PNS to Improve Vascular Function and Limb Health in Veterans

The overarching goal of this project is to define how targeted afferent activation can be used to restore impaired neurovascular reflexes, improve skin perfusion, and ultimately prevent further decline in limb health in Veterans. By integrating functional and structural imaging with neural modulation, this work will establish foundational evidence for diagnostic and therapeutic strategies aimed at early detection of neurovascular decline and prevention of tissue breakdown in both Diabetic Peripheral Neuropathy (DPN) and residual-limb contexts. Furthermore, this work will establish the feasibility of preventing or delaying the mechanical trauma of the insensate distal limb which invariably leads to deep pressure injuries, infections, and amputation in Veterans with DPN. The findings have the potential to transform care by enabling earlier diagnosis, improving neurovascular responsiveness, and optimizing neuromodulation protocols to prevent skin complications, delay progression toward amputation, and improve quality of life in Veterans with DPN or limb loss.

• Chronically Implanted Neural and Muscular Interface (Device): The implanted neural and and muscular interface will be used to characterize neurovascular reflex testing (thermal axon reflex \& pressure-induced vasodilation) and microvascular imaging using Laser Doppler Flowmetry and PAI. Reflex responses will be evaluated under baseline and stimulation conditions (sham, tonic, biomimetic), with direct stimulation performed by the CFINE cohort for modality comparison. Structural-functional relationships will be modeled by integrating metrics from PAI with reflex outcomes.
• Peripheral Nerve Stimulation (PNS) (Device): The cutaneous peripheral nerve stimulation interface will be used to characterize neurovascular reflex testing (thermal axon reflex \& pressure-induced vasodilation) and microvascular imaging using Laser Doppler Flowmetry and PAI. Reflex responses will be evaluated under baseline and stimulation conditions (sham, tonic, biomimetic). Structural-functional relationships will be modeled by integrating metrics from PAI with reflex outcomes.

Primary outcomes

• Cutaneous Vascular Conductance [baseline and visits 1-15 until study completion, average 1 year]: Autonomic reflex testing including thermal axon reflex and pressure induced vasoconstriction will be applied. The cutaneous blood flow in the lower limb will be measured using laser doppler flowmetry. The flux is divided by mean arterial pressure to calculate cutaneous vascular conductance. This provides a physiologically relevant metric of microvascular control by accounting for systemic pressure fluctuations
• Vessel Density [baseline and visits 1-15 until study completion, average 1 year]: Defined as the percentage of tissue volume occupied by vascular structures. The investigators use photoacoustic imaging of microvascular structure to quantify microvascular structural integrity at distal and proximal skin sites. From the reconstructed volumetric data, the investigators will extract the vessel density
• Tissue Oxygen Saturation [baseline and visits 1-15 until study completion, average 1 year]: Tissue oxygen saturation or sO2 will be measured during different conditions of the study such as thermal axon reflex and pressure induced vasoconstriction using reflectance spectroscopy
• Mean Vessel Diameter [baseline and visits 1-15 until study completion, average 1 year]: Calculated from the cross-sectional profiles of resolved vessels obtained from the photoacoustic imaging of microvascular structures
• Hemoglobin Oxygenation [baseline and visits 1-15 until study completion, average 1 year]: From photoacoustic imaging, hemoglobin oxygenation is derived and compared across different study conditions

Sex: All, ages: 18 Years to any, accepts healthy volunteers

Inclusion Criteria:

Inclusion Criteria - All Participants:

* English-speaking
* Veteran

Inclusion Criteria - Diabetic Peripheral Neuropathy (DPN) Participants:

* Confirmed diagnosis of type 1 or type 2 diabetes mellitus for at least 5 years
* Clinical signs and/or symptoms consistent with diabetic peripheral neuropathy Or confirmation of neuropathy via physical exam

Inclusion Criteria - Lower Limb Amputees:

* Unilateral transtibial or transfemoral amputation
* Medically stable for at least 3 months
* For the designated subset of the limb-loss cohort (n = 6): implanted with C-FINEs on the sciatic and/or tibial nerves

Exclusion Criteria:

Exclusion Criteria - All Participants:

* Severe neurological disorders impairing ambulation
* Visual or hearing impairments interfering with study participation
* Cardiovascular or respiratory conditions posing risk during participation
* Cognitive or psychiatric conditions compromising informed consent
* Participation in other clinical trials interfering with outcomes
* Pregnancy
* History of photosensitivity or known sensitivity to laser light

Additional Exclusion Criteria - Amputees:

* Active skin breakdown or infection at residual limb
* Significant phantom or residual limb pain interfering with study procedures
* Bilateral lower-limb amputation

• Hamid Charkhkar, PhD, Principal investigator, Louis Stokes VA Medical Center, Cleveland, OH