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NIH grant 1I21RD000485-01A1: Targeted muscle reinnervation: Evaluation of changes in spontaneous activity and neuroinflammation
Institute: {'code': 'VA', 'abbreviation': 'VA', 'name': 'Veterans Affairs', 'admin_org_id': '12500964', 'admin_funding_url': ''}. PI: Gwendolyn Maria Bethenis M Hoben. Award: $.
Start: 2026-10-01T00:00:00.
Significance to the VA: From recent combat veterans to the older veterans receiving care for diabetes and
vascular disease at the VA, amputation care is a priority in the VA health system. Amputation surgery has
undergone a paradigm shift as targeted muscle reinnervation (TMR) can be used at the time of amputation or
shortly after to prevent or significantly reduce both phantom and residual limb pain. However, for the 50,000+
veterans living with chronic amputations, of whom more than 60% experience pain, TMR results in much less
analgesia. The goal of this proposal is to examine the mechanisms behind TMR analgesia in an animal model
to work towards improving analgesia outcomes in chronic amputees.
Innovation and Impact: Little is known about the mechanisms behind analgesia in TMR because there is
almost no pre-clinical data. There are only 2 prior publications, including our own, using an animal model of
TMR and assessing pain. Building off our work with spared nerve injury and TMR in rats, we have developed a
hindlimb amputation model with TMR. We can use this model to examine electrophysiologic, cellular, and
biomolecular changes occurring with varying delay to TMR and correlating them to pain outcomes. Based on
these findings we can design alterations in the TMR procedure or adjunctive therapies to improve pain relief.
Specific Aims:
1. Assess changes in spontaneous activity (SA) source related to injury and delay to intervention: We
hypothesize that TMR stops SA originating from the injury site, but with increased delay to TMR, there is
continued SA originating from the DRG somata that is not affected by TMR.
2. Evaluation of immune cell and biomolecular response in the DRG related to amputation and intervention at
varying time intervals: We hypothesize that acute TMR reduces overall macrophage infiltration and activation,
while increased delay to TMR results in accumulation of immune cells and increasing inflammatory cytokine
production.
Methodology: The basis of our studies is using a rat hindlimb amputation model with sham versus TMR
intervention. In our preliminary data we have shown that this model results in measurable pain behaviors and
there is analgesia with TMR. Based on clinical and preliminary work we will compare TMR performed
immediately at the time of amputation, within the subacute period 3 weeks following amputation and the
chronic time period, 12 weeks following amputation. In Aim 1 we will used teased fiber recordings to
differentiate spontaneous afferent activity originating from the peripheral injury site versus the DRG to
determine if one site becomes more dominant over time. In Aim 2, we will use immunohistochemistry, a
cytokine protein array, and RNAscope assays to identify the key immune cells and cytokines acting in the DRG
before and after intervention with TMR at the varying time periods.
Path to translation: As TMR is already in clinical use, translation of our findings clinically can be rapid.
Answering these very fundamental questions (the locus of the spontaneous activity, the changes in the DRG
related to delay to intervention) will provide critical targets for clinical intervention that can be explored in a full
Merit proposal.document fetched 2026-10-24 02:46