theories of empathy as motivational in nature, and suggest that limitations in empathic concern may include a motivational component.

Voluntary modulation of anterior cingulate response to negative feedback.

Anterior cingulate and medial frontal cortex (dACC/mFC) response to negative feedback represents the actions of a generalized error-monitoring system critical for the management of goal-directed behavior. Magnitude of dACC/mFC response to negative feedback correlates with levels of post-feedback behavioral change, and with proficiency of operant learning processes. With this in mind, it follows that an ability to alter dACC/mFC response to negative feedback may lead to representative changes in operant learning proficiency. To this end, the present study investigated the extent to which healthy individuals would show modulation of their dACC/mFC response when instructed to try to either maximize or minimize their neural response to the presentation of contingent negative feedback. Participants performed multiple runs of a standard time-estimation task, during which they received feedback regarding their ability to accurately estimate a one-second duration. On Watch runs, participants were simply instructed to try to estimate as closely as possible the one second duration. On Increase and Decrease runs, participants performed the same task, but were instructed to "try to increase [decrease] their brain's response every time they received negative feedback". Results indicated that participants showed changes in dACC/mFC response under these differing instructional conditions: dACC/mFC activity following negative feedback was higher in the Increase condition, and dACC activity trended lower in the Decrease condition, compared to the Watch condition. Moreover, dACC activity correlated with post-feedback performance adjustments, and these adjustments were highest in the Increase condition. Potential implications for neuromodulation and facilitated learning are discussed.

Examining the effect of psychopathic traits on gray matter volume in a community substance abuse sample.

Psychopathy is believed to be associated with brain abnormalities in both paralimbic (i.e., orbitofrontal cortex, insula, temporal pole, parahippocampal gyrus, posterior cingulate) and limbic (i.e., amygdala, hippocampus, anterior cingulate) regions. Recent structural imaging studies in both community and prison samples are beginning to support this view. Sixty-six participants, recruited from community corrections centers, were administered the Hare psychopathy checklist-revised (PCL-R), and underwent magnetic resonance imaging (MRI). Voxel-based morphometry was used to test the hypothesis that psychopathic traits would be associated with gray matter reductions in limbic and paralimbic regions. Effects of lifetime drug and alcohol use on gray matter volume were covaried. Psychopathic traits were negatively associated with gray matter volumes in right insula and right hippocampus. Additionally, psychopathic traits were positively associated with gray matter volumes in bilateral orbital frontal cortex and right anterior cingulate. Exploratory regression analyses indicated that gray matter volumes within right hippocampus and left orbital frontal cortex combined to explain 21.8% of the variance in psychopathy scores. These results support the notion that psychopathic traits are associated with abnormal limbic and paralimbic gray matter volume. Furthermore, gray matter increases in areas shown to be functionally impaired suggest that the structure-function relationship may be more nuanced than previously thought.

Neural development of mentalizing in moral judgment from adolescence to adulthood.

The neural mechanisms underlying moral judgment have been extensively studied in healthy adults. How these mechanisms evolve from adolescence to adulthood has received less attention. Brain regions that have been consistently implicated in moral judgment in adults, including the superior temporal cortex and prefrontal cortex, undergo extensive developmental changes from adolescence to adulthood. Thus, their role in moral judgment may also change over time. In the present study, 51 healthy male participants age 13­53 were scanned with functional magnetic resonance imaging (fMRI) while they viewed pictures that did or did not depict situations considered by most individuals to represent moral violations, and rated their degree of moral violation severity. Consistent with predictions, a regression analysis revealed a positive correlation between age and hemodynamic activity in the temporo-parietal junction when participants made decisions regarding moral severity.This region is known to contribute to mentalizing processes during moral judgment in adults and suggests that adolescents use these types of inferences less during moral judgment than do adults. A positive correlation with age was also present in the posterior cingulate. Overall, the results suggest that the brain regions utilized in moral judgment change over development.

Modeling conflict and error in the medial frontal cortex.

