Jessica R. Cohen - US grants

[unreadable] DESCRIPTION (provided by applicant): OBJECTIVE: A loss of self-control is a defining feature of substance abuse. However, there are many different types of self-control. For example, slamming on the brakes when a child runs in front of one's car, walking away from a successful poker game so as not to risk losing one's winnings, putting a paycheck into savings instead of spending it immediately, or suppressing anger so as to seem composed in a professional situation all require self-control in vastly different ways. Evidence suggests individuals with substance abuse may be deficient in each of these forms of self-control. In the laboratory, they have been shown to be deficient in motor inhibition tasks, behavioral choice tasks such as risk-taking and delaying gratification, and emotion regulation tasks that require inhibition of the "hot" emotional system to allow the "cool" cognitive system to make decisions. It is therefore possible that deficient self-control is a risk factor for developing substance abuse. Previous research has assumed all forms of self-control rely on a single neural mechanism involving the right ventrolateral prefrontal cortex (rVLPFC), yet this theory has not been directly tested. Thus, this proposal aims to reveal whether there is a single self-control system by directly relating both behavioral performance and neural activity in multiple tasks requiring different forms of self-control. METHOD: Both a behavioral and an fMRI study will be conducted in healthy adults relating performance on tasks in the four self-control domains mentioned above. Self-control ability on each task will be related to one another and to responses on self-report questionnaires probing impulsivity and risky behavior in both studies. The fMRI study will further explore whether there is overlap in the regions recruited during acts requiring self-control, specifically focusing on the rVLPFC, and whether behavioral performance relates to degree of rVLPFC involvement. It is hypothesized that a unitary self-control system will be noted, as indicated by related behavioral performance on all tasks and common rVLPFC involvement that increases relative to improved performance. RELEVANCE: This research will lead to an increased understanding of the nuances of successful self-control. This is crucial considering that a greater understanding of an intact self-control mechanism may lead to new treatments that efficiently target the self-control system and help individuals with disorders such as substance abuse and dependence that result from deficient self-control. [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant): The brain has an amazing ability to flexibly engage different functional networks based on the demands of a constantly changing environment. Sometimes forces acting on an intrinsic, baseline environment are transient, such as the dynamic cognitive demands of daily life. At other times they are longer term, and occasionally permanent, such as the changes that occur due to aging, brain damage, or psychiatric disorders. Recently there has been a focus on measuring the intrinsic functional connectivity of networks of brain regions during rest using functional MRI (fMRI). The application of graph theoretical tools taken from the field of mathematics to these intrinsic brain networks allows for the quantification of network properties, such as the degree to which groups of brain regions separate themselves into largely independent networks (or modules), and the identification of the role of individual brain regions, such as whether a region is integral for communication across multiple brain regions and networks, or whether a region limits its interactions to a small subset of brain regions within a single network. This proposal aims to extend this characterization of intrinsic brain networks to other contexts to assess the brain's potential for plasticity in different contexts. The proposed research, therefore, will investigate both the reconfiguration of global brain organization and the changing roles of individual brain regions from intrinsic network configuration in two different contexts: 1) disruption of functioning due to focal brain lesions, and 2) specific cognitive demands due to administration of different conditions of a cognitive task. METHOD: This research proposal will apply state-of-the-art methodologies and analyses to address the specific aims. The first experiment will analyze data that was collected from patients with focal brain lesions and age-matched healthy controls to assess the extent of network reconfiguration after brain damage. I hypothesize that adaptive network reconfiguration will occur if the role of intact tissue within the network that sustained te brain damage changes to be more similar to the role that the damaged tissue had in healthy, intrinsic brain organization. I predict that within-network adaptation is a more accurate manner of characterizing compensatory changes in brain organization than is focusing purely on intact tissue anatomically close to the damaged tissue (i.e., perilesional tissue) or on intact tissue in homologous regions in the undamaged (i.e., contralesional) hemisphere. The second experiment will examine the brain's ability to reconfigure in different cognitive contexts in healty young adults. I hypothesize that adaptive network reconfiguration will occur by changing network organization toward a single context-specific network made up of cognitively relevant regions and connections across separate intrinsic networks. Critically, the adaptive nature of this reconfiguration will be assessed by relating behavioral performance to the degree to which regions integral for task performance are important for communication within that context-specific network. PUBLIC HEALTH RELEVANCE: This research will further knowledge of the adult brain's potential for plasticity due to changes to its intrinsic, baseline environment, including brain damage, aging, and the cognitive demands of a dynamically altering environment. It is proposed that a potential mechanism underlying neural plasticity is the changing role of individual brain regions to adapt to the demands of the current environment and that this plasticity results in reconfiguration that is adaptive (as assessed by network organization close to a healthy state after brain damage and a relationship between reconfiguration and performance in healthy networks during cognitive performance). Crucially, this increased knowledge can lead to treatments involving cognitive training and rehabilitation in cognitively impaired or brain-damaged individuals that target adaptive reconfiguration.

