Abnormal cortical gyrification in criminal psychopathy.

Background: Psychopathy is a personality disorder characterized by interpersonal and emotional abnormalities (e.g., lack of empathy and guilt) and antisocial behavior. Psychopathy has been associated with a number of structural brain abnormalities, most notably in orbital frontal and anterior/medial temporal regions, that may underlie psychopathic individuals' problematic behaviors. Past research evaluating cortical structure in psychopathy has considered thickness and volume, but to date no study has investigated differences in cortical gyrification, a measure of cortical complexity thought to reflect early neurodevelopmental cortical connectivity. Methods: We measured the local gyrification index (LGI) in a sample of 716 adult male inmates and performed a whole brain analysis assessing the relationship between LGI and total and factor scores on the Hare Psychopathy Checklist-Revised (PCL-R). Results: PCL-R scores were negatively associated with LGI measures within the right hemisphere in the midcingulate cortex (MCC) and adjacent regions of the superior frontal gyrus as well as lateral superior parietal cortex. Additionally, PCL-R Factor 1 scores (interpersonal/affective traits) predicted less LGI within the right MCC and adjacent dorsomedial frontal cortex and greater LGI in bilateral occipital cortex. Scores on PCL-R Factor 2, indicating impulsivity and antisocial behaviors, did not predict LGI in any regions. Conclusions: These findings suggest that psychopathy, particularly the interpersonal and affective traits, are associated with specific structural abnormalities that form during neurodevelopment and these abnormalities may underlie aberrant brain functioning in regions important in emotional processing and cognitive control.

Information processing capacity in psychopathy: Effects of anomalous attention.

Hamilton and colleagues (2015) recently proposed that an integrative deficit in psychopathy restricts simultaneous processing, thereby leaving fewer resources available for information encoding, narrowing the scope of attention, and undermining associative processing. The current study evaluated this parallel processing deficit proposal using the Simultaneous-Sequential paradigm. This investigation marks the first a priori test of the Hamilton et al.'s theoretical framework. We predicted that psychopathy would be associated with inferior performance (as indexed by lower accuracy and longer response time) on trials requiring simultaneous processing of visual information relative to trials necessitating sequential processing. Results were consistent with these predictions, supporting the proposal that psychopathy is characterized by a reduced capacity to process multicomponent perceptual information concurrently. We discuss the potential implications of impaired simultaneous processing for the conceptualization of the psychopathic deficit. (PsycINFO Database Record

Disrupted Prefrontal Regulation of Striatal Subjective Value Signals in Psychopathy.

Psychopathy is a personality disorder with strong links to criminal behavior. While research on psychopathy has focused largely on socio-affective dysfunction, recent data suggest that aberrant decision making may also play an important role. Yet, the circuit-level mechanisms underlying maladaptive decision making in psychopathy remain unclear. Here, we used a multi-modality functional imaging approach to identify these mechanisms in a population of adult male incarcerated offenders. Psychopathy was associated with stronger subjective value-related activity within the nucleus accumbens (NAcc) during inter-temporal choice and with weaker intrinsic functional connectivity between NAcc and ventromedial prefrontal cortex (vmPFC). NAcc-vmPFC connectivity strength was negatively correlated with NAcc subjective value-related activity; however, this putative regulatory pattern was abolished as psychopathy severity increased. Finally, weaker cortico-striatal regulation predicted more frequent criminal convictions. These data suggest that cortico-striatal circuit dysregulation drives maladaptive decision making in psychopathy, supporting the notion that reward system dysfunction comprises an important neurobiological risk factor.

Smith and Lilienfeld's meta-analysis of the response modulation hypothesis: Important theoretical and quantitative clarifications.