Despite intensive study, the role of the dorsal medial frontal cortex (dMFC) in error monitoring and conflict processing remains actively debated. The current experiment manipulated conflict type (stimulus conflict only or stimulus and response selection conflict) and utilized a novel modeling approach to isolate error and conflict variance during a multimodal numeric Stroop task. Specifically, hemodynamic response functions resulting from two statistical models that either included or isolated variance arising from relatively few error trials were directly contrasted. Twenty-four participants completed the task while undergoing event-related functional magnetic resonance imaging on a 1.5-Tesla scanner. Response times monotonically increased based on the presence of pure stimulus or stimulus and response selection conflict. Functional results indicated that dMFC activity was present during trials requiring response selection and inhibition of competing motor responses, but absent during trials involving pure stimulus conflict. A comparison of the different statistical models suggested that relatively few error trials contributed to a disproportionate amount of variance (i.e., activity) throughout the dMFC, but particularly within the rostral anterior cingulate gyrus (rACC). Finally, functional connectivity analyses indicated that an empirically derived seed in the dorsal ACC/pre-SMA exhibited strong connectivity (i.e., positive correlation) with prefrontal and inferior parietal cortex but was anti-correlated with the default-mode network. An empirically derived seed from the rACC exhibited the opposite pattern, suggesting that sub-regions of the dMFC exhibit different connectivity patterns with other large scale networks implicated in internal mentations such as daydreaming (default-mode) versus the execution of top-down attentional control (fronto-parietal).

Aberrant neural processing of moral violations in criminal psychopaths.

A defining characteristic of psychopathy is the willingness to intentionally commit moral transgressions against others without guilt or remorse. Despite this "moral insensitivity," the behavioral and neural correlates of moral decision-making in psychopathy have not been well studied. To address this issue, the authors used functional magnetic resonance imaging (fMRI) to record hemodynamic activity in 72 incarcerated male adults, stratified into psychopathic (n = 16) and nonpsychopathic (n = 16) groups based on scores from the Hare Psychopathy Checklist-Revised (R. D. Hare, 2003), while they made decisions regarding the severity of moral violations of pictures that did or did not depict moral situations. Consistent with hypotheses, an analysis of brain activity during the evaluation of pictures depicting moral violations in psychopaths versus nonpsychopaths showed atypical activity in several regions involved in moral decision-making. This included reduced moral/nonmoral picture distinctions in the ventromedial prefrontal cortex and anterior temporal cortex in psychopaths relative to nonpsychopaths. In a separate analysis, the association between severity of moral violation ratings and brain activity across participants was compared in psychopaths versus nonpsychopaths. Results revealed a positive association between amygdala activity and severity ratings that was greater in nonpsychopaths than psychopaths, and a negative association between posterior temporal activity and severity ratings that was greater in psychopaths than nonpsychopaths. These results reveal potential neural underpinnings of moral insensitivity in psychopathy and are discussed with reference to neurobiological models of morality and psychopathy.

Testing predictions from personality neuroscience. Brain structure and the big five.

We used a new theory of the biological basis of the Big Five personality traits to generate hypotheses about the association of each trait with the volume of different brain regions. Controlling for age, sex, and whole-brain volume, results from structural magnetic resonance imaging of 116 healthy adults supported our hypotheses for four of the five traits: Extraversion, Neuroticism, Agreeableness, and Conscientiousness. Extraversion covaried with volume of medial orbitofrontal cortex, a brain region involved in processing reward information. Neuroticism covaried with volume of brain regions associated with threat, punishment, and negative affect. Agreeableness covaried with volume in regions that process information about the intentions and mental states of other individuals. Conscientiousness covaried with volume in lateral prefrontal cortex, a region involved in planning and the voluntary control of behavior. These findings support our biologically based, explanatory model of the Big Five and demonstrate the potential of personality neuroscience (i.e., the systematic study of individual differences in personality using neuroscience methods) as a discipline.

A functional imaging investigation of moral deliberation and moral intuition.

Prior functional imaging studies of moral processing have utilized 'explicit' moral tasks that involve moral deliberation (e.g., reading statements such as 'he shot the victim' and rating the moral appropriateness of the behavior) or 'implicit' moral tasks that involve moral intuition (e.g., reading similar statements and memorizing them for a test but not rating their moral appropriateness). Although the neural mechanisms underlying moral deliberation and moral intuition may differ, these have not been directly compared. Studies using explicit moral tasks have reported increased activity in several regions, most consistently the medial prefrontal cortex and temporo-parietal junction. In the few studies that have utilized implicit moral tasks, medial prefrontal activity has been less consistent, suggesting the medial prefrontal cortex is more critical for moral deliberation than moral intuition. Thus, we hypothesized that medial prefrontal activity would be increased during an explicit, but not an implicit, moral task. Participants (n=28) were scanned using fMRI while viewing 50 unpleasant pictures, half of which depicted moral violations. Half of the participants rated pictures on moral violation severity (explicit task) while the other half indicated whether pictures occurred indoors or outdoors (implicit task). As predicted, participants performing the explicit, but not the implicit, task showed increased ventromedial prefrontal activity while viewing moral pictures. Both groups showed increased temporo-parietal junction activity while viewing moral pictures. These results suggest that the ventromedial prefrontal cortex may contribute more to moral deliberation than moral intuition, whereas the temporo-parietal junction may contribute more to moral intuition than moral deliberation.

