# Functional and Structural Correlates of Cognitive Dysfunction following TBI > **NIH VA I01** · PHILADELPHIA VA MEDICAL CENTER · 2024 · — ## Abstract Summary: Although cognitive dysfunction is a frequent and debilitating symptom of traumatic brain injury (TBI), there are currently no effective treatments available for this often persistent deficit. The neurophysiological basis for these symptoms are unclear, as are the relative contributions of focal/diffuse pathologies in moderate/severe TBI. We have developed and characterized two large animal (pig) models of focal brain injury with a diffuse component. New advances in high-density electrophysiology are finally able to reveal how neuronal coding of memory is altered by TBI, however it is unknown how this process is differentially affected in biomechanically accurate translational animal models of focal/diffuse brain injury. Without a mechanistic understanding of how coding that underlies cognition and memory is disrupted post injury, rational design of neuromodulatory and other therapies remains challenging. Therefore, a critical need exists to determine the underlying mechanisms of the disruption of memory encoding in cognitive networks TBI, and whether and how theta neuromodulation can restore function in these models. In additional, the structural basis for these changes must be identified using advanced imaging techniques validated by neuropathology. The long-term goal of this research is to elucidate the underlying mechanisms whereby TBI leads to the disruption of memory and recall in limbic networks, and to develop novel treatment strategies to improve memory and cognitive function. The overall objective of the current application is to determine how the coding of memory in the hippocampus and associated circuitry is disrupted following TBI in a gyrencephalic brain, the structural basis for this dysfunction, and whether and how theta neuromodulation restores function. Our central hypothesis is that focal TBI disrupts communication within the extended hippocampal network via axonal injury, disrupting oscillatory interactions required for encoding and recall of memory in networks of synchronized neuronal ensembles. Furthermore, fronto-parietal CCI (CCI-FP) will disrupt specific pathways between structures while leaving local circuitry intact, leading to loss of entrainment to HC oscillations in PFC, whereas occipito-temporal (CCI-OT) will have direct effects on HC circuitry that propogate to PFC. We will therefore first determine whether TBI affects phase amplitude coupling, phase precession, theta sequences and replay in area CA1 of the hippocampus during tasks designed for these measures. In addition, we will determine the mechanism of learning and memory dysfunction following TBI by examining neuronal ensemble activity across HC-PFC, quantifying ripple features and replay, and correlating these measures with complex behavioral function relying on these networks. We will then examine whether and how neuromodulation restores spatial/working memory in pigs via simultaneous fimbria-fornix (FF) stimulation and high-density laminar hippocam... ## Key facts - **NIH application ID:** 10916845 - **Project number:** 1I01BX006511-01 - **Recipient organization:** PHILADELPHIA VA MEDICAL CENTER - **Principal Investigator:** John Allen Wolf - **Activity code:** I01 (R01, R21, SBIR, etc.) - **Funding institute:** VA - **Fiscal year:** 2024 - **Award amount:** — - **Award type:** 1 - **Project period:** 2024-05-01 → 2028-04-30 ## Primary source NIH RePORTER: https://reporter.nih.gov/project-details/10916845 ## Citation > US National Institutes of Health, RePORTER application 10916845, Functional and Structural Correlates of Cognitive Dysfunction following TBI (1I01BX006511-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10916845. Licensed CC0. --- *[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*