In the first meta-analytic review of the response modulation hypothesis (RMH), an attention-based model for understanding the etiology of psychopathy, Smith and Lilienfeld (2015) report that the average effect size for response modulation deficits in psychopathic individuals fell in the small to medium range (r = .20; p < .001, d = .41). Moreover, support for the RMH extended to both psychopathy dimensions, applied across diverse assessments and settings, and spanned child, adult, female, and male samples. The analysis also revealed good empirical support for a central tenet of the RMH, namely that response modulation deficits are not limited to the processing of threat or other emotion stimuli. Unfortunately, the Smith and Lilienfeld meta-analysis contains several theoretical and quantitative problems, including failing to distinguish adequately between the tasks used to evaluate RMH predictions and the theory itself, confusion regarding the evolution of the RMH and its impact on effect sizes, misinterpretations of RMH predictions and evidence regarding dominant response sets, passive avoidance, and primary task performance, and biased statements promoting the low fear model over the RMH. In this response, we endeavor to reduce misunderstanding by addressing the most salient issues, with the hope that increasing clarity will sharpen the focus of future research and result in more valid assessments of the RMH. (PsycINFO Database Record

Selective Mapping of Psychopathy and Externalizing to Dissociable Circuits for Inhibitory Self-Control.

Antisociality is commonly conceptualized as a unitary construct, but there is considerable evidence for multidimensionality. In particular, two partially dissociable symptom clusters - psychopathy and externalizing - have divergent associations to clinical and forensic outcomes and are linked to unique patterns executive dysfunction. Here, we used fMRI in a sample of incarcerated offenders to map these dimensions of antisocial behavior to brain circuits underlying two aspects of inhibitory self-control: interference suppression and response inhibition. We found that psychopathy and externalizing are characterized by unique and task-selective patterns of dysfunction. While higher levels of psychopathy predicted increased activity within a distributed fronto-parietal network for interference suppression, externalizing did not predict brain activity during attentional control. By contrast, each dimension had opposite associations to fronto-parietal activity during response inhibition. These findings provide neurobiological evidence supporting the fractionation of antisocial behavior, and identify dissociable mechanisms through which different facets predispose dysfunction and impairment.

Endogenous attention modulates early selective attention in psychopathy: An ERP investigation.

Psychopathic individuals are prone to act on urges without adequate consideration of future consequences or the rights of other individuals. One interpretation of this behavior is that it reflects abnormal selective attention (i.e., a failure to process information that is incongruent with their primary focus of attention; Hiatt, Schmitt, & Newman, Neuropsychology, 18, 50-59, 2004). Unfortunately, it is unclear whether this selective attention abnormality reflects top-down endogenous influences, such as the strength or specificity of attention focus (i.e., top-down set) apart from other, more exogenous (bottom-up), effects on attention. To explore this question, we used an early visual event-related potential (N2pc) in combination with a modified visual search task designed to assess the effect of early endogenous (i.e., top-down) attention on the processing of set-congruent information. The task was administered to a sample of 70 incarcerated adult males, who were assigned to high, intermediate, and low psychopathy groups using Hare's Psychopathy Checklist-Revised (Hare, 2003). Based on the assumption that their failure to process set-incongruent information reflects the exaggerated effects of endogenous attention, we predicted that participants with high psychopathy scores would show an exaggerated N2pc response to set-congruent information. The results supported the hypothesis and provide novel electrophysiological evidence that psychopathy is associated with exaggerated endogenous attention effects during early stages of processing. Further research is needed to examine the implications of this finding for the well-established failure of psychopathic individuals to process set-incongruent information and inhibit inappropriate responses.

Impaired integration in psychopathy: A unified theory of psychopathic dysfunction.

