Chad M. Sylvester, MD PhD - US grants

[unreadable] DESCRIPTION (provided by applicant): [unreadable] [unreadable] An important component of goal-directed behavior is the ability to voluntarily attend to a specific location, even before objects appear at that location. Brain regions in the parietal and temporal lobes control the allocation of spatial attention by modulating activity in early sensory regions, including visual cortex. These control regions are damaged in disorders of spatial attention such as unilateral neglect, a common and devastating syndrome that afflicts many stroke victims. Fortunately, visual cortex is often spared direct damage in many patients with neglect, although activity in this region is abnormal due to lack of appropriate modulation by control regions. Restoration of control over visual cortex is a potential means of intervention in patients with neglect. The long-term objective of this research proposal, therefore, is to understand the changes that higher-level brain regions produce in visual cortex to produce the behavioral phenomenon of spatially directed attention. Because there are independent resources for attending to the left and right sides of space, it is important to understand the changes in visual cortex that allow for the specific allocation of attention across (specific aim 1) and within (specific aim 2) visual hemifields. Blood oxygen level dependent (BOLD) imaging in healthy human subjects will be used to meet these objectives. By measuring neural signals following auditory spatial cues and prior to visual stimulation, it is possible to examine endogenous control signals in visual cortex uncontaminated by visual stimulus-evoked activity. Measurement of the distribution of endogenous signals across visual cortex during explicit manipulation of the locus of spatial attention as well as the location of upcoming distracting visual objects will indicate how precisely visual cortex can be modulated. Furthermore, the relationship of endogenous control signals to accuracy on an upcoming perceptual task at the locus of spatial attention provides a strong indication of the modulations essential for optimal goal-directed behavior. Some of the dysfunction associated with unilateral neglect, a disorder of spatial attention, is due to the loss of normal control over structurally intact brain regions. The goal of this research is to understand how control is exerted over these regions in healthy individuals, with the long-term aim of restoring appropriate control in sufferers of neglect. In addition, understanding the neural mechanisms of spatial attention may inspire directed therapies in other disorders of attention, including traumatic brain injury, schizophrenia, and attention deficit hyperactivity disorder. [unreadable] [unreadable] [unreadable]

PROJECT SUMMARY Anxiety disorders are the most common class of mental illness in children, affecting up to 30% of individuals prior to their eighteenth birthday. Children who develop an anxiety disorder often experience significant family, social, and academic impairments and are at increased risk for developing additional psychiatric disorders as adults. Although successful treatment has been linked to benefits that extend into adulthood, many children remain highly symptomatic even with the best available treatments. New early interventions are clearly needed for this highly prevalent condition. The mission statement of the National Institute of Mental Health offers a general approach to finding new treatments: ?to understand mind, brain, and behavior, and thereby to reduce the burden of mental illness through research.? Functional brain networks are collections of brain regions with a common function. Understanding pathology at the level of functional brain networks holds enormous promise for unlocking the development, etiology, and treatment of mental illnesses such as pediatric anxiety disorders. With this framework in mind, the purpose of this Mentored Patient-Oriented Career Development Award (K23) is to enable the candidate to develop a research program investigating alterations in functional brain networks in childhood anxiety disorders. The applicant's long-term goal is to use functional brain networks to predict longitudinal course, treatment response, and develop new treatments for pediatric anxiety disorders. To help achieve this goal, the training plan in this application addresses the applicant's need for training in clinical developmental psychopathology research. Training and mentorship are provided in: 1) clinical assessments of children for research purposes, 2) understanding emotional and cognitive development, 3) pediatric neuroimaging, 4) longitudinal study design and analysis, and 5) treatment development. The research plan for this project is closely linked to the training plan and includes the assistance of a multidisciplinary team of mentors and consultants. The research proposal tests the hypothesis that alterations in one particular functional network, the ventral attention network (VAN), are associated the development of anxiety disorders. General alterations in the VAN are proposed to result in anxiety by increasing the orientation of attention to threatening stimuli. To test these hypotheses, children ages 8-12 years with and without anxiety disorders are assessed twice, 24 months apart, using neuroimaging and behavioral methods in a prospective design. Data from this study will be used to inform an application for a more definitive R01 project that maps developmental relations between the ventral attention network and development of anxiety in young at-risk children before the onset of anxiety disorders. Results from this application are expected to have immediate treatment implications, by determining whether treatment development should target the ventral attention network. This proposal also develops a framework for examining additional functional brain network pathophysiology associated with pediatric anxiety disorders.

Anxiety disorders are the most common form of pediatric psychiatric illness, affecting up to 30% and severely impairing up to 20% of all youth prior to age 18. Unfortunately, up to 50% of children remain symptomatic even with the best available treatment, making anxiety disorders a major public health problem. A major barrier to devising new treatments for anxiety disorders is that the brain pathophysiology likely starts at birth or earlier, but little is known about the earliest stages of abnormal brain development. This proposal measures brain activity and brain connectivity in neonates at high versus low risk for developing an anxiety disorder; uncovers the first steps in the neurodevelopmental pathway that results in an anxiety disorder; and provides a framework for early identification, prevention, and new treatment development. Anxiety disorders in adults are associated with increased activity in brain networks that respond to changes in the environment or `novelty', coupled with decreased activity in brain networks that regulate this novelty response. Behavioral and EEG data suggest that these processes may start in infancy. Infants with an enduring enhanced behavioral and neural (as measured by EEG) reaction to novelty are described as having the `behavioral inhibition (BI)' temperament and are at high risk for later development of an anxiety disorder. High maternal prenatal anxiety is similarly associated with both increased reactivity to novelty and increased risk for developing an anxiety disorder in offspring. The objective of this application is to identify the specific brain networks in newborn infants that are associated with this enduring enhanced response to novelty and that represent increased risk for later development of an anxiety disorder. To achieve this objective, we will use task-based fMRI to measure regional brain activity that is elicited by sudden, unexpected auditory stimuli (`oddballs') in sleeping neonates. Activity evoked by the initial oddballs represents the initial novelty response, while activity evoked by later oddballs represents the potential regulatory response. The central hypotheses are that neonates at high risk for developing an anxiety disorder (on the basis of either high maternal anxiety or high BI) demonstrate increased activity in brain networks that respond to novelty; coupled with decreased activity in regulatory networks after repeated presentation of the stimuli. We will also use resting-state fMRI to measure network connectivity, and we predict that risk for anxiety disorders will be associated with altered connectivity in networks that respond to novelty. We will test these hypotheses by recruiting pregnant mothers and obtaining MRI in offspring (n=150) within 2 weeks of birth. We will then assess the neonates and mothers at 3 additional visits over the first 2 years of life. We will assess maternal anxiety during pregnancy with questionnaires and infant temperament in the first 2 years with observational measures. Results may open new avenues for preventative measures in high-risk infants, such as repeated exposure to new stimuli; or stimulation of problematic brain networks. Such measures would have major public health impact, by preventing the most prevalent childhood psychiatric disorder.