I am a postdoc with a strong research interest in the neuronal mechanisms underlying altered network connectivity in severe brain injury and impaired consciousness. My immediate goal is to transition into a junior faculty position within the next two years. I have assembled a detailed career and training plan including the development of technical skills to investigate the causal relationship between altered cellular mechanisms and functional connectivity. I have worked in the field of severe traumatic brain injury (TBI) for the last 10 years and have thorough expertise in neuroimaging and network analyses in patients with impaired consciousness. During the mentored phase of this proposed K99 award, I want to expand my methodological repertoire using optogenetic functional magnetic resonance imaging (fMRI) to explore the causal effects of impaired neuronal mechanisms on functional connectivity. I propose to receive this training at UCLA under the mentorship of Dr. David Hovda in collaboration with my advisors Drs. Martin Monti, Neil Harris, and Weizhe Hong. Dr. Hovda is a highly respected researcher in the field of TBI and has an outstanding track-record in mentoring young researchers during their transition into independent research. With the help of my advisors I will learn optogenetic fMRI to explore causal effects of altered functional connectivity in TBI. Combining my computational expertise in clinical neuroimaging with the neuroscientific expertise in optogenetic manipulation allows a profound investigation of neuronal mechanisms underlying TBI and significantly enhances my opportunities when becoming an independent researcher. Besides the technical training, I will acquire complementary skills in teaching, lab management, and funding, which are essential when establishing a successful and independent research laboratory. Severe TBI is a leading cause of death and disability. Understanding spontaneous brain reorganization following severe brain injury and its association to recovery of cognitive function is crucial for patient diagnosis, prognosis, and the development of neurorestorative interventions. While there is a strong premise that functional connectivity of several hot spots within the cortico-basal ganglia-thalamo-cortical circuit are associated with impairments in TBI, recent intervention studies focus merely on the thalamus, and thus, ignore the picture as a whole. A systematic investigation manipulating different pathways within this circuit in the TBI model does not exist. During my postdoctoral fellowship, however, I found evidence indicating that the thalamus is not systematically related to recovery of consciousness. The proposed project is now a logical progression from my earlier work. I will (1) implement a method that allows the investigation of causal effects using optogenetics, (2) combine clinical expertise in measuring functional connectivity at the network level with insights into the cellular mechanisms, and (3) systematically explore the whole network (instead of focusing on single targets). My goal is to shed further light on how altered neuronal mechanisms affect fMRI measures in TBI, how these alterations give rise to impaired consciousness and cognitive function, and how this knowledge can then be translated into clinical intervention strategies. In a first step, I will investigate the effects of silencing different cell types and pathways within this circuit on functional connectivity and behavioral measures. These experiments will lead to a better understanding of how impairments at the cellular level modify functional connectivity. In the second part of my project, I will directly compare the effectiveness of stimulation between these different targets in respect to enhanced cortical activation and increased functional connectivity in the TBI model providing guidance for different therapeutic approaches manipulating the neuronal mechanisms within this circuit.
Severe brain injury is a leading cause of disability. Many patients do not recover fully with some remaining in a state of impaired consciousness and minimal cognitive function. Altered functional connectivity within the cortico- basal ganglia-thalamo-cortical circuit is associated with impaired cognitive functions but the exact neuronal mechanisms governing recovery are yet to be understood. Intervention studies have shown divergent findings regarding possible targets. However, recent therapeutic strategies such as deep-brain stimulation focus entirely on the thalamus ignoring the circuit as a whole. The goal of this study is to understand the neuronal mechanisms underlying altered functional connectivity and recovery in TBI using optogenetic fMRI. The findings of my study will lead to a better understanding of TBI and possibly guide the choice of targets for future therapeutic interventions.
