# Network Dysfunction and Neuromodulation following TBI

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2024 · $389,213

## Abstract

Summary:
Although memory dysfunction is a frequent and debilitating symptom of traumatic brain injury (TBI), there are
currently no effective treatments available for this often persistent deficit. In addition, the neurophysiological
basis of this dysfunction remains unknown, hindering rational treatment design. There is mounting evidence that
precisely coordinated communications between brain regions are necessary to encode and recall information in
the neuronal ensembles that represent episodic, spatial, and working memory. The hippocampus (HC) is the
most well-studied region of memory encoding and is considered to be selectively vulnerable in both human and
animal TBI. We and others have demonstrated disruptions of oscillations in the HC following TBI, with the loss
of theta a notable finding. Rodent studies have demonstrated that restoration of theta using stimulation
(neuromodulation) can restore aspects of HC dependent memory. However, the mechanism remains unknown,
as does the complex relationship of these neuronal ensembles to oscillations and their correlation with memory
deficits after TBI. Without a deeper understanding of how ensemble coding underlying 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 coding in networks underlying
memory formation after TBI, and how a reintroduction of theta restores 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, and how theta neuromodulation restores function. Our central hypothesis is that TBI
disrupts communication within the larger hippocampal network which disrupts oscillatory interactions required
for encoding and recall of memory in networks of synchronized neuronal ensembles. This hypothesis is based
in part on our preliminary data demonstrating that neurons in the hippocampus synchronize improperly with
oscillations following injury, and that prominent interactions between oscillations are lost. We therefore propose
to determine whether TBI affects phase precession, theta sequences, and phase amplitude coupling in area CA1
of the hippocampus during overtrained tasks designed for these measures, as well as whether both hippocampi
are affected by a unilateral injury. 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 behavioral memory function relying on HC-PFC networks. We
will also examine the mechanism of neuromodulatory restoration of spatial/working memory in rats via
simultaneous medial septal stimulation and high-density laminar hippocampal/mPFC recordings.
Accomplishment of these goals will provide the first detailed an...

## Key facts

- **NIH application ID:** 10784771
- **Project number:** 5R01NS101108-07
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** John Allen Wolf
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $389,213
- **Award type:** 5
- **Project period:** 2017-04-01 → 2028-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10784771

## Citation

> US National Institutes of Health, RePORTER application 10784771, Network Dysfunction and Neuromodulation following TBI (5R01NS101108-07). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10784771. Licensed CC0.

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