Peripheral and Trigeminal Nerve Stimulation Improve Functional Outcomes of Nerve Recovery in a Rodent Forelimb Gap Repair Model

doi:10.21203/rs.3.rs-2493047/v1

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Peripheral and Trigeminal Nerve Stimulation Improve Functional Outcomes of Nerve Recovery in a Rodent Forelimb Gap Repair Model

https://doi.org/10.21203/rs.3.rs-2493047/v1

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published 01 Jan, 2024

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Background: It is well established that peripheral nerve stimulation (PNS) improves outcomes following nerve injury. By contrast, the trigeminal nerve has not yet been explored as a target of electrical stimulation (ES) for this indication. The hypothesis of this study is that the trigeminal nerve stimulation (TNS) and PNS improve functional outcomes of peripheral nerve injury in a rat forelimb model when compared to rats not receiving ES.

Methods: Forty-five male Lewis rats were randomized into 4 groups: (1) sham injury, (2) nerve injury with sham ES, (3) nerve injury with PNS, and (4) nerve injury with TNS. Following repair, rats in the PNS group were stimulated for 1 hour. During rehabilitation, the TNS group received a 500ms train of ES immediately following each successful reach and grasp. Functional motor and sensory metrics were collected both pre-injury and throughout rehabilitation.

Results: The sham ES group did not recover their pre-injury baseline functional outcome measurements by the final week of recovery. In contrast, the PNS and TNS groups fully recovered following injury as there was no difference in functional outcomes between the pre-injury baseline and final week of rehabilitation (p > 0.05, all).

Conclusions: Trigeminal nerve stimulation and PNS are viable therapies to improve outcomes of nerve injury.

Biological sciences/Neuroscience/Peripheral nervous system

Biological sciences/Neuroscience/Neurogenesis/Adult neurogenesis

Peripheral nerve injury (PNI) is a relatively rare but devastating for patients.¹ Patients with PNIs often have lasting morbidity and loss of function even with standard-of-care surgical treatment.² This is in part due to the imperfect process of peripheral nerve regeneration. Following nerve transection, the nerve cell body upregulates regeneration associated genes (RAGs), which mediate the transition from manufacturing neurotransmitters to cytoskeletal elements for assembly into the growth cone.³ These growth cones, comprised of microtubules and actin, randomly sample the site of nerve injury, using a mixture of chemical and physical signaling. Schwann cells guide the regenerating axons into the appropriate nerve tube at the distal aspect of the injury site. The process of bridging the space of ultrastructural loss in the peripheral nerve is termed “staggered growth.”⁴

If the growth cone does not find the appropriate nerve tube after a period, the nerve cell body will undergo apoptosis (i.e., chronic axotomy).⁵ In nerves with higher axon counts, each axon finding its appropriate nerve tube becomes less likely. Additionally, Schwann cells can only maintain the nutrient-rich milieu for regenerating axons distal to the site of injury for a set period. Therefore, the longer the regenerating axon must travel to reach its target organ, the more likely it is to fail reinnervation (i.e., chronic denervation).⁵ These concepts are reflected in validated patient reported outcome measures for PNI patients: the more proximal the injury and the higher the axon count of the injured nerve, the larger the functional impairment for the patient post-repair.^6,7

For these reasons, adjunct therapies, such as clinical electrical stimulation (ES), have been explored to address the limitations of peripheral nerve regeneration. There is a robust body of literature in support of peripheral nerve stimulation (PNS) to improve outcomes of PNI.^8–11 Brief intraoperative ES to the proximal nerve stump has been demonstrated to improve functional outcomes following peripheral nerve injury. The proposed mechanism involves depolarization of voltage-gated calcium channels with the concomitant release of calcium intracellularly.⁸ This signal propagates retrograde to the nerve cell body, causing an earlier and supraphysiologic upregulation of RAGs like brain-derived neurotrophic factor (BDNF) and synchronization of staggered growth with more axons crossing the injury site earlier than they would under normal conditions.¹²

Another form of ES that has been demonstrated to improve PNI outcomes is cranial nerve stimulation. During the process of nerve regeneration a number of axons inevitably innervate the inappropriate nerve tube which results in uncoordinated muscle activation and aberrant sensory signaling from the affected extremity. To account for this, the cerebral cortex must reorganize to regain function of the injured limb, a process known as neuroplasticity. Mechanistically, a cortical neuron can alter its synaptic connections when bound to both a neurotransmitter like glutamate and certain neuromodulators like acetylcholine and norepinephrine.¹³ The vagus nerve is a cranial nerve responsible parasympathetic innervation to visceral organs and motor function of the larynx. However, it also contains afferent nerves that project to deep brain nuclei like the basal nucleus and locus coeruleus.¹⁴ These deep brain nuclei possess cholinergic and norepinephrinergic neurons that project widely to the cerebral cortex. Vagus nerve stimulation temporally coupled with a learned motor task has been shown to induce targeted neuroplasticity in the motor cortex.¹⁴ Additionally, vagus nerve stimulation has been shown to improve functional outcomes of PNI when coupled with functional rehabilitation of the injured extremity in a rodent model.¹⁵ However, vagus nerve stimulation in humans requires surgical implantation of a cuff electrode deep in the neck, and therapeutic current delivery is often limited by adverse effects like vocal cord spasm.¹⁶

In contrast, the trigeminal nerve is a cranial nerve that predominantly contains sensory afferents from the face. It offers projections bilaterally to similar deep brain nuclei as the vagus nerve, and studies have demonstrated increased markers of neuronal activity in these nuclei with stimulation.^17,18 It also can be reliably stimulated transcutaneously in humans with surface electrodes.¹⁹ Its superficial nature and relatively benign function make it an attractive alternative to the vagus nerve for stimulation to augment neuroplasticity post-PNI. To date, no study has applied trigeminal nerve stimulation (TNS) for this indication.

