Emil F. Coccaro - US grants

Human aggression constitutes a multidetermined act which often results in physical (or verbal) assault to others or self (or objects) as the end product. It appears in several forms and may be defensive, premeditated (e.g., predatory) or impulsive (e.g., irritable), in nature. Research into the etioogic determinants of premeditated and impulsive human aggression have focused on variojs sociologic, psuchologic, and biogenetic factors. Among these, the most consistent biogenetic factor associated with impulsive (but not premeditated) aggression is a reduction in the activity of the central monoamine neurotransmitter serotonin (5-HT). 5-HT's role in the regulation of impulsive aggressive behavior is thought to arise from its role in neuronal inhibition, through which it raises the threshold for action in response to an outward (or inward) stimulus. In this formulation, 5-HT acts to restrain the individual from assaulting the object of stimulus. Empirically, a role for central 5-HT in the regultion of impulsive aggression and/or suicidal (i.e., of a violent and/or impulsive nature) behavior in humans is suggested by the association of reductions in indices of central 5-HT activity (e.g. brain 5-HT/5-HIAA; lumbar CSF 5-HIAA; neuroendocrine responses to 5-HT agents) in psychiatric patients with prominent histories of impulsive aggressive and suicidal behavior, particularly patients with DSM-III-R personality disorders. In this RSDA (Level II) Application, the principal investigator proposes to conduct sysematic studies regarding the relationship between indices of central 5-HT function (i.e., CSF 5-HIAA concentration and prolactin response to d-Fenfluramine Challenge) and indices of impulsive aggressive and suicidal behaviors in personality disorder patients of both genders in order to test the hypothesis that central 5-HT function and these behaviors are inversely related. Family studies will also be conducted in order to test the hypotheseis that indices of reduced central 5-HT function in these patients are also correlated with a increased morrid risk of these behaviors in their first-degree biological relatives. Studies investigating the intra-individual stability, and the 5-HT receptor subtype components, of the PRL response to d-Fenfluramine Challenge will also be conducted in order to est the adequacy of this index as a "trait" marker of central 5-HT function and to elucidate the 5-HT receptor subtype possibly associated with impulsive aggression in these patients. Finally, a double-blind, placebo-controlled, treatment trial of the 5-HT uptake inhibitor, Fluoxetine, will be conducted in patients with prominent histories of impulsive aggression in order to experimentally test the hypothesis that enhancement of central 5-HT function will be correlated with this response to central 5-HT targeted pharmacologic treatment.

Despite the wealth of data supporting the hypothesis that central pre- synaptic serotonin (5-HT) function is reduced in male patients with suicidal and/or impulsive aggressive behaviors, little is conclusively known concerning the relationship between these behaviors and indices of post-synaptic or overall ("integrated" or "net") 5-HT function. Moreover, since little is known regarding the relationships among different putative indices of 5-HT function, our understanding of how to best interpret these data is limited. Finally, since few studies of central 5-HT activity and impulsive aggressive behavior in female subjects have been performed, little is known regarding these issues in women and the possibility of a gender difference in these relationships remains to be tested. In order to address these issues we propose to conduct three parallel studies which assess the relationship between central 5-HT function and suicidal and impulsive aggressive behavior in a psychiatric and in a normal control population. We propose to examine three indices of central 5-HT function in male and female patients with DSM-III-R personality disorder (PD) and in age and sex matched normal controls. These indices include: a) lumbar CSF concentrations of 5-HIAA as an index of "pre-synaptic" 5-HT activity; b) PRL responses to the direct post-synaptic 5-HT agonist m- chlorophenylpiperazine (m-CPP) as an index of "post-synaptic" receptor function; and c) PRL responses to the 5-HT releasing/uptake-inhibiting agent d-fenfluramine (d-FEN) as an index of integrated "pre-/post-synaptic" function). We have chosen to study personality disorder patients as the experimental group because suicidal and impulsive aggressive behaviors exist across a wide continuum in this group and because of previous data which indicate that PD patients consistently demonstrate inverse relationships between indices of central 5-HT function and both suicidal and impulsive aggressive behavior. Based upon previous work, we hypothesize that: a) the proposed indices of central 5-HT function will be intercorrelated; b) CSF 5-HIAA concentrations (5-HT "pre-synaptic") and PRL responses to both m-CPP (5-HT "post- synaptic") and d-FEN (5-HT "integrated pre-/post-synaptic") will be inversely related to suicidal and impulsive aggressive in behaviors in both male and female PD patients; and c) relationships between the PRL response to d-FEN, as an index of "integrated pre-/post-synaptic" index of 5-HT function, and those observed between the above behavioral variables will be stronger than those observed with either CSF 5-HIAA 95-HT "pre-synaptic") or the PRL response to m-CPP ("post-synaptic").