This article introduces a novel theoretical framework for psychopathy that bridges dominant affective and cognitive models. According to the proposed impaired integration (II) framework of psychopathic dysfunction, topographical irregularities and abnormalities in neural connectivity in psychopathy hinder the complex process of information integration. Central to the II theory is the notion that psychopathic individuals are "'wired up' differently" (Hare, Williamson, & Harpur, 1988, p. 87). Specific theoretical assumptions include decreased functioning of the Salience and Default Mode Networks, normal functioning in executive control networks, and less coordination and flexible switching between networks. Following a review of dominant models of psychopathy, we introduce our II theory as a parsimonious account of behavioral and brain irregularities in psychopathy. The II theory provides a unified theoretical framework for understanding psychopathic dysfunction and integrates principle tenets of affective and cognitive perspectives. Moreover, it accommodates evidence regarding connectivity abnormalities in psychopathy through its network theoretical perspective. (PsycINFO Database Record

Discovery of Novel DNA Gyrase Inhibiting Spiropyrimidinetriones: Benzisoxazole Fusion with N-Linked Oxazolidinone Substituents Leading to a Clinical Candidate (ETX0914).

A novel class of bacterial type-II topoisomerase inhibitor displaying a spiropyrimidinetrione architecture fused to a benzisoxazole scaffold shows potent activity against Gram-positive and fastidious Gram-negative bacteria. Here, we describe a series of N-linked oxazolidinone substituents on the benzisoxazole that improve upon the antibacterial activity of initially described compounds of the class, show favorable PK properties, and demonstrate efficacy in an in vivo Staphylococcus aureus infection model. Inhibition of the topoisomerases DNA gyrase and topoisomerase IV from both Gram-positive and a Gram-negative organisms was demonstrated. Compounds showed a clean in vitro toxicity profile, including no genotoxicity and no bone marrow toxicity at the highest evaluated concentrations or other issues that have been problematic for some fluoroquinolones. Compound 1u was identified for advancement into human clinical trials for treatment of uncomplicated gonorrhea based on a variety of beneficial attributes including the potent activity and the favorable safety profile.

Interpersonal traits of psychopathy linked to reduced integrity of the uncinate fasciculus.

Psychopathy is a personality disorder characterized by callous lack of empathy, impulsive antisocial behavior, and criminal recidivism. Here, we performed the largest diffusion tensor imaging (DTI) study of incarcerated criminal offenders to date (N = 147) to determine whether psychopathy severity is linked to the microstructural integrity of major white matter tracts in the brain. Consistent with the results of previous studies in smaller samples, we found that psychopathy was associated with reduced fractional anisotropy in the right uncinate fasciculus (UF; the major white matter tract connecting ventral frontal and anterior temporal cortices). We found no such association in the left UF or in adjacent frontal or temporal white matter tracts. Moreover, the right UF finding was specifically related to the interpersonal features of psychopathy (glib superficial charm, grandiose sense of self-worth, pathological lying, manipulativeness), rather than the affective, antisocial, or lifestyle features. These results indicate a neural marker for this key dimension of psychopathic symptomatology.

Mapping the association of global executive functioning onto diverse measures of psychopathic traits.

Psychopathic individuals display a callous-coldhearted approach to interpersonal and affective situations and engage in impulsive and antisocial behaviors. Despite early conceptualizations suggesting that psychopathy is related to enhanced cognitive functioning, research examining executive functioning (EF) in psychopathy has yielded few such findings. It is possible that some psychopathic trait dimensions are more related to EF than others. Research using a 2-factor or 4-facet model of psychopathy highlights some dimension-specific differences in EF, but this research is limited in scope. Another complicating factor in teasing apart the EF-psychopathy relationship is the tendency to use different psychopathy assessments for incarcerated versus community samples. In this study, an EF battery and multiple measures of psychopathic dimensions were administered to a sample of male prisoners (N = 377). Results indicate that using the Psychopathy Checklist-Revised (PCL-R), the independent effect of Factor 2 was related to worse EF, but neither the independent effect of Factor 1 nor the unique variance of the Factors (1 or 2) were related to EF. Using a 4-facet model, the independent effects of Facet2 (Affect) and Facet4 (Antisocial) were related to worse EF, but when examining the unique effects, only Facet2 remained significant. Finally, the questionnaire-based measure, Multidimensional Personality Questionnaire-Brief, of Fearless Dominance was related to better EF performance, whereas PCL-R Factor 1 was unrelated to EF. Overall, the results reveal the complex relationship among EF and behaviors characteristic of psychopathy-related dimensions. Moreover, they demonstrate the interpersonal and affective traits measured by these distinct assessments are differentially related to EF.

