Ten interdisciplinary research teams at Duke have been selected to receive the 2015-2016 Duke Institute for Brain Sciences Research Incubator Awards (five new awards and five continuation awards). The Research Incubator Awards program is designed to encourage innovative approaches to problems of brain function that transcend the boundaries of traditional disciplines. The award provides seed funding for collaborative research projects that will lead to a better understanding of brain function and translate into innovative solutions for health and society.
2015-2016 New Awards:
- Optimized Temporal Patterns of Spinal Cord Stimulation to Treat Chronic Pain
Investigators: Warren Grill (Biomedical Engineering), Ru-Rong Ji (Anesthesiology), Nandan Lad (Surgery)
Project Summary: Chronic pain is a prevalent and clinically challenging condition for which there are often not adequate treatments. For example, chronic low back pain is the most common cause of lost time due to disability, and imposes an annual economic burden of >$100 billion. Standard treatments for chronic pain, such as physical rehabilitation, pharmaceuticals, and surgery, work for some individuals, but for others who do not receive satisfactory pain relief from standard treatments, alternative approaches are required. Spinal cord stimulation (SCS) is an established surgical device therapy widely used for treating chronic pain, where an implanted battery-powered pulse generator (pacemaker) delivers electrical pulses to an electrode array placed in the spine. Although, SCS is FDA approved for treating chronic low back and limb pain, only ~ 60% of recipients experience a reduction of 50% or more in their pain. We propose to investigate a novel method of SCS that is expected to increase substantially the degree of pain reduction. The outcome of these collaborative studies will be an assessment of the feasibility of using a novel approach to treat chronic pain, and will provide the foundation for translational studies of this innovative approach in patients with chronic pain.
- The Power of Imagination
Investigators: Felipe De Brigard (Philosophy), Kevin LaBar (Psychology & Neuroscience), Zachary Rosenthal (Psychiatry & Behavioral Sciences)
Project Summary: Our tendency to entertain thoughts about alternative ways in which past events could have occurred but did not is ubiquitous. Usually, these episodic counterfactual thoughts are fleeting and infrequent. But not so for individuals suffering from anxiety. The constant presence of such thoughts in their lives and their incapacity to disengage from ruminating on regret-provoking counterfactual simulations is not only a hallmark of their condition, but also one of their most debilitating traits. Unfortunately, little is known about the cognitive and neural mechanisms underlying this maladaptive form of counterfactual rumination. The primary purpose of our proposed project is contribute to our understanding of the neural and cognitive basis of such abnormal counterfactual rumination in individuals with anxiety. In addition, we seek to test the hypothesis that, at the basis of their abnormal counterfactual rumination, lies a malfunction in the memory reconsolidation processes of individuals with anxiety. By uncovering the neural and cognitive mechanisms underlying abnormal counterfactual rumination in individuals with anxiety, as well as the precise ways in which counterfactual thinking and autobiographical memory interact in this population, we hope to unveil important clues that may help pursuing more effective clinical therapies for this condition.
- A developmental approach to the pathophysiology of pediatric medulloblastoma
Investigators: Yiping He (Pathology), Anne West (Neurobiology)
Project Summary: Although all cells in the body have the same DNA they use their genome in very different ways. During normal development genes are turned on or off to let each specialized cell develop its unique function. By contrast, aberrant regulation of the genome during development frequently leads to childhood cancers. Among these cancers is medulloblastoma, which is the most common brain tumor in infants and young children. This cancer frequently causes death or results in life-long disability both due to damage done by the tumor to the developing brain and from the toxicity of cancer treatments delivered to prolong the child’s life. Thus new ideas that might help to treat this cancer are desperately needed. Recent research has identified novel changes in the regulation of gene expression from the genome in medulloblastoma that may explain why normal brain cells become tumors in this disease. Here we propose to directly test whether these changes in genome regulation are sufficient to cause the formation of tumors and we will work toward developing a mouse model that could provide a means to test new ways to treat medulloblastoma based on this idea. Together these studies will provide important new insights into a fundamental molecular process of brain development that has importance for understanding brain tumors.
- Mechanisms of increased hippocampal excitability in the D801N knock-in mouse model of Na/K ATPase dysfunction an rescue with AAV-mediated gene therapy
Investigators: Dwight Koeberl (Pediatrics), Mohamad Mikati (Pediatrics), Scott Moore (Psychiatry & Behavioral Sciences), Victor Nadler (Pharmacology & Cancer Biology)
Project Summary: Fifty percent of the energy consumed by brain cells is expended by a cellular pump called the sodium potassium (Na/K) ATPase pump. This pump moves sodium and potassium ions across the cell membrane and, thus, is critical for maintaining the integrity of the brain cells and their normal function. It is also vulnerable and can malfunction under the stress of such conditions as epilepsy, stroke, decreased blood sugar, loss of oxygen and other conditions such as Alternating Hemiplegia of Childhood (AHC). AHC is a severe disorder with bouts of paralysis, spasms, and epileptic seizures. It is caused by mutations in the gene, Atp1a3, coding for a protein in this pump. We recently generated a mouse model bearing the most common mutation in AHC and it presents with the symptoms of AHC. In this study we propose to investigate the cell circuitry that regulates the balance between excitation and inhibition in the brain, and determine how this circuitry is altered by dysfunction of the Na/K ATPase pump. We also plan to use gene therapy to correct the manifestations of this disorder in our mouse model. This approach may lead to new therapies for humans suffering from AHC, epilepsy, and other related conditions.
- Pediatric neurotrauma
Investigators: Mohamed Abou-Donia (Pharmacology & Cancer Biology), Cameron R. ‘Dale’ Bass (Biomedical Engineering), Bruce Capehart (Psychiatry & Behavioral Sciences), Carrie Muh (Surgery), Carolyn Pizoli (Pediatrics)
Project Summary: Pediatric brain injury is common, but we know little about how impacts cause brain injuries, how to determine the injury severity, and how to treat brain injuries, especially for milder severities. Further, the long term consequences of repeated brain injuries are unknown. To address these pressing issues, we study adolescent elite female soccer players who are known to have a high incidence of on-field head injuries. Our collaborators have developed a novel way to determine the severity of the impacts using an ear based sensor (DASHR) that has been shown to be well-coupled to the human head, unlike any commercially-available system. Measuring on-field impacts with the DASHR system, we will investigate several novel techniques to sensitively determine the severity and time course of potential head injuries. These techniques include a blood test for markers of neurotrauma, a magnetic resonance imaging (MRI) technique to image changes in brain function, a noninvasive technique to measure the stiffness of the brain, a test for eye function, and a test for cognitive abilities and reaction times. All of these techniques have been found to potentially assess brain injuries by our collaborators, either in model systems or in adults. Using these techniques, we will characterize brain injury from impact through clinical/biological response, and will assess which technique or combination of techniques most effectively identifies brain injuries. Success of this project will provide new ways to understand and treat brain injuries in children.
2015-2016 Continuation Awards
- Measuring Implicit Moral Attitudes
Investigators: Murali Doraiswamy (Psychiatry & Behavioral Sciences), Tobias Egner (Psychology & Neuroscience), Scott Huettel (Psychology & Neuroscience), Walter Sinnott-Armstrong (Philosophy and the Kenan Institute for Ethics)
Project Summary: When a psychopath kills a stranger for money, does he have any sense that his act is immoral—as most of us would? Do people who say sincerely that nothing is wrong with homosexual sodomy actually have an implicit negative attitude that they need to overcome? Do people who lie have any inclination to think that lying is immoral? Are all of our moral judgments ultimately based on such implicit moral attitudes? To answer such questions, we need some way to determine who has an implicit moral attitude and, if so, how strong it is. Unfortunately, no such test exists yet. Our goal is to develop several measures of implicit attitudes, using reaction times, accuracy rates, subliminal primes, eye movements, and brain activity. We plan to develop, refine, and validate these varied tests by comparing their results to each other as well as to independent measures of moral judgment. These new tests will enable us to test popular theories in moral psychology, to study the effects of implicit moral attitudes on behaviors in a variety of contexts, and eventually to improve the diagnosis, treatment, and prediction of recidivism in psychopaths and other mental illnesses associated with deficits in moral judgment and behavior. These new tools could thereby aid both theory and practice.
- Translation-Dependent Molecular Signature of Synaptic Plasticity
Investigators: Marc G. Caron (Cell Biology), Arthur Moseley (Proteomics), Scott H. Soderling (Cell Biology)
Project Summary: We are all in part defined by the memories of our experiences, which not only record our past, but also inform how we react to present actions and predict future events. A remarkable feature of our memory is its longevity. Multiple lines of evidence spanning a half-century of research suggest it is the alteration and modification of specific connections (synapses) between neurons that enable for the long-term coding of experience into memory in a process termed synaptic plasticity. Moreover, abnormalities in this process are thought to underlie many of our most devastating neurodevelopmental disorders, including intellectual disability and autism spectrum disorders. One mechanism that has emerged to modify neuronal synapses is the specific translation (production) of proteins at sites of neuronal communication, enabling a long-term enhancement of their connectivity. Mutations in genes, such as FMR1 disrupt this process leading to Fragile X Syndrome in humans and related phenotypes in mice. Unfortunately, it has previously not been possible to decode the identity of proteins that are translated at the synapse, severely hampering our understanding of the mechanisms of synaptic plasticity and the basis for disorders related to its disruption.
- Novel Retinal Imaging Biomarkers in Early Alzheimer’s Disease
Investigators: James Burke (Neurology); Scott Cousins (Ophthalmology); Sina Farsiu (Biomedical Engineering and Ophthalmology); Eleonora Lad (Ophthalmology); Guy Potter (Psychiatry & Behavioral Sciences); and Heather Whitson (Medicine, Geriatrics)
Project Summary: Imaging of the retina, an extension of the brain, is becoming increasingly used for the diagnosis of neurodegenerative disorders such as multiple sclerosis. Recent studies have shown that retinal changes occur in Alzheimer’s disease (AD). We believe that retinal changes can be utilized for early diagnosis of AD and have the great advantages of being more sensitive, cheaper and significantly less invasive than other diagnostic techniques. We believe that both retina and the brain in AD undergo inflammation, which results in specific retinal changes that can be quantified using automated software developed by our group. The goal of this study is to compare retinal images between normal subjects and subjects with different stages of AD and to confirm that specific retinal changes occur in subjects with early AD. Novel imaging systems to quantify these retinal abnormalities will facilitate early diagnosis as well as fast and convenient monitoring of dementia progression in AD patients. In addition, quantification of these specific retinal changes can be employed to monitor efficacy of future therapies for AD.
- Real Time Workload Detection in Supervisory Control Applications Using fNIRS
Investigators: Greg Appelbaum (Psychiatry & Behavioral Sciences); Mary (Missy) Cummings (Mechanical Engineering and Materials Science)
Project Summary: With increasing use of automation in complex system operations like air traffic or nuclear plant control, the role of human operators is increasingly shifting from hands-on control to remote supervision, known as human supervisory control. When critical events occur, such as the need to scram a reactor or redirect an aircraft in distress, operators can be stressed by the sudden increase in workload, to the point of making erroneous decisions. The ability to remotely detect a psychophysiologic state that is likely to lead to problematic human performance would be especially useful for supervisors of such systems. By combining the measured hemodynamic and metabolic responses of brain and cognitive activity using functional Near-Infrared Spectroscopy (fNIRS), it is possible to determine a change in a subject’s cognitive activity while performing different tasks. Whether such data can be reliably connected to workload and performance in actual supervisory control settings, where most other psychophysiological efforts have failed, is an open question. Using fNIRS in a human supervisory control environment (in this case supervising multiple unmanned vehicles), this proposal will examine whether measured hemodynamic fNIRS data correlates to an actual change in low, moderate, and high workload in supervisory control settings, as well as whether this correlates to different human performance aspects such as decision quality and reaction time. Moreover, we will explore whether fNIRS data can be used by instructors to tailor individual training, and provide for quality control for existing training material.
- The Role of Microbiota in the Treatment of Anxiety and Abdominal Pain in Young Children
Investigators: Geraldine Dawson (Psychiatry & Behavioral Sciences); Helen Egger (Psychiatry & Behavioral Sciences); Cynthia Kuhn (Pharmacology & Cancer Biology); Kevin LaBar (Psychology & Neuroscience); Patrick Seed (Pediatrics); Nancy Zucker (Psychiatry & Behavioral Sciences)
Project Summary: Emerging preclinical evidence in animal models suggests that changes in the composition of the gut microbiome can both indirectly and directly influence CNS function. Evidence of “bottom-up modulation” has been demonstrated: treatments that alter the microbiome, such as probiotics, can influence anxiety and stress reactivity. Evidence of “top-down modulation” has also been demonstrated. For example, stress has been found to impact the composition of the microbiome. These preclinical findings have led researchers to the intriguing speculation that altering the composition of gut-microbiome in humans may affect psychiatric conditions such as anxiety. The use of probiotics as a clinical tool has yielded mixed findings with the most robust effects seen in the domain of pain perception/abdominal discomfort in individuals with irritable bowel syndrome. There remain numerous questions about the potential efficacy and mechanism of gut-CNS relationships. Part of this confusion and these conflicting results may be due to the developmental periods in which probiotic administration has been conducted. In animal models, alterations in HPA-axis reactivity, a marker of stress reactivity, were more sustained when interventions with probiotics occurred during the post-natal period. Similar findings support that gut-brain manipulations have more potent influence earlier in development. In this high-risk, high-impact study, we conduct the first trial open-label trial of probiotics in 30 young children with anxiety and abdominal pain. We examine changes in anxiety, pain/visceral sensitivity, and stress reactivity. Further, we will conduct exploratory analyses to compare the composition of the gut microbiome at baseline to typically developing children.