DESCRIPTION (provided by applicant): Attention deficit hyperactivity disorder (ADHD) is the most commonly diagnosed developmental disorder of childhood, affecting ~5% of children worldwide. ADHD is a great public health concern as its core symptoms, which include increased impulsivity/hyperactivity and difficulty in sustaining attention, increase the risk for por academic achievement, substance abuse, and criminal behavior. Research into the neural basis of ADHD is crucial to improve early detection and treatment of the disorder. ADHD is hypothesized to result from dysfunctional connectivity. However, there are two main limitations with extant research: 1) there is a large emphasis on studying intrinsic connectivity while participants are at rest, despite evidence from the primary mentor's lab that dysfunctional connectivity during impaired cognitive processes is more strongly related to behavioral deficits than intrinsic connectivity; and 2) most research is limited to probing specific networks or connections despite strong evidence that ADHD is associated with a distributed pattern of abnormality across much of the brain. The groundbreaking application of mathematical graph theoretical tools to functional neuroimaging data allows for the first time the quantification of complex properties of large-scale brain network organization that can be assessed during cognitive task performance, when children with ADHD display the greatest behavioral deficits. The candidate has successfully applied graph theoretical analyses to fMRI data in adults, and has conducted preliminary analyses in children with ADHD. This application tests the hypothesis that children with ADHD are impaired in the ability to flexibly adapt network organization to shifting cognitive demands during the exertion of cognitive control, leading to behavioral deficits and observed symptoms. This will be tested by employing innovative functional connectivity and graph theoretical tools to functional neuroimaging data in children with ADHD and typically developing (TD) children. The first aim (K99) will characterize large-scale neural organization during a response control task in children with ADHD. By the end of year 2 the data for aims 1 and 2 will be collected, the candidate will have received sufficient clinical and methodological training to execute the remaining aims independently, and a manuscript regarding aim 1 will have been submitted. The second aim (K99/R00) will quantify the change in organization from an intrinsic, resting state to different conditions of a response control task in children with ADHD. The data will be independently analyzed and a manuscript completed during year 3. The candidate will also set up her independent laboratory, submit an IRB application for human subjects testing, and create the infrastructure necessary to recruit ADHD and TD children for aim 3. The third, exploratory aim (R00) will assess the changes in network dynamics that result from stimulant administration in children with ADHD and how those changes relate to changes in behavior. In year 4 data will be collected and initial analyses conducted; aim 3 will be completed in year 5. Results from these studies will lead to the identification of biomarkers to improve early diagnosis of ADHD and treatments targeting the dysfunctional systems, and will form the basis of an R01 application written during the R00 phase. The candidate is trained in cognitive neuroscience and advanced functional MRI (fMRI) methodology and has conducted functional connectivity and graph theoretical analyses such as those she is proposing. She also has experience working with TD children and clinical populations. The proposed training will fill gaps in the candidate's current knowledge and provide a solid basis for her to independently conduct translational research in functional neuroimaging and developmental disorders. The candidate's clinical training will include formal coursework, seminars, clinics, and individual clinical training in the recruitment and assessment of children with ADHD, behavioral techniques to ensure compliance during behavioral and MRI testing, safe stimulant administration, and theoretical understanding of developmental disorders and therapeutic approaches. It will be led by her primary mentor, Dr. Stewart Mostofsky, a pediatric neurologist and clinical investigator at Kennedy Krieger Institute (KKI) and Johns Hopkins University (JHU) whose research focuses on neuroimaging and cognitive dysfunction in developmental brain disorders, and supplemented by KKI/JHU clinical psychologists Drs. Mark Mahone and Keith Slifer and child psychiatrist Dr. Roma Vasa (consultants). She will receive additional training to supplement her already strong