Altering the Cognitive-Affective Dysfunctions of Psychopathic and Externalizing Offender Subtypes with Cognitive Remediation.

Cognitive remediation is a treatment approach with the potential to translate basic science into more specific, mechanism-based interventions by targeting particular cognitive skills. The present study translated understanding of two well-defined cognitive-emotion dysfunctions into novel deficit-matched interventions and evaluated whether cognitive remediation would demonstrate specific and generalizable change. Two antisocial-subtypes, individuals with psychopathy and externalizing traits, are characterized by cognitive-affective problems that predispose them to engage in significant substance abuse and criminal behavior, culminating in incarceration. Whereas individuals with psychopathy fail to consider important contextual information, individuals with externalizing traits lack the capacity to regulate affective reactions. Training designed to remedy these subtype-specific deficits led to improvement on both trained and non-trained tasks. Such findings offer promise for changing neural and behavioral patterns, even for what many consider to be the most recalcitrant treatment population, and presage a new era of translating cognitive-affective science into increasingly specific and effective interventions.

Narcissism dimensions differentially moderate selective attention to evaluative stimuli in incarcerated offenders.

Narcissistic personality disorder is associated with distinguishing traits including self-enhancement, arrogance, and intense reactivity to ego threat. Theoretical accounts of narcissism suggest these heterogeneous behaviors reflect a defensive motivational style that functions to both uphold and protect the self-concept. However, the notion that narcissism can be characterized by grandiose and vulnerable dimensions raises the possibility that these diverse behaviors represent distinct expressions of narcissistic defensiveness. The present study examined whether both dimensions exhibit a general defensive style marked by selective attention to evaluative stimuli or are differentially associated with selective attention to positive and negative information, respectively. Using a dot probe task consisting of valenced and neutral trait adjectives, we evaluated these hypotheses in a group of male offenders. Results indicated that vulnerable narcissism was associated with attention biases for both positive and negative stimuli, though the dimension was further distinguished by disengagement difficulties and a greater recognition memory bias in response to negative words. Conversely, grandiose narcissism was associated with increased accuracy when attending to positive stimuli and directing attention away from negative stimuli. Overall, these findings suggest narcissistic individuals share motivated selective attention in response to evaluative stimuli, while simultaneously highlighting important phenotypic differences between grandiose and vulnerable dimensions.

Relation of frontal N100 to psychopathy-related differences in selective attention.

Research indicates that psychopathy may be characterized by early attentional abnormalities that undermine the processing of peripheral information during goal-directed activity (Baskin-Sommers & Newman, 2012). Past work has found that psychopathic individuals show reduced interference on the Box Stroop task, in which color names are spatially separated from (i.e., peripheral to) colored stimuli (Hiatt, Schmitt, & Newman, 2004). The present study sought to replicate and extend these findings. A priori predictions were that psychopathy scores would be inversely related to interference and that psychopathy-related differences in Box Stroop conflict processing would emerge at an early stage as measured by event-related potentials (ERP). Results supported both hypotheses. Moreover, the association between the early attention-related component (N100) and interference was moderated by level of psychopathy. These findings suggest that psychopathic individuals have less coordinated responses to conflict than healthy individuals, a conjecture that has implications for information integration and self-regulation.

Psychopathic and externalizing offenders display dissociable dysfunctions when responding to facial affect.