Human aggression constitutes a complex a multidetermined act which results in physical or verbal assault to others, self, or objects. Research into the etiologic determinants of premeditated and impulsive human aggression have focused on various sociologic, psychologic, and biogenetic factors. Among these, the most consistent biogenetic factor associated with impulsive (but not premeditated) aggression is a reduction in the activity of the central monoamine neurotransmitter serotonin (5-HT). 5-HT's role in the regulation of impulsive aggressive behavior is thought to arise from its role in neuronal inhibition, through which it raises the threshold for action in response to an outward (or inward) stimulus. In this formulation, 5-HT acts to restrain the individual from assaulting the object of stimulus. Empirically, a role for central 5-HT in the regulation of impulsive aggression and/or suicidal (i.e., of a violent and/or impulsive nature) behavior in humans is suggested by the association of reductions in indices of pre-synaptic activity (e.g. brain 5-HT/5-HIAA; lumbar CSF 5-HIAA; brain 3-H-IMI binding; platelet 3-H-IMI binding; platelet 5-HT uptake) in psychiatric patients with prominent histories of impulsive aggressive and suicidal behavior. Experimental data from animal studies strongly suggest an inverse relationship between "overall" central 5-HT activity and aggression. Further, reduced PRL responses to the 5-HT releaser/uptake inhibitor FENFLURAMINE (i.e., reflected by peak PRL[FEN] values) in mood/personality disordered patients with history of attempted suicide and prominent histories of impulsive aggression suggest that reduced "overall" central 5-HT activity is also associated with these behaviors in humans. If central 5-HT plays an important role in the regulation of impulsive aggressive and suicidal behaviors, then treatment with a potent and selective 5-HT enhancing agent should diminish impulsive aggressive and/or suicidal behaviors in patients with prominent histories of these behaviors. Patients with primary personality disorder (PD) belong to a group for which impulsive aggressive and suicidal behaviors are particularly prominent. Moreover, central 5-HT function has been shown to correlate inversely with these behaviors in these patients. Hence, the present study proposes to test the primary hypothesis that a pharmacologic treatment which putatively enhances central 5-HT function (i.e., FLUOXETINE, a potent and selective inhibitor of central 5-HT uptake) will be more efficacious than placebo in the treatment of impulsive aggressive behavior in patients with DSM-III-R personality disorder. The study's second hypothesis is that there will be a relationship between a pre-treatment index of central 5-HT system function (i.e., PRL[FEN] values) and the "anti-aggressive" effect of FLUOXETINE in these patients. To our knowledge, this represents the first double-blind placebo-controlled trial to assess the efficacy of FLUOXETINE (and to do so with pre-treatment measures of central 5-HT system function) in the treatment of impulsive aggressive behavior as a behavioral dimension in DSM-III-R personality disorder patients.

DESCRIPTION (Adapted from applicant's abstract): Human aggression constitutes a complex a multidetermined act which results in physical or verbal assault to others, self, or objects. Among the various biological factors studied, the most consistent factor associated with impulsive (but not premeditated) aggression is a reduction in the activity of the central monoamine neurotransmitter serotonin (5-HT). 5-HT's role in the regulation of impulsive aggressive behavior is thought to arise from its role in neuronal inhibition, through which it raises the threshold for action in response to an outward (or inward) stimulus. 5-HT appears to act to restrain the individual from assaulting the object of stimulus. A role central 5-HT in the regulation of impulsive aggression and/or suicidal (i.e., of a violent and/or impulsive nature) behavior in humans is suggested by the association of alterations in indices of 5-HT activity (e.g., reductions in brain 5-HT/5-HIAA, lumbar CSF 5-HIAA, brain/platelet 5-HT Transporter binding, PRL response to 5-HT Challenge) in psychiatric, increases in brain/platelet 5-HT-2a receptor binding) patients with prominent histories of impulsive aggressive and suicidal behavior. During the current grant period, the applicant conducted an experimental clinical trial in which the selective 5-HT uptake inhibitor, Fluoxetine, was found to significantly reduce the frequency and severity of impulsive aggressive behaviors in a 12-week randomized, double-blind, placebo-controlled trial in personality disordered subjects with prominent histories of impulsive aggressive behavior. Subjects in this were found to have reduced PRL responses to d-Fenfluramine Challenge (PRL[d-FEN]). In addition, PRL[d-FEN] values appeared to correlate positively with anti-aggressive response to fluoxetine and to decrease after successful treatment with fluoxetine in responders. In this renewal application, the applicant proposes to: a) extend their clinical trial to include a 12-week Maintenance Treatment Phase and a 12-week Placebo-Controlled Discontinuation Phase in order to collect data regarding anti-aggressive efficacy beyond the initial 12 weeks of treatment and to determine the stability of remission in impulsive aggressive behaviors after 24 weeks of treatment with Fluoxetine; b) determine the relationship between Pre-Treatment and Post-Treatment indices of 5-HT activity (i.e., PRL[d-FEN] responses and Platelet 5-HT Transporter/5-HT-2a Receptor Binding) and anti-aggressive efficacy to Fluoxetine; and c) test the relative anti-aggressive efficacy of Fluoxetine in the three most prominent Personality Disorder subtypes occurring in DSM-IV Personality Disordered subjects with prominent histories of impulsive aggressive behavior.

Human aggression constitutes a multidetermined act which often results in physical (or verbal) assault to others or self (or objects) as the end product. It appears in several forms and may be defensive, premeditated (e.g., predatory) or impulsive (e.g., irritable), in nature. Research into the etioogic determinants of premeditated and impulsive human aggression have focused on variojs sociologic, psuchologic, and biogenetic factors. Among these, the most consistent biogenetic factor associated with impulsive (but not premeditated) aggression is a reduction in the activity of the central monoamine neurotransmitter serotonin (5-HT). 5-HT's role in the regulation of impulsive aggressive behavior is thought to arise from its role in neuronal inhibition, through which it raises the threshold for action in response to an outward (or inward) stimulus. In this formulation, 5-HT acts to restrain the individual from assaulting the object of stimulus. Empirically, a role for central 5-HT in the regultion of impulsive aggression and/or suicidal (i.e., of a violent and/or impulsive nature) behavior in humans is suggested by the association of reductions in indices of central 5-HT activity (e.g. brain 5-HT/5-HIAA; lumbar CSF 5-HIAA; neuroendocrine responses to 5-HT agents) in psychiatric patients with prominent histories of impulsive aggressive and suicidal behavior, particularly patients with DSM-III-R personality disorders. In this RSDA (Level II) Application, the principal investigator proposes to conduct sysematic studies regarding the relationship between indices of central 5-HT function (i.e., CSF 5-HIAA concentration and prolactin response to d-Fenfluramine Challenge) and indices of impulsive aggressive and suicidal behaviors in personality disorder patients of both genders in order to test the hypothesis that central 5-HT function and these behaviors are inversely related. Family studies will also be conducted in order to test the hypotheseis that indices of reduced central 5-HT function in these patients are also correlated with a increased morrid risk of these behaviors in their first-degree biological relatives. Studies investigating the intra-individual stability, and the 5-HT receptor subtype components, of the PRL response to d-Fenfluramine Challenge will also be conducted in order to est the adequacy of this index as a "trait" marker of central 5-HT function and to elucidate the 5-HT receptor subtype possibly associated with impulsive aggression in these patients. Finally, a double-blind, placebo-controlled, treatment trial of the 5-HT uptake inhibitor, Fluoxetine, will be conducted in patients with prominent histories of impulsive aggression in order to experimentally test the hypothesis that enhancement of central 5-HT function will be correlated with this response to central 5-HT targeted pharmacologic treatment.

Violence against women is a significant social concern in the United States. Most women who are assaulted are attacked by someone they know. The consequences of these injuries to women are magnified by the costs of decreased occupational function by the victims, mental health services required by the victims, and services required by children of the victims who may also be abused by the male batterer. While primary and secondary prevention programs have great appeal, a more immediate method to reducing male violence against women is to identify arid treat the male batterer. Most male batterer treatment programs target the psychological or psychosocial origins of male violence against women. The results of these interventions have generally been promising though limited. One major limitation of psychological intervention is that it ignores recent research findings relevant to the biology of aggressive behavior and neglects to consider that for many male batterers, there may be "biological" factors which increase the risk and incidence of aggressive behavior against women. There is a substantial literature suggesting that biological factors, such as a reduction in central serotonergic (5-HT) system function, plays an important role in the expression of aggression. This neglect also closes off the possibility of any psychopharmacological intervention with which to enhance the efficacy of other more commonly used, psychosocial intervention strategies. Accordingly, the proposed project has two major specific aims. The first aim is a biological evaluation of the central serotonergic system of men who abuse their wives. The second aim is to test the efficacy of psycho pharmacologic (Fluoxetine) and psychologic (Cognitive-Behavioral Treatment: CBT) treatments in a 12-week "Acute Treatment Phase" and in a 24-26 week "Relapse/Prevention Phase". Biologic evaluation will include d- Fenfluramine Challenge (CSF 5-HIAA in a subgroup) and Platelet measures of 5-HT Uptake (3H-Paroxetine Binding) and 5-HT-2 receptors (125I-LSD Binding) to simultaneously assess multiple aspects of 3-HT system function. Treatment will be composed of four (4) arms: 1) CBT + Placebo (+ Ratings); 2) Fluoxetine + CBT (+ Ratings); 3) Fluoxetine + Ratings (No CBT); 4) Placebo + CBT (+ Ratings). The main hypotheses to be tested are: 1) male batterers have reduced central 5-HT system function in comparison with healthy controls and non-batterers; 2) Pretreatment 5-HT indices correlate with aggressive behavior in male batterers; and, 3) FLUOX (alone) and CBT (alone) are each more efficacious than Placebo in decreasing spousal abuse and that Fluoxetine and CBT are more efficacious than either treatment alone in the treatment of spousal abuse.

DESCRIPTION (Adapted from applicant's abstract): This is a Resubmission of a Competitive Renewal Application of NIMH Grant R01-MH46948. During the current grant period, the presence of a relationship between impulsive aggressive/suicidal behavior and selected indices of 5-HT function (e.g., PRL response to d-Fenfluramine (d-FEN) Challenge) in personality disordered subjects was confirmed. Despite this, neuropharmacologic nature of these relationships is unclear. Little is known about the specific role that various 5-HT receptor subtype systems play in mediating aggressive and/or suicidal behavior. While 5-HT antagonist studies suggest that the PRL response to d-FEN reflects activation of post-synaptic 5-HT-2a/2c receptors, little is known about the role of central 5-HT-1a receptors in human aggression. A role for 5-HT-1a receptors in aggression is suggested by the potent antiaggressive effects of 5-HT-1a agonists in animal studies and by preliminary data showing inverse relationships between aggression and the hormonal responses to 5-HT-1a agents. In addition, only limited data is available regarding the role of central noradrenergic (NE) systems in human aggression. A role for central NE systems is suggested by animal studies and limited neurochemical/pharmaco-challenge studies in psychiatric patients. In contrast to 5-HT, the NE system has a direct relationship with aggression. Since the NE system plays a critical role in the detection of novel (aversive) stimuli, the PI hypothesizes that sensitivity to aversive stimuli (e.g., irritability) plays a role on setting the threshold at which aversive stimuli are detected and lead to a behavioral response which can be aggressive in nature. Accordingly, the PI wishes to extend his biological studies of impulsive aggressive/suicidal behavior in personality disordered subjects, and healthy volunteers, to include an examination of the limbic-hypothalamic systems involving 5-HT-1a (Ipsapirone Challenge) and alpha-2 NE (Clonidine Challenge) receptors. Simultaneous evaluation of the limbic-hypothalamic 5-HT-2a/2c system with d-FEN Challenge will allow a comprehensive assessment of these three potentially important central neuronal systems in aggressive/suicidal behavior in human subjects. Impulsive aggressive behavior will be comprehensively assessed through the use of self-report, historical, and direct laboratory indices of aggression.

DESCRIPTION (Adapted from applicant's abstract): Among the various sociologic, psychologic, and biogenetic factors associated with impulsive, as opposed to premeditated, human aggression, the most consistent biological factor appears to be a reduction in central serotonergic (5-HT) neurotransmission. 5-HT's role in the regulation of impulsive aggressive behavior is thought to arise from its role in neuronal inhibition, through which it constrains behavioral action in response to an outward (or inward) aversive stimulus or provocation. In this formulation, 5-HT acts to restrain the individual from assaulting the object of stimulus and other neuronal systems (e.g., catecholamines) modulate the detection of, and/or the response to, the aversive stimulus. At this time, there is little knowledge regarding this role of specific 5-HT receptor subsystems and of the role of catecholamines, such as norepinephrine, in the mediation of these behaviors. In this renewal of the Principal Investigator's RSDA (Level II) Application, the PI proposes to conduct expanded and systematic studies regarding the relationship between indices of 5-HT-1a, 5-HT-2a/2c, and alpha-2 NE function and comprehensive indices of impulsive aggressive and suicidal behaviors in personality disorder (PD) subjects. In addition, the PI plans to expand his clinical drug trial research regarding the antiaggressive efficacy of Fluoxetine by conducting a nine-month continuation and relapse/remission study in PD subjects. A new direction in this area of antiaggressive efficacy is represented by a combined Fluoxetine/Cognitive-Behavioral treatment trial in male spouse abusers. The development, during the current grant, of reliable criteria for a disorder of Impulsive Aggression will allow further work (i.e., Family Study, DNA Polymorphism Study, Epidemiologic Survey) to test the full spectrum of construct validity for impulsive aggressive behavior as a clinical entity. The skills to implement these and other studies will be acquired during the next five years if this RSDA award.

The primary specific aim of this study is to test the hypothesis that Intermittent Explosive Disorder (IED) is familial. IED is a disorder characterized by recurrent, sudden eruptions of aggressive behavior not due to psychosis, substance intoxication, or other frank organic causes. Accordingly, IED is the categorical expression of recurrent, problematic, impulsive aggressive behavior. While it is thought that the personality dimension of impulsive aggression is familial (and possibly under substantial genetic influence), there is a paucity of systematically collected data to support this hypothesis with regard to clinically significant impulsive aggressive behavior. A family history study by the PI demonstrates that IED (by research criteria) aggregates in first degree relatives of IED+ Probands. Aggregation of IED in these first degree relatives was not accounted for by co-morbidity of other Axis I or II conditions in the IED+ Probands. While aggregation of other Axis I disorders was also noted in the first degree relatives of IED+ Probands (e.g., major depression, alcohol/drug use disorders, etc.), the risk of IED in relatives was not affected by the risk of these other disorders in the relatives. That is, IED was transmitted independently of these other Axis I disorders. The formal specific aims of this study are as follows: a) to compare the familiality of IED, and of dimensional measures of aggression, in first degree relatives of IED+ Probands (n = 80), in first-degree relatives of Psychiatric Control Probands (n = 80) and in first-degree relatives of Outpatient Surgical Control Probands (n = 80) using the direct Family Study Method; b) to compare the familiality of Major Depression and Alcohol/Drug Use Disorders in first degree relatives of Probands meeting Research Criteria for IED (by research criteria) and in relatives of the two Control groups; and, c) to explore phenomenologic and biologic correlates of familial IED in probands and in family members of IED probands (i.e., relatives of IED probands with and without IED).

[unreadable] DESCRIPTION (provided by applicant): The primary specific aim of this study is to examine the genetic and environmental influences underlying the human behavioral traits of aggression and impulsivity in a sample of population-based twin subjects. While these dimensions of behavior have previously been studied in twin samples, no study has: a) examined both behavioral dimensions in the same subjects, b) utilized different and multiple modes of assessment (e.g., clinical and laboratory based assessments), c) examined the relevance of specific measures reflective of environmental factors (e.g., "experienced" and "witnessed" aggression), d) examined the nature of differences in genetic and environmental influence as a function of gender or, e) examined measures of 5-HT and aggression in twin subjects. In this study, both aggression and impulsivity will be examined using a variety of self-report (clinical and personality based) and laboratory assessments of aggression and impulsivity. In Phase I of this project, twins will be administered two (2) self-report measures each for aggression and impulsivity. One measure each will assess history of actual aggressive and impulsive behaviors. In addition, one measure each will constitute a personality assessment of aggressive and impulsive tendencies. In addition, other questionnaires will be administrated to assess selected variables relevant to environmental factors putatively involved in impulsive aggressive behavior (e.g., experience of aggression, witnessed aggression, perception of parenting practices). Mixed-Gender DZ twin pairs will also be studied in this phase so that analysis of potential gender differences in aggression can be examined. In Phase II, 420 twin pairs will be studied in our laboratory at The University of Chicago using two sets of analogue laboratory assessments of aggression (Point Subtraction Aggression Paradigm: PSAP, and Taylor Aggression Paradigm: TAP) and impulsivity (Cherek Impulsivity Paradigm: CIP and the Immediate and Delayed Memory Task: IMT/DMT). Finally, structural (5-HT Transporter Binding), functional (5-HT Uptake), and genetic (DNA Polymorphism for the 5-HT Transporter) measures of the Platelet Serotonin Transporter will be assessed so that the genetic correlation between indices relevant to serotonin and aggression/impulsivity can be compared with the inverse phenotypic correlation previously established, between these two sets of variables, over the past two decades of research.

DESCRIPTION (provided by applicant): This proposed project has three (3) specific aims. The first aim is to compare the efficacy of two different psychopharmacologic agents (fluoxetine or divalproex sodium) in the treatment of impulsive aggressive behavior by men and women with Intermittent Explosive Disorder (lED). The second aim is to explore the serotonergic correlates of clinical response to these treatment modalities. The third aim is to compare lED subjects and Normal Control subjects in regard to the assessments of 5-HT receptor function and to the assessment of the 5-HT Transporter. In the context of the first two aims, we will also be testing the possibility of a differential anti-aggressive response to treatment with fluoxetine or divalproex in lED subjects as a function of "severity of lifetime aggressiveness" (e.g., "Moderately Aggressive" vs. "Highly Aggressive"lED subjects). Specifically, we hypothesize that fluoxetine is preferentially efficacious in "moderately aggressive" lED and that divalproex is preferentially efficacious in "highly aggressive" lED. In additIon, this study proposes to more fully examine the nature of the relationship between pretreatment 5-HT receptor function and anti-aggressive response to these agents. Biologic evaluation of the 5-HT system will include m-CPP and ipsapirone Challenges, Platelet Tritiated (3H) Paroxetine 5-HT Transporter Binding and 5-HTRelated DNA Polymorphisms. m-CPP Challenge is included to assess the function of post-synaptic 5-HT-2c receptors (ACTH and Thermal Responses) while Ipsapirone Challenge is included to assess the function of both pre-synaptic 5-HT-1a (Thermal Response)and post-synaptic 5-HT-1a (ACTH Response)receptors. Platelet 5-HTT binding is assessed in this context because fluoxetine (but not divalproex) acts at brain 5- HTT sites and because Platelet (and brain) 5-HTT binding correlates inversely with lifetime aggressiveness. Participants will be randomly assigned, and stratified by lifetime aggressiveness (i.e, Life History of Aggression Score: "Moderate Aggression" = LHA < 17; "High Aggression" = LHA > 18), to one of three (3) treatment conditions as follows: 1) Fluoxetine; 2) Divalproex Sodium; Placebo. Duration of treatment will be twelve weeks.

DESCRIPTION (provided by applicant): In this R21 application, we propose to develop S-Citalopram (S-CIT) as a Psychopharmacologic Challenge (PPC) agent used in conjunction with the fMRI examination of social-emotional processing. PPC studies have been in use in biological psychiatry for more than 30 years. Optimally, PPC studies involve the use of an agent that selectively activates a central neurotransmitter synapse or that acts at a known receptor (or receptors) of a specific neurotransmitter system. While behavioral and/or peripheral hormonal responses were useful as outcome measures both lack the ability to localize brain areas of differences between patient subjects and controls. With the advent of brain imaging there is an opportunity to use central outcome measures in the context of PPC. Some studies have used PET imaging with PPC and have begun to localize the source of patient-control differences. However, PET has limited temporal resolution and is not typically used in conjunction with behaviorally relevant tasks. In contrast, fMRI has excellent temporal resolution and is always used in the context of behaviorally relevant tasks. We propose to develop this method, first, in impulsive aggressive subjects because: a) aggression and impulsivity are inversely correlated with 5-HT function in human subjects, b) social-emotional information processing is partly mediated by 5-HT and, c) social-emotional information processing is altered in impulsive aggressive subjects and patient control differences regarding impulsivity and socio-emotional information processing are localized to relevant regions of the brain (e.g., Orbitomedial Prefrontal Cortex, Anterior Cingulate Cortex and Amygdala). Ultimately, this study will examine both Impulsive Aggressive subjects and Healthy Controls to determine if S-CIT/fMRI Challenge can be developed as a new procedure to examine 5-HT function in the context of relevant behavioral tasks that are simultaneously located to specific brain regions. PUBLIC HEALTH RELEVANCE Recurrent, impulsive aggressive behavior poses a significant concern for our society both from the viewpoint of the individual who engages in these behaviors and of the people and property that these behaviors target. Emerging epidemiological data suggest that "recurrent, problematic, impulsive aggressive behavior" is far from rare and is present in at least 5.4% of the general population lifetime (~ 16 million). This study will examine the neurotransmitter function correlates of impulsivity and social-emotional information processing in impulsive aggressive subjects to determine whether or not 5-HT is relevant to impulsivity and social-emotional information processing in these subjects and if there are subjects-control differences in this regard. In addition, this work has the potential to advance the field of neuropsychopharmacology so that we can examine neurotransmitter function underlying behavioral tasks in specific brain regions. Unlike outcome measures such as behavior and neuroendocrine responsiveness, we can now look directly into the brain to assess the role of specific neurotransmitters.

DESCRIPTION (provided by applicant): Previous studies have suggested that certain neuropsychological traits, including socio- emotional information processing, emotion regulation, and behavioral inhibition/impulsivity are associated with aggression. Moreover, converging lines of animal and human lesion evidence have highlighted the role of specific neural substrates such as the amygdala (AMYG), orbital- medial prefrontal cortex (OMPFC), and dorsal anterior cingulate cortex (dACC) in socio- emotional processing and behavioral inhibition (e.g., cognitive control). Therefore, the goal of the present study is to collect multimodal data on specific neuropsychological traits and functional brain reactivity using a sample of twins in order to elucidate the different genetic pathways that may be related to aggressive behavior. Specifically, we propose to measure socio-emotional information processing, emotion regulation, and behavioral inhibition/impulsivity using a series of laboratory-based neuropsychological assessments in a population-based sample of 200 adult twin pairs (100 MZ, 100 DZ) from our PENNTwins Study Program. In addition, we will further conduct BOLD-sensitive functional magnetic resonance imaging (fMRI) studies of Amygdala and OMPFC function during a socio-emotional information processing (SEIP) task and fMRI studies of dACC function during an impulsivity task to assess neurophsyiological patterns of brain response. By investigating the extent to which these characteristics share common genes with aggression and related behaviors, we have the unique opportunity to "bridge the gap" between phenotype and genotype by examining neuropsychological traits and neurophysiological patterns of brain response as potential mediators of the genetic influence on aggression and related behaviors. Moreover, by applying theoretically-based multivariate models to multimodal assessments of aggression, socio- emotional information processing, and impulsivity, we can also begin to better understand the underlying structure of aggression. Public Health Relevance: Aggression and interpersonal violence are leading worldwide public health problems, both from the viewpoint of the individual who engages in these behaviors and of the people/property that these behaviors target. One of the goals of psychiatric genetic research on aggression is to uncover specific genetic variants that are risk factors for aggression and related disorders. However, it is unlikely that genes code for aggressive behavior directly, but rather influence behavior through indirect mechanisms or pathways. To gain a better understanding of these potential genetic mechanisms, twin studies can be used to identify biologically-based traits that may serve as endophenotpyes for aggression and related behaviors.

DESCRIPTION: Suicide and lesser forms of intentional self-harm behaviors produce devastating medical, social and economic costs. Self-harm is integrally related to depressive disorders and Borderline Personality Disorder. Selective Serotonin Reuptake Inhibitors (SSRIs), like escitalopram, are front-line pharmacological treatments for these disorders, putatively regulating depressed mood and reducing suicidality. However, data from case studies and retrospective meta-analyses of depression clinical trials is mixed, with some (but not all ) studies suggesting that during the first months of treatment, SSRIs may increase the risk of suicidal ideation in select individuals, particularly younger individuals. These post-hoc analyses, though informative, are based on studies that provide limited sampling of the self-harm domain. No study, to date, has implemented a direct prospective examination of the effects of early SSRI use on self-harm thoughts and behaviors using a multi-method measurement involving both the laboratory (standard self-aggression paradigm: SAP) and home environments (ecological momentary assessment: EMA). Also, no study has examined the influence of impaired 5-HT function and emotion dysregulation as moderators of outcome with escitalopram. The proposed randomized clinical trial will prospectively assess the impact of eight weeks exposure to SSRI treatment on self-harm ideation and behavior among a sample of 200 subjects with Borderline Personality Disorder and current major depression. After a one week single-blind placebo lead-in, participants will be randomly assigned double blind to either placebo or escitalopram for eight (8) weeks. The primary dependent variable will be EMA of self-harm ideation and behavior obtained several times each day. Self-harm will also be assessed using a laboratory analogue task (SAP) at baseline and again after the eight week trial. Age will be evaluated as a moderator of SSRI response. 5-HT dysfunction and emotion dysregulation will be evaluated as candidate moderators of SSRI response. 5-HT functioning will be assessed using psychophysiological (loudness dependence of the auditory evoked potential: LDAEP) and genetic (5-HT transporter promoter polymorphism: 5-HTTLPR) markers. Measures of emotion dysregulation will include trait aggression, impulsivity and socioemotional information processing. At the conclusion of the eight-week randomized trial, all participants will receive eight weeks of escitalopram administered single-blind, with continued EMA and other assessment. PUBLIC HEALTH RELEVANCE: The proposed randomized clinical trial will prospectively assess the impact of 8 weeks exposure to SSRI treatment on self-harm ideation and behavior among a sample of 200 subjects with Borderline Personality Disorder and current major depression. After a one week single-blind placebo lead-in, participants will be randomly assigned double blind to either placebo or escitalopram daily for eight (8) weeks. The primary dependent variable will be EMA of self-harm ideation and behavior obtained several times each day. Selfharm will also be assessed using a laboratory analogue task (SAP) at baseline and again after the eight week trial. Age, 5-HT dysfunction and emotion dysregulation will be evaluated as potential moderators of SSRI response.

DESCRIPTION (provided by applicant): In this R21 application, we propose to build on work with recently developed Social-Emotional Information processing (SEIP) visual stimuli. These stimuli are composed of short video clips based on written SEIP vignettes that have already been shown to have excellent psychometric properties. We propose to develop and refine an fMRI protocol to examine neural networks related to the various aspects of SEIP. These relate to viewing (encoding), hostile attribution, and negative emotional response. The first group of subjects will include healthy volunteer subjects. The second group of subjects will include individuals with prominent histories of recurrent, problematic, impulsive aggression (Intermittent Explosive Disorder: IED). The fMRI-SEIP protocol will define the neural networks involved in the different aspects of SEIP in healthy volunteers. Then the fMRI protocol will be studied in subjects with histories of recurrent, problematic, impulsive aggression (IED). We hypothesize that: a) during the Viewing Phase, increased fMRI BOLD signal response will be observed in brain regions associated with cognitive appraisal (DLPFC, OFC, PHG) and affective reaction (AMYG, ACC, INS), b) during the Attribution Phase, increased fMRI BOLD signal response will be observed in brain regions associated with cognitive appraisal (DLPFC, OFC, PHG, PCN), c) during the Negative Emotional Response Phase, increased fMRI BOLD signal response will be observed in brain regions associated with affective reaction (AMYG, ACC, INS) and that, d) scores of Hostile Attribution and of Negative Emotional Response (which both connote the extent of provoked anger/hostility/negative affect) scores will correlate with activation of AMYG, ACC, OFC, and INS. Finally, we hypothesize that, compared with Healthy Control subjects, impulsive aggressive subjects (IED) will demonstrate reduced brain activation during the Attribution (cognitive appraisal) in DLPFC, OFC, PHG, and PCN and heightened brain activation during the Negative Emotional Response (affective reaction) in AMYG, ACC, INS.