knowledge base of advanced fMRI methodology, with a focus on functional connectivity and graph theoretical analyses, led by her co-mentor, Dr. Mark D'Esposito, a clinical neurologist and researcher at the University of California, Berkeley (UCB) whose research focuses on the effects of disruptions to brain circuitry and developing multivariate fMRI methodology, and supplemented by Dr. Brian Caffo, a biostatistician at JHU, and Dr. Fernando Perez, a physicist and applied mathematician at UCB (consultants). The candidate's training will also enhance her scientific writing and presentation skills. This training will ensure that the proposed R00 studies can be implemented independently. Both the candidate's mentors, who collaborate with each other, have strong track records supervising fellows into becoming independent investigators and are strongly committed to transitioning the candidate to independence. KKI, a world-renowned institute focusing on research of developmental disorders with close ties to JHU, is an ideal location in which the candidate can receive outstanding training in the clinical aspects of research on developmental disorders, as well as training to supplement her methodological skills. Completion of this research application and training plan will enable her to gain proficiency relevant to her goal of becoming an independent investigator in the fields of developmental disorders, cognitive neuroscience, and advanced neuroimaging methodologies.

PROJECT SUMMARY/ABSTRACT Attention-deficit/hyperactivity disorder (ADHD) is the most commonly diagnosed developmental disorder of childhood, affecting ~9% of children nationwide. Although ADHD dramatically increases the risk for poor academic achievement, substance abuse, and criminal behavior, particularly in adolescence, too little is known regarding how neurobiological developmental trajectories underlie these behavioral and clinical outcomes. This remains the case in spite of the importance of such work for earlier identification of risk factors, more targeted treatment models, and, in turn, education, juvenile justice, and healthcare savings for individuals, families, and society. The goal of the current project, therefore, is to characterize longitudinal neural, behavioral, and clinical trajectories of youth with ADHD from late childhood to mid-adolescence. Brain systems underlying cognitive control and motivation in particular have been identified as centrally important both to the neural etiology of ADHD and to the general increase in risk-taking behavior and poor decision-making observed in typically developing (TD) adolescents. An important aspect of these models is how brain regions underlying these processes form coherent networks, as well as how these networks interact and influence each other to produce behavior. Here we bring together these two disparate literatures to gain understanding of the transition to adolescence in youth with ADHD. Thus, this proposal focuses on the maturational course of the cognitive control and motivation systems, individually and in interaction, in youth with and without ADHD in a multi-session longitudinal design. The aims of this proposal include: 1) Characterize behavioral trajectories of cognitive control, motivation, and their interaction in ADHD and TD youth from childhood into adolescence; 2) Characterize the development of structural and functional brain network organization during the same time period, focusing on brain networks underlying cognitive control and motivation; and 3) Identify neural, behavioral, and clinical features of pre-adolescent ADHD that predict clinical outcomes and risk-taking behavior during adolescence. To address these aims, innovative network analytic tools based on graph theory and structural equation modeling will be applied to structural and functional connectivity estimates of MRI data during diffusion-weighted imaging (structural) and during rest, cognitive control, motivation, and risk-taking tasks (functional). These techniques are uniquely able to simultaneously characterize the strength and coherence of within-network structural/functional connectivity and across-network interactions, as well as to identify important brain network features that differentiate across groups. Additionally, behavioral performance on the cognitive control, motivation and risk- taking tasks, ADHD symptomatology, and risk-taking attitudes and behavior will be assessed. This program of research is directly in line with the NIH Strategic Plan and builds on the RDoC framework. Together, these findings will provide the groundwork that can lead to early identification and, ultimately, prevention of ADHD trajectories that are more likely to lead to adverse outcomes in adolescence.