Double dissociation between perspective-taking and empathic-concern as predictors of hemodynamic response to another's mistakes.

Identifying another's mistakes requires a basic representation of other's action patterns as well as recognition and understanding of their failed goal-attainment. In previous work, we identified several regions, including inferior parietal cortex and rostral/ventral anterior cinguli (r/vACC), that show unique sensitivity to the observation of another's errors. Here we utilize the same sample to show that participants' level of self-reported perspective-taking (but not empathic concern) correlated with hemodynamic response in IPC, while participants' level of self-reported empathic concern (but not perspective taking) correlated with hemodynamic response in r/vACC. This functional dissociation provides strong evidence for separate roles for IPC and r/vACC in the processing of observed errors. IPC may foster a sense of agency by distinguishing self- from other-performed actions; r/vACC may, in turn, promote a more contextually-mediated understanding of the other's failed goal-attainment.

Gender differences in neural mechanisms underlying moral sensitivity.

Researchers have proposed that females and males differ in the structure of their moral attitudes, such that females tend to adopt care-based moral evaluations and males tend to adopt justice-based moral evaluations. The existence of these gender differences remains a controversial issue, as behavioral studies have reported mixed findings. The current study investigated the neural correlates of moral sensitivity in females and males, to test the hypothesis that females would show increased activity in brain regions associated with care-based processing (posterior and anterior cingulate, anterior insula) relative to males when evaluating moral stimuli, and males would show increased activity in regions associated with justice-based processing (superior temporal sulcus) relative to females. Twenty-eight participants (14 females) were scanned using fMRI while viewing unpleasant pictures, half of which depicted moral violations, and rated each picture on the degree of moral violation that they judged to be present. As predicted, females showed a stronger modulatory relationship between posterior cingulate and insula activity during picture viewing and subsequent moral ratings relative to males. Males showed a stronger modulatory relationship between inferior parietal activity and moral ratings relative to females. These results are suggestive of gender differences in strategies utilized in moral appraisals.

Neural correlates of the processing of another's mistakes: a possible underpinning for social and observational learning.

Recent work suggests that a generalized error monitoring circuit, which shows heightened activation when one commits an error in goal-directed behavior, may exhibit synonymous activity when one watches another person commit a similar goal-directed error. In the present study, fMRI was utilized to compare and contrast those regions that show sensitivity to the performance, and to the observation, of committed errors. Participants performed a speeded go/no-go task and also observed a video of another person performing the same task. Dorsal anterior cingulate, orbitofrontal cortex, and supplementary motor regions were commonly activated to both performed and observed errors, providing evidence for common neural circuitry underlying the processing of one's own and another's mistakes. In addition, several regions, including inferior parietal cortex and anterorostral and ventral cinguli, did not show activation during performed errors, but were instead uniquely activated by the observation of another's mistakes. The unique nature of these 'observer-related' activations suggests that these regions, while of potential import towards recognition of another's errors, are not core to circuitry underlying error monitoring. Rather, we suggest that these regions may represent components of a distributed network important for the representation and interpretation of complex social actions.

Defensive copers show a deficit in passive avoidance learning on Newman's go/no-go task: implications for self-deception and socialization.

The present study investigated whether passive avoidance learning was retarded by defensive coping strategies designed to minimize exposure to negatively valenced stimuli. High-anxious individuals, low-anxious individuals, and defensive copers completed a computerized go/no-go task, in which they learned when to press or not to press a button, in response to contingent positive and negative feedback. The duration that feedback remained onscreen was self-regulated. Defensive copers showed preferential reflection away from negative feedback, committed more passive-avoidance errors, and were characterized by impaired learning, overall. Further, the ratio of reflection on negative feedback to reflection on positive feedback directly mediated both passive-avoidance errors and overall learning. Defensive coping strategies, therefore, appear to interfere with passive avoidance learning, thereby fostering perseverative, dysfunctional action patterns by reducing knowledge gained from previous mistakes. Implications for the learning of effective socialization strategies, and for psychopathy-which is commonly characterized by similar passive-avoidance deficits-are subsequently considered.