In the present study, we explore the effect of two modalities of electrical stimulation –peripheral nerve and trigeminal nerve stimulation – on the recovery of rat forelimb function following nerve transection and repair. We hypothesized that rats treated with either PNS or TNS would have a more robust recovery of motor and sensory function post-injury than rats who did not receive either therapy. Our aims were to (1) to compare the efficacy of TNS and PNS in improving functional outcomes following nerve injury, and (2) to demonstrate TNS as a viable alternative to vagus nerve stimulation for the purpose of improving functional outcomes post nerve transection and gap repair.

Subjects

Forty-five adult male Lewis rats weighing approximately 250g were included in the study. Lewis rats were selected because they possess the lowest rate of denervation-related autophagy in rat strains and have demonstrated competence in food-rewarded behavioral tasks.²⁰ All aspects of the protocol were approved by the University of Wisconsin Institutional Animal Care and Use Committee, designed in accordance with ARRIVE guidelines, and all methods were performed in accordance with the relevant guidelines and regulations. All subjects were housed in individual cages in the vivarium with a 12-hour light cycle environment.

Behavioral Apparatus

All subjects were trained to perform an isometric pull task with their right forelimb using the MotoTrak system (Vulintus, Inc., Dallas, TX), which has been used previously to train rats in isometric pull tasks under similar conditions.¹⁵ The behavioral chamber consisted of an acrylic cage with a 1cm-wide slot through which the animal interacted with the aluminum pull lever at the back wall of the cage (Pull Behavior Module, Vulintus, Inc., Dallas, TX). The lever was mounted on a slide, allowing the lever to be placed at fixed distances relative to the slot in the behavioral chamber, and fitted to a force transducer, which measured the pull force the animal applied on the lever. There was an acrylic fin mounted to the backwall of the chamber immediately to the right of the slot, disallowing the animal from interacting with the lever with their left forelimb when the lever was placed outside of the chamber. A food pellet dispenser was on the back wall on the opposite side of the fin from the lever slot. Each time the subject interacted with the lever and reached the activation force threshold for the given behavioral stage, they were rewarded with a single food pellet (45 mg dustless chocolate precision pellet, BioServ, Frenchtown, NJ). Custom MATLAB software was used to aggregate data on behavioral sessions. A microcontroller sampled the force transducer at 100 Hz, and the data was displayed on the computer monitor real-time for data acquisition and analysis.

Pre-Injury Training

All subjects were trained in two 30-minute sessions daily with a minimum of two hours between behavioral sessions. To incentivize interaction with the lever, animals were food-restricted to 10 g of food pellets per 24-hour period, unless their interactions with the lever during behavioral sessions resulted in greater than 10 g of food pellets rewarded. In which case, animals received only what they were rewarded during their behavioral sessions and were not supplemented further. All subjects were maintained at no less than 90% of their starting body weight. The first training stage consisted of the lever 1.0 cm inside the cage and a non-adaptive activation threshold of 10 g pull force. Food pellets were crushed and mixed with water to create a paste, and this paste was placed on the lever to encourage animal interaction. When the animals had 100 successful lever interactions across two consecutive sessions, they were advanced to the second training stage.

The second stage consisted of the lever beginning flush with the cage wall and an adaptative activation force threshold (10 g minimum, 50 g maximum) without food paste. The adaptative activation force threshold algorithm recorded the median pull force from the animals’ last 10 attempts and set that force as the new activation threshold for the next 10 attempts. This way, the animal is encouraged to give maximal effort pulling the lever. Also, the lever receded from flush with the chamber wall to 2.0 cm outside the chamber wall in 0.5 cm increments every 50 successful lever interactions. When the subject reached 75% success rate (percent of interactions per 30-minute session above maximum activation threshold) with the lever 2.0 cm outside the chamber wall for a single session, they progressed to the third training stage.

The third training stage consisted of the lever 2.0 cm outside the chamber wall and an adaptive force threshold (50 g minimum, 120 g maximum). When a 75% success rate was reached in a single session, the animal was progressed to the final training stage.

The final training stage consisted of the lever at 2.0 cm outside the chamber wall and a non-adaptative activation threshold of 120 g. When the animal had reached 70% success rate averaged over 10 consecutive sessions, they were considered proficient in the isometric pull task, and the average percent success and median peak force over these sessions served as their pre-injury baseline motor functional status.

Functional Sensory Assessment

When the subjects completed their pre-injury training, their baseline functional sensory data was collected using an automated dynamic plantar aesthesiometer apparatus (Ugo Basile, Varese, Italy). This device consisted of six acrylic booths atop a metal grid floor and a Von Frey filament (500 µm diameter) mounted on a force transducer that can move freely under the metal grid floor. This filament then advanced gradually into the center of the animal’s forelimb paw, and when the animal withdrew from the stimulus, the force required to elicit the paw withdrawal flexion response was automatically captured for data acquisition. For rat forelimbs, the manufacturