Michael McCloskey - US grants

The specific aim of the proposed project is to examine the relationship between neuroanatomical pathways and emotional information processing deficits among individuals with Intermittent Explosive Disorder (lED). To accomplish this goal. Two groups of individuals: 16 participants with lED and 16 participants who are free of any clinical psychopathology, will be asked to complete two tasks of emotional information processing (the emotional counting stroop and the emotional faces task) during a one-hour functional imaging session. Both tasks will be presented using a block design. Tasks will be counterbalanced across subjects. The emotional counting stroop task will consist of 1-4 words presented on a screen, to which the subject identifies how many words were shown. Four types of words are used: positive (e.g. happy, puppy), neutral (e.g. sink, chair), general negative (e.g. vomit, regret) and anger (e.g. fury, idiot). Words were selected based on previous research. Pilot research by the authors suggest that individuals with lED are slower and less accurate when anger words are shown as compared to neutral words. During the emotional faces task, participants will intermittently be shown faces with angry, neutral, fearful, or happy expressions. During the first two runs they will be asked to identify the gender of the face presented using two 2-button response panels on their right hand. During the latter two runs participants will be asked to note the emotional expression of the pictures, but will not be asked to make a response. Past research has shown that individuals with a number of clinical disorders (e.g. Borderline Personality Disorder, Major Depression) exhibit an impaired ability to identify some types of emotional faces. Participants will then identify the emotional faces outside of the fMRI environment. Recently it has been demonstrated that lED patients are less accurate in identifying emotional faces than control subjects. It is hypothesized that lED subjects will (1) be less accurate at the emotional stroop tasks than control subjects when anger words are presented, (2) be less accurate at identifying emotional faces than control subjects, and (3) show a differential pattern of brain activation to emotional faces and words including increased amygdala activation for fear words and faces and decreased orbitofrontal activity for anger words and faces.

[unreadable] DESCRIPTION (provided by applicant): Research in the areas of suicide and self-aggression has traditionally relied on non-experimental methodologies (e.g., case studies and correlational findings). Though useful in identifying correlates of lethal and non-lethal acts of self-aggression, these methodologies are unable to specify causality. A similar problem with aggression research was addressed via the use of laboratory analogues of aggression. However, early attempts at creating a laboratory analogue of self-aggression were methodologically flawed, and no studies have been published using a laboratory measure of self-aggression for almost 20 years. The proposed investigation will assess the validity of a newly developed laboratory measure of self-aggression, using a largely clinical population. Participants will consist of 108 individuals with a DSM-IV Borderline Personality Disorder (BPD) and 27 psychopathology-free control participants with no past self-aggressive behavior. Participants with a BPD will be placed in one of four groups based on their history of suicidal behavior (past attempts vs. no past attempts) and non-suicidal self-injurious behavior (SIB vs. no SIB). All participants will complete self-report and interview measures. Some measures will assess risk factors for self-aggression (e.g., depression, hopelessness, impulsivity), while others will assess unrelated constructs (e.g., competitiveness, social desirability). Increased platelet serotonin (5-HT)-2a receptor binding has been found to be positively correlated with suicidal behavior. Therefore, blood will be drawn to assess platelet 5- HT-2a receptor density. Participants will then begin the self-aggression paradigm (SAP) in which they will compete against a fictitious opponent. Prior to each of the SAP trials, participants will select the level of shock they will receive if they lose that trial. Shock settings will range from no shock to a shock level the participant believes is twice what they previously stated was very unpleasant. Construct validity for the SAP would be evidenced by: (1) significantly higher mean and maximum self-selected shocks among groups with a history of self-aggressive behaviors, (2) significant correlations between self-selected shocks on the SAP and other known correlates of self-aggression, (3) non-significant differences for self-selected shock between the BPD and non-BPD groups with no history of self-aggressive behaviors, and (4) non-significant correlations between self-selected shock and constructs unrelated to self-aggression. [unreadable] [unreadable]

[unreadable] DESCRIPTION (provided by applicant): Intermittent Explosive Disorder (IED) is increasingly acknowledged as a common, potentially disabling psychiatric condition. Despite this, there are currently no empirically supported behavioral treatments for patients with IED. The purpose of the proposed study is to assess the short-term and long-term efficacy of a cognitive-behavioral treatment (CBT), previously found to be successful in treating dysfunctional anger, for treating IED. Secondary goals of the project are to (a) explore mechanisms involved in the successful treatment of IED, and (b) examine individual differences associated with treatment response. This request for a Patient-Oriented Mentored Scientist Award (K23) serves to cultivate the candidate's research acumen as it relates to randomized clinical trials, advanced biostatistical methodologies, and cognitive neuroscience. Ninety subjects meeting criteria for both current research and current DSM IED criteria will be randomly assigned to either 12 weeks of CBT or 12 weeks of a supportive psychotherapy control condition. Subjects will be assessed before and after therapy as well as at 6 month and 12 month follow-up. Primary outcome measures will assess aggressive behavior, anger, and the presence of an IED diagnosis at post-treatment, 6-month follow-up and 12-month follow-up. Social and emotional information processing will be evaluated as potential mechanism of change. Trait aggression will be assessed as a potential moderating variable. [unreadable] [unreadable] [unreadable]

[unreadable] DESCRIPTION (provided by applicant): Aggression is a worldwide public health problem, with devastating effects to perpetrators, victims, and society, and with associated costs of over 100 billion dollars in the U.S. alone. Alcohol is the drug that is most commonly linked to violent behavior, with the majority of serious violent acts (e.g., homicide) occurring under the influence of alcohol. Despite correlational research showing interpersonal violence occurs across gender, laboratory studies of aggression (which rely almost exclusively on community/college samples) have failed to demonstrate alcohol-facilitated physical aggression for women. In contrast, laboratory studies have repeatedly shown that alcohol facilitates aggression in men who are high in trait aggressiveness and/or low in executive functioning (i.e., planning, reasoning, response inhibition). The proposed project will compare the physically aggressive behavior of clinically aggressive (as defined by a current diagnosis of Intermittent Explosive Disorder [IED]; N=75) and control (healthy volunteer: N=75) women after administration of either (a) approximately 0.90g/kg (adjusted for BMI) of alcohol, (b) an active placebo drink, or (c) a clearly marked non-alcoholic drink. The study will occur over 2 days. On day 1, subjects will complete a diagnostic evaluation, related measures, and an executive functioning battery that includes: trails B, Stroop task, conditional associative learning task, Wisconsin card sort task, porteus maze and the go nogo task. On day 2, subjects will consume the alcohol/placebo/no-alcohol drink, then complete a laboratory task of physical aggression - the Taylor Aggression Paradigm (TAP) approximately 20 minutes after cessation of drink consumption. Aggression on the TAP is defined as the intensity of shock the subject administers to a (unbeknownst to the subject) fictitious opponent. It is hypothesized that alcohol will facilitate aggression only for women in the IED condition, and that alcohol-facilitated aggression would be moderated by executive functioning. Furthering our understanding of the inter-relationship between history of physical aggression, executive functioning, and alcohol-facilitated aggression in women will help guide development of intervention programs for aggressive women and spur additional research into models of alcohol-facilitated aggression in women. [unreadable] [unreadable] The proposed project will compare the physically aggressive behavior of clinically aggressive (as defined by a current diagnosis of Intermittent Explosive Disorder [IED]) and control women after administration of either approximately 0.90g/kg of alcohol, an active placebo drink, or a clearly marked non-alcoholic drink. [unreadable] [unreadable] [unreadable]

Intellectual Merit:

Algae play a major role in two areas of global concern, climate change and renewable biofuels, are emerging as prime topics on the world stage. Algae of all types account for approximately one-half of carbon dioxide (CO2) recycled from the atmosphere and 'fixed' via photosynthesis into sugars, proteins, and organic substances needed by all living organisms on earth, including humans. Thus, algae are critical to maintaining low levels of atmospheric CO2, a potent greenhouse gas. The fact that many fast growing, easy to culture algae also are oil-rich has recently drawn the attention of scientists and engineers around the globe to the possibility of using algae as an abundant, potentially inexpensive, source of renewable and sustainable biofuels that will lessen the needs for highly polluting, expensive and environmentally nonfriendly fossil fuels. Research to be conducted collaboratively between the laboratories of Dr. Don Weeks at the University of Nebraska-Lincoln and Dr. Martin Spalding at Iowa State University is aimed at elucidating the mechanisms underlying the ability of algae to serve as ?super sponges? of CO2 from the environment. The Spalding/Weeks laboratories recently discovered two proteins, HLA3 and LCIA, which provide the algal cell, Chlamydomonas reinhardtii, with the ability to scavenge very low levels of inorganic carbon (CO2 and bicarbonate) from their aquatic environment. Ongoing research sponsored by NSF will focus on the molecular mechanisms by which these inorganic carbon transporters work, where in the cell they are located and how these molecules interact with other components of the cell to allow efficient CO2 uptake and utilization for photosynthesis. In addition, the use of the newly discovered inorganic carbon transporters to augment CO2 uptake and photosynthetic efficiency in algal cells involved in biofuel production will be explored.

Broader Impacts:

This research will contribute significantly to the training of undergraduate and graduate students and postdoctoral associates participating in the project at both Iowa State University and at the University of Nebraska. It also will contribute to broadening the education of high school and undergraduate students and of high school biology teachers that will participate during summer internships and camps. Because members of underrepresented groups (e.g., African Americans, Hispanics, and Native Americans) are specifically recruited for the high school and undergraduate internships, this research also will provide opportunities for broadening educational experiences for these groups. Postdoctoral associates and students trained in our projects will find ample opportunities in academic and industrial positions focused on algal biology and biotechnology and its application to critical societal needs.

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.

? DESCRIPTION (provided by applicant): The goal of the proposed research is to investigate how the brain represents scene geometry and functionality. Recognizing the visual environment is central to our daily interactions with the world. When we walk into a new space, we rapidly recognize whether there is a path to follow, whether there are crossable boundaries, and whether there are obstacles that block our view and potential navigation. The theoretical framework of this proposal is based on evidence that there are distinct but complementary levels of scene representation across a group of scene-selective regions in the brain (Park et al., 2011; Park et al., 2014; Park & Chun, 2009; Park, Chun, & Johnson, 2010; Park, Intraub, Yi, Widders, & Chun, 2007). The PI proposes that scene geometry (e.g., spatial layout, three-dimensional scene boundary) and functionality (e.g., navigability, limitations of a boundary) are two fundamental scene properties represented in these regions. Specific Aims: Aim 1 investigates whether the brain displays acute sensitivity to the presence of vertical boundaries, and how such sensitivity is modulated by the functional impediment that a boundary presents to the viewer's potential navigation. Aim 2 investigates the neural representation of the scene navigability, and how this representation differs from representation of scene geometry. Aim 3 investigates whether the neural representation of real world scenes is modulated by acquired knowledge about the spatio-temporal context of a scene, which are important for functionality of a scene. Throughout her aims, the PI tests medial temporal lobe regions in human adults that process scene and spatial information: with particular focus on anterior and posterior parahippocampal gyri and retrosplenial cortex. Methods include univariate and multi-voxel fMRI pattern analyses (linear support vector machine classification and representational similarity analysis) in combination with both region-of-interest (ROI) based and whole-brain based (search light) approaches. Hypothesis and preliminary results throughout the proposal suggest that scene geometry is represented in the parahippocampal gyrus, while scene functionality is represented in the retrosplenial cortex.