Post-stroke trans-neuronal degeneration (TND) refers to secondary neuron deaths following the disruption of input from or output to other synapsed neurons sustaining ischemic insults after few days to several weeks of stroke onset. Secondary TND in the thalamus following ischemic infarct of the middle cerebral arterial (MCA) territory has been reported associated with the degeneration of the thalamocortical fibers. Given the integral role of the thalamus in the sensorimotor and other neurocognitive functions, damage to the thalamus or its projections is likely to have detrimental consequences. Although global morphological changes of thalamus have been reported after MCA infarcts, in vivo studies of TND on the intrinsic integrity of specific nuclei and their effects on distinct cortical functions have yet to be fully described. The questions whether the TND is nucleus-specific, how the nucleic degeneration may affect clinical recovery, and can the trans-synapse apoptosis be prevented remain unclear. To effectively translate the results in animal models into human stroke, mechanisms underlying the ischemic injury of TND need to be elucidated with more comparative studies across human and animals. We will first implement thalamic parcellation to determine the major nuclear topography in rat and man using structural MRI. Based on the thalamic parcellation, quantitative measurements of the microstructural and functional alterations in selective thalamic nuclei will be implemented using advanced MRI technology. TND will be conducted on a photothrombotic rat stroke model for specific thalamo-cortical pathways and translated into human stroke by correlating the imaging findings with pathological data from the animal model. The relevant pathophysiological mechanisms underpinning the imaging findings can then be assessed. By the novel imaging design and a longitudinal follow-through study using high Tesla MRI (7T and 3T), we will integrate these measurements and the neurological function tests of sensorimotor, memory, language and other neurocognitive functions as well as immunohistopathological results to explore the relations between the neuroimaging and clinical findings. We will test the hypothesis that the effects of TND on the thalamus would be nucleus-specific and the functional modifications following neuronal insults would be interrelated with the distinct connection of thalamic nuclei to the cerebral cortex associated with sensorimotor and other neurocognitive functions. We will further evaluate the longitudinal changes of TND by characterizing the time course of TND-related brain injury to provide the optimal time window for possible therapeutic strategies using integrated measurements. A specific rehabilitation training of robot-assisted gait training (RAGT) system designed to enhance neuroplasticity and facilitate functional recovery will be enrolled in this study to investigate the changes of thalamic connectivity for patients with chronic stroke after therapeutic intervention. We will use MRI to identify how the functional and structural remodeling of the thalamocortical pathway will be correlated with locomotor changes after RAGT therapeutic intervention. We aim to develop imaging biomarkers that can predict the risk of specific neurological function deterioration and thereby identify subjects for targeted intervention to provide the potential recovery biomarkers and assist therapeutic approaches.
|Effective start/end date||8/1/17 → 7/31/18|