Despite similarity in their disinhibited behaviors, the cognitive-affective mechanisms that characterize psychopathy and externalizing are relatively distinct. One theoretical perspective suggests that psychopathy is associated with an early attention bottleneck that precludes the processing of contextual information, leading to a rigid goal-directed focus. Alternatively, externalizing may be associated with an overallocation of processing resources to motivationally salient information, which disrupts the use of cognitive control. In this study, male prisoners assessed on psychopathic and externalizing traits performed a new gaze detection task involving affective faces. As predicted, psychopathy but not externalizing was associated with superior performance on the gaze-detection task when the necessity of using contextual affect to regulate goal-directed behavior was minimized. Conversely, externalizing but not psychopathy was associated with increased errors on trials that required participants to use affective expressions, specifically fear, as a cue to inhibit dominant responses. These results have theoretical and applied significance for both psychopathic and externalizing forms of disinhibition. Recognition and utilization of facial affect are important for socialization and interpersonal interactions; therefore, any cognitive-affective processes that interrupt the fluency with which this information is processed may be important for understanding the underpinnings of disinhibition.

Neural correlates of substance abuse: reduced functional connectivity between areas underlying reward and cognitive control.

Substance use disorders (SUD) have been associated with dysfunction in reward processing, habit formation, and cognitive-behavioral control. Accordingly, neurocircuitry models of addiction highlight roles for nucleus accumbens, dorsal striatum, and prefrontal/anterior cingulate cortex. However, the precise nature of the disrupted interactions between these brain regions in SUD, and the psychological correlates thereof, remain unclear. Here we used magnetic resonance imaging to measure rest-state functional connectivity of three key striatal nuclei (nucleus accumbens, dorsal caudate, and dorsal putamen) in a sample of 40 adult male prison inmates (n = 22 diagnosed with SUD; n = 18 without SUD). Relative to the non-SUD group, the SUD group exhibited significantly lower functional connectivity between the nucleus accumbens and a network of frontal cortical regions involved in cognitive control (dorsal anterior cingulate cortex, dorsolateral prefrontal cortex, and frontal operculum). There were no group differences in functional connectivity for the dorsal caudate or dorsal putamen. Moreover, the SUD group exhibited impairments in laboratory measures of cognitive-behavioral control, and individual differences in functional connectivity between nucleus accumbens and the frontal cortical regions were related to individual differences in measures of cognitive-behavioral control across groups. The strength of the relationship between functional connectivity and cognitive control did not differ between groups. These results indicate that SUD is associated with abnormal interactions between subcortical areas that process reward (nucleus accumbens) and cortical areas that govern cognitive-behavioral control.

Neural correlates of reward and loss sensitivity in psychopathy.

Psychopathy is a personality disorder associated with callous and impulsive behavior and criminal recidivism. It has long been theorized that psychopaths have deficits in processing reward and punishment. Here, we use structural and functional magnetic resonance imaging to examine the neural correlates of reward and loss sensitivity in a group of criminal psychopaths. Forty-one adult male prison inmates (n = 18 psychopaths and n = 23 non-psychopaths) completed a functional magnetic resonance imaging task involving the gain or loss of money. Across the entire sample of participants, monetary gains elicited robust activation within the ventral striatum (VS). Although psychopaths and non-psychopaths did not significantly differ with respect to overall levels of VS response to reward vs loss, we observed significantly different correlations between VS responses and psychopathy severity within each group. Volumetric analyses of striatal subregions revealed a similar pattern of correlations, specifically for the right accumbens area within VS. In a separate sample of inmates (n = 93 psychopaths and n = 117 non-psychopaths) who completed a self-report measure of appetitive motivation, we again found that the correlation with psychopathy severity differed between groups. These convergent results offer novel insight into the neural substrates of reward and loss processing in psychopathy.

The impact of cognitive control, incentives, and working memory load on the P3 responses of externalizing prisoners.

The P3 amplitude reduction is one of the most common correlates of externalizing. However, few studies have used experimental manipulations designed to challenge different cognitive functions in order to clarify the processes that impact this reduction. To examine factors moderating P3 amplitude in trait externalizing, we administered an n-back task that manipulated cognitive control demands, working memory load, and incentives to a sample of male offenders. Offenders with high trait externalizing scores did not display a global reduction in P3 amplitude. Rather, the negative association between trait externalizing and P3 amplitude was specific to trials involving inhibition of a dominant response during infrequent stimuli, in the context of low working memory load, and incentives for performance. In addition, we discuss the potential implications of these findings for externalizing-related psychopathologies. The results complement and expand previous work on the process-level dysfunction contributing to externalizing-related deficits in P3.