? DESCRIPTION (provided by applicant): In this application, we propose to build on previous work regarding the role of neuroinflammation in aggression and in social-emotional information processing. Both preclinical animal studies and recent human studies from our lab, and other labs, support the hypothesis that inflammatory processes are an important modulator that facilitates aggressive behavior. Work in human subjects have all been from the study of peripheral, as opposed to central, inflammatory marker/mediators and have been limited to only one or two markers (e.g., C-Reactive Protein and IL-6). In this study, we propose to test the hypothesis that: (a) various inflammatory marker/mediators in the central nervous system (i.e., measured in cerebrospinal fluid) are dimensionally related to aggressive behavior (i.e., if they mirror, and/or better relate to aggression than, peripheral inflammatory measures) and, (b) that these inflammatory marker/mediators play a role in social-emotional information processing, an important component of human aggressive behavior, as expected based on experimental work in human subjects and from our own pilot data.

Project Summary: The specific aim of this project is to experimentally examine the effect of alcohol on aggressive and impulsive responding, and on social-emotional information processing (SEIP) responses to threat, in individuals as a function of Alcohol Use Disorder (AUD) and prominent history of recurrent, problematic, impulsive aggressive behavior (AGG). While alcohol use is associated with impulsive aggression, little is known about the system neuroscience nature of this association except that the link between alcohol and aggression is most clear, and strongest, in individuals who are already high in trait aggression. Recent reports suggest that history of high lifetime alcohol use, in addition to acute alcohol dosing, dampens both cortical and subcortical responses to threat. In addition, acute alcohol administration appears to reduce cortical-subcortical connectivity, which some suggest is the primary correlate of alcohol-related aggressive behavior. However, this cannot explain all cases of alcohol-related aggression because neuronal correlates of aggression in non-alcoholics include an over, rather than under-activation of subcortical structures (i.e., amygdala) in the alcohol-free state. To advance our understanding of these complex relationships, we propose to study neuronal responses to socio-emotional threat in four groups of subjects: a) AUD and AGG (AUD+AGG); b) AUD without AGG (AUD); c) IED without AUD (AGG); and d) Healthy Controls (AUD-/AGG-), to uncover behavioral and neuro-circuitry differences in impulsive aggression and in the neuronal response to threat as a function of a history of AUD. Specifically, this study proposes to test the hypothesis that alcohol intoxication (0.08 mg%) is associated with increases in aggressive responding, and impairment in measures of SEIP, and to test the hypothesis that alcohol intoxication further affects cortico-limbic function in ways to increase the risk of impulsive aggression, though, perhaps, by different neuronal mechanisms as a function of AUD. Subjects will complete two (2) study sessions, in randomized order, in which each will receive intravenous alcohol (using alcohol clamp methodology), with alcohol doses clamped to achieve steady state alcohol breath levels of 0.08 mg%. Subjects will then complete a human laboratory aggression task and then an fMRI scanning session including two social-emotional information processing tasks: a) one that taps into the processing of explicit emotional cues of threat and, b) one that taps into the processing of ambiguous social cues of threat.

Project Summary In this application, we propose to build on previous work regarding the role of glutamate in impulsive aggression. Both preclinical animal studies and recent human studies from our labs and other labs support the hypothesis that glutamate is an important modulator that facilitates aggressive behavior. In this study, we propose to use an FDA approved glutamatergic modulator, Nitrous Oxide (N2O), to determine if N2O has the ability to normalize cortico-limbic circuits previously associated with impulsive aggressive behavior in humans. Impulsive aggressive, and healthy non-aggressive control, study participants will undergo two inhalation protocols (50% N2O / 50% O2 as active and 50% N2 / 50% O2 as control) separated by at least one week and undergo an fMRI Scan 24 hours after each inhalation study session. If this mechanistic study demonstrates that N2O inhalation can normalize the functioning of these circuits, N2O may represent a candidate as an anti-aggressive agent.