Neuromodulation and Neuroplasticity in Sleep-Disrupted Post-Traumatic Epileptogenesis

Principal Investigator: SHANDRA, OLEKSII

Proposal Number: EP230013

Award Number: HT9425-24-1-0116

Period of Performance: 2/15/2024 - 2/14/2027

PUBLIC ABSTRACT

In the past 20 years, over half a million military personnel have sustained traumatic brain injury (TBI). The harsh realities of military life, from unpredictable sleep patterns to the inherent risks of battlefield operations and rigorous training, contribute to this alarmingly high figure. This convergence of demanding circumstances often culminates in the onset of a serious neurological condition known as post-traumatic epilepsy (PTE). PTE is characterized by spontaneous, recurring seizures that may arise months, or even years, after the traumatic incident.

Our research aims to decipher the intricate process of the development of epilepsy following TBI. We focus on the correlation between sleep disruption and seizures, a topic that remains enigmatic despite extensive study. By analyzing the intersection of sleep, trauma and brain stimulation, our work innovatively challenges existing paradigms, promising to uncover hidden mechanisms, formulate predictive biomarkers and unearth potential therapeutic strategies.

We employ our established, clinically relevant mouse model of diffuse TBI to evaluate the effects of chronic sleep disruption on PTE progression. Central to our study is the neurotransmitter gamma-aminobutyric acid (GABA), a regulator of brain excitability. We innovatively monitor alterations in GABA activity in live mice using advanced imaging techniques, a venture poised to identify pivotal indicators of PTE.

Our exploration extends to transcranial magnetic stimulation (TMS), a non-invasive, cost-effective procedure. While TMS has improved sleep quality and treated neurological disorders, its potential in mitigating PTE in TBI's aftermath remains largely unexplored. Our research predicts TMS to be an effective intervention, enhancing sleep quality and tempering brain hyperexcitability, thereby preventing PTE following TBI.

Understanding the implications of sleep disruption on PTE risk after TBI, especially given the high prevalence of sleep disturbances is a Topic of Interest for military. With the potential of TMS as a preventative intervention might revolutionize treatment protocols, providing a non-pharmacological, non-invasive alternative, our proposed studies aligned with two Fiscal Year 2023 CDMRP Focus Areas: (1) Markers and Mechanisms: (a) predictive biomarkers of epileptogenesis (acute and chronic) and (b) research into the prevention of epilepsy and/or seizures; and (2) Longitudinal Studies: (a) treatment and healthcare outcomes research, including quality of care. Our research is thereby poised to improve the quality of life for individuals living with PTE, with broader implications for understanding epileptogenesis in the general population.

The research contributes to the advancement of PTE research, patient car, and overall quality of life while also serving the PIs career goals. As a tenure-track faculty at Florida International University, Dr. Shandra (PI) secured preliminary data, honed required techniques, and advanced technology for studying epileptogenesis. This opportunity enables him to integrate data and technology, thereby expanding his independent ideas on PTE research and translating them into practical applications in the future. This critical step in Dr. Shandra’s career trajectory will secure his standing as an established investigator in PTE research.

TECHNICAL ABSTRACT

Background: Traumatic brain injury (TBI) has affected approximately 500,000 U.S. military members in the past two decades, with disrupted sleep increasing the risk of TBI and exacerbating its effects. A concerning outcome of TBI is post-traumatic epilepsy (PTE), characterized by recurrent seizures. There is evidence that chronic sleep disruption can elevate the risk of PTE in military personnel who have sustained a TBI. Despite substantial investigation into the relationship between sleep and epilepsy, data regarding the impact of sleep disruption on post-traumatic epileptogenesis remains sparse. In addition, we explore the relatively untapped field of transcranial magnetic stimulation (TMS). TMS is a safe, non-invasive, and cost-effective neuromodulation technique that has the potential to play a pivotal role in addressing these issues and serve as an effective therapeutic approach. This research proposes an innovative application of TMS, targeting the mechanism of chronic sleep disruption-induced hyperexcitability, aiming to create a breakthrough in PTE treatment strategies.

Hypothesis or Objectives: This study hypothesizes that chronic sleep disruption contributes to a hyperexcitable brain network that intensifies injury-induced neuroplasticity, leading to post-traumatic epileptogenesis. It also hypothesizes that TMS neuromodulation, administered in the latent period after TBI, may reduce this hyperexcitability and promote endogenous anti-epileptic mechanisms.

Specific Aims and Study Design:

Aim 1: To determine the effects of sleep disruption on injury-induced neuroplasticity and the risks of posttraumatic epileptogenesis. The study design involves inducing chronic sleep disruption in mice prior to TBI and evaluating post-traumatic sleep architecture changes, followed by two-photon imaging of intensity-based gamma-aminobutyric acid (GABA) sensing fluorescence reporter (iGABASnFR) and immunohistochemical analysis of changes in GABA A- and B receptor subunits and glutamic acid decarboxylase.

Aim 2: To determine the effects of repetitive TMS on GABAergic signaling, sleep and PTE. The study design includes performing daily repetitive TMS treatment for two weeks post-TBI, recording the mice for up to two months post-TBI, evaluating the effects of TMS on GABAergic signaling, and comparing the inflammatory profiles in blood samples from TMS-treated and untreated mice.

Impact: In the short-term, our findings will offer multiple lines of evidence pertaining to the effects of sleep disruption on post-traumatic epileptogenesis and the potential therapeutic role of TMS. Our study will critically examine whether chronic sleep disruption exacerbates the risks and effects of post-traumatic epilepsy (PTE), focusing on the changes in GABAergic signaling and associated inflammatory profiles. These results will challenge existing notions that the hyperexcitability of brain networks following traumatic brain injury (TBI) is the primary link to epileptogenesis, and will provide valuable insights into the complex relationship between sleep disruption, neuroinflammation and PTE.

The long-term impact of this project will be the advancement of therapeutic approaches and interventions to mitigate the secondary effects of TBI, namely PTE. Effective therapeutic strategies, such as the implementation of TMS during the latent period after TBI, could significantly enhance recovery outcomes and diminish the burden of TBI on patients and their caregivers, both in terms of health and economic costs. This study will also pave the way for precise timing of therapeutic interventions, enhancing the overall management of inflammation associated sequelae in TBI, ultimately improving neurological function and quality of life for patients and veterans.

Career Development and Sustainability: Participation in the Virtual Post-Traumatic Epilepsy Research Center (P-TERC) will foster the faculty member’s independent research, encourage collaboration and expand their professional network. An individualized Career Development and Sustainment Plan, designed in collaboration with Dr. Richard Staba, UCLA, will bolster their skill set and guide the production of high-impact papers and competitive grant proposals. This methodical approach, coupled with the supportive environment at Florida International University (FIU), will secure and enhance their career as a leading PTE investigator. This research is aligned with the CDMRP's current strategic focus, ensuring project relevance and potential for sustained funding and career progression