Feature-based attention and conflict monitoring in criminal offenders: interactive relations of psychopathy with anxiety and externalizing.

As predicted by the response modulation model, psychopathic offenders are insensitive to potentially important inhibitory information when it is peripheral to their primary focus of attention. To date, the clearest tests of this hypothesis have manipulated spatial attention to cue the location of goal-relevant versus inhibitory information. However, the theory predicts a more general abnormality in selective attention. In the current study, male prisoners performed a conflict-monitoring task, which included a feature-based manipulation (i.e., color) that biased selective attention toward goal-relevant stimuli and away from inhibitory distracters on some trials but not others. Paralleling results for spatial cuing, feature-based cuing resulted in less distracter interference, particularly for participants with primary psychopathy (i.e., low anxiety). This study also investigated the moderating effect of externalizing on psychopathy. Participants high in psychopathy but low in externalizing performed similarly to primary psychopathic individuals. These results demonstrate that the abnormal selective attention associated with primary psychopathy is not limited to spatial attention but, instead, applies to diverse methods for establishing attentional focus. Furthermore, they demonstrate a novel method of investigating psychopathic subtypes using continuous analyses.

The interplay of attention and emotion: top-down attention modulates amygdala activation in psychopathy.

Psychopathic behavior has long been attributed to a fundamental deficit in fear that arises from impaired amygdala function. Growing evidence has demonstrated that fear-potentiated startle (FPS) and other psychopathy-related deficits are moderated by focus of attention, but to date, no work on adult psychopathy has examined attentional modulation of the amygdala or concomitant recruitment of relevant attention-related circuitry. Consistent with previous FPS findings, here we report that psychopathy-related differences in amygdala activation appear and disappear as a function of goal-directed attention. Specifically, decreased amygdala activity was observed in psychopathic offenders only when attention was engaged in an alternative goal-relevant task prior to presenting threat-relevant information. Under this condition, psychopaths also exhibited greater activation in selective-attention regions of the lateral prefrontal cortex (LPFC) than did nonpsychopaths, and this increased LPFC activation mediated psychopathy's association with decreased amygdala activation. In contrast, when explicitly attending to threat, amygdala activation did not differ in psychopaths and nonpsychopaths. This pattern of amygdala activation highlights the potential role of LPFC in mediating the failure of psychopathic individuals to process fear and other important information when it is peripheral to the primary focus of goal-directed attention.

Emotion-modulated startle in psychopathy: clarifying familiar effects.

The behavior of psychopathic individuals is thought to reflect a core fear deficit that prevents these individuals from appreciating the consequences of their choices and actions. However, growing evidence suggests that psychopathy-related emotion deficits are moderated by attention and, thus, may not reflect a reduced capacity for emotion responding. The present study attempts to reconcile this attention perspective with one of the most cited findings in psychopathy, which reports emotion-modulated startle deficits among psychopathic individuals during picture viewing. In this study, we evaluate the potential effects of a putative attention bottleneck on the emotion processing of psychopathic offenders during picture viewing by manipulating picture familiarity and examining emotion-modulated startle and late positive potential (LPP). As predicted, psychopathic individuals displayed the classic deficit in emotion-modulated startle during novel pictures, but they showed no deficit in emotion-modulated startle during familiar pictures. Conversely, results for LPP responses revealed psychopathy-related differences during familiar pictures and no psychopathy-related differences during novel pictures. Important differences related to the two factors of psychopathy are also discussed. Overall, the results of this study not only highlight the differential importance of perceptual load on emotion processing in psychopathy, but also raise interesting questions about the varied effects of attention on psychopathy-related emotion deficits.