Steering Toward Normative Wide-Dynamic-Range Neuron Activity in Nerve-Injured Rats With Closed-Loop Peripheral Nerve Stimulation.

OBJECTIVES: Chronic pain is primarily treated with pharmaceuticals, but the effects remain unsatisfactory. A promising alternative therapy is peripheral nerve stimulation (PNS), but it has been associated with suboptimal efficacy because its modulation mechanisms are not clear and the current therapies are primarily open loop (ie, manually adjusting the stimulation parameters). In this study, we developed a proof-of-concept computational modeling as the first step toward implementing closed-loop PNS in future biological studies. When developing new pain therapies, a useful pain biomarker is the wide-dynamic-range (WDR) neuron activity in the dorsal horn. In healthy animals, the WDR neuron activity occurs in a stereotyped manner; however, this response profile can vary widely after nerve injury to create a chronic pain condition. We hypothesized that if injury-induced changes of neuronal response can be normalized to resemble those of a healthy condition, the pathological aspects of pain may be treated while maintaining protective physiological nociception. MATERIALS AND METHODS: Using an in vivo electrophysiology data set of WDR neuron recordings obtained in nerve-injured rats and naïve rats, we constructed sets of linear phenomenologic models of WDR firing rate during windup stimulation for both conditions. Then, we applied robust control systems techniques to identify a closed-loop PNS controller, which can drive the dynamics of WDR neuron response in neuropathic pain model into ranges associated with normal physiological pain. RESULTS: The sets of identified linear models can accurately predict, in silico, nonlinear neural responses to electrical stimulation of the peripheral nerve. In addition, we showed that continuous closed-loop control of PNS can be used to normalize WDR neuron firing responses in three injured cases. CONCLUSIONS: In this proof-of-concept study, we show how tractable, linear mathematical models of pain-related neurotransmission can be used to inform the development of closed-loop PNS. This new application of robust control to neurotechnology may also be expanded and applied across other neuromodulation applications.

Mapping Spinal Cord Stimulation-Evoked Muscle Responses in Patients With Chronic Spinal Cord Injury.

OBJECTIVES: Epidural spinal cord stimulation (eSCS) has shown promise for restoring some volitional motor control after spinal cord injury (SCI). Maximizing therapeutic response requires effective spatial stimulation generated through careful configuration of anodes and cathodes on the eSCS lead. By exploring the way the spatial distribution of low frequency stimulation affects muscle activation patterns, we investigated the spatial specificity of stimulation-evoked responses for targeted muscle groups for restoration after chronic SCI (cSCI) in participants in the Epidural Stimulation After Neurologic Damage (E-STAND) trial. MATERIALS AND METHODS: Fifteen participants with Abbreviated Injury Scale A cSCI from the E-STAND study were evaluated with a wide range of bipolar spatial patterns. Surface electromyography captured stimulation-evoked responses from the rectus abdominis (RA), intercostal, paraspinal, iliopsoas, rectus femoris (RF), tibialis anterior (TA), extensor hallucis longus (EHL), and gastrocnemius muscle groups bilaterally. Peak-to-peak amplitudes were analyzed for each pulse across muscles. Stimulation patterns with dipoles parallel (vertical configurations), perpendicular (horizontal configurations), and oblique (diagonal configurations) relative to the rostral-caudal axis were evaluated. RESULTS: Cathodic stimulation in the transverse plane indicated ipsilaterally biased activation in RA, intercostal, paraspinal, iliopsoas, RF, TA, EHL, and gastrocnemius muscles (p < 0.05). We found that caudal cathodic stimulation was significantly more activating only in the RF and EHL muscle groups than in the rostral (p < 0.037 and p < 0.006, respectively). Oblique stimulation was found to be more activating in the RA, intercostal, paraspinal, iliopsoas, and TA muscle groups than in the transverse (p < 0.05). CONCLUSIONS: Cathodic stimulation provides uniform specificity for targeting laterality. Few muscle groups responded specifically to variation in rostral/caudal stimulation, and oblique stimulation improved stimulation responses when compared with horizontal configurations. These relations may enable tailored targeting of muscle groups, but the surprising amount of variation observed suggests that monitoring these evoked muscle responses will play a key role in this tailoring process. CLINICAL TRIAL REGISTRATION: The Clinicaltrials.gov registration number for the study is NCT03026816.

Sustained Relief of Complex Regional Pain Syndrome (CRPS) Pain Following a 60-Day Peripheral Nerve Stimulation: A Report of Three Cases.

Patients who present to pain clinics with complex regional pain syndrome (CRPS) typically have debilitating pain, including hyperalgesia and allodynia, and additional substantial quality-of-life concerns related to the motor and autonomic-related symptoms of CRPS. Present treatments for CRPS such as neuropathic pain medications and sympathetic blocks are often unsatisfactory for managing symptoms. The present cases highlight the use of a 60-day percutaneous peripheral nerve stimulation (PNS) treatment for three patients with CRPS Type I affecting the foot. In all three patients, the tibial and common peroneal nerves were targeted separately at the popliteal fossa with two percutaneous leads each placed a remote distance (~1 cm) from the target nerve under ultrasound guidance. All three patients reported substantial pain relief and resolution of autonomic symptoms (e.g., swelling, edema, erythema), with sustained relief lasting 8-10 months in two patients, and 34 months (as of this writing) in the third patient. There were no medical complications. These three cases suggest that 60-day PNS is a safe and efficacious treatment for CRPS.

Predicting Wide-Dynamic Range Neuron Activity from Peripheral Nerve Stimulation using Linear Parameter Varying Models.

Neuromodulation treatments for chronic pain are programmed with limited knowledge of how electrical stimulation of nerve fibers affects the dynamic response of pain-processing neurons in the spinal cord and the brain. By modeling these effects with tractable representations, we may be able to improve efficacy of stimulation therapy. However, pain transmitting neurons in the dorsal horn of the spinal cord, the first pain relay station in the nervous system, have complex responses to peripheral nerve stimulation (PNS) with nonlinearities and history effects. Wide-dynamic range (WDR) neurons are well studied in pain models and respond to peripheral noxious and non-noxious stimuli. We propose to use linear parameter varying (LPV) models to capture PNS responses of WDR neurons of the deep lamina in the dorsal horn in the spinal cord. Here we show that LPV models perform better than a single linear time-invariant (LTI) model in representing the responses of the WDR neurons to widely varying amplitudes of PNS current. In the future, we can use these models alongside LPV control techniques to design closed-loop PNS stimulation that may accomplish optimal pain treatment goals.Clinical Relevance- Electrical nerve stimulation as a therapy for chronic pain is in need of a more informed approach to programming. By describing the effects of stimulation on the pain system with tractable mathematical models, we may be able to titrate the stimulation to more effectively treat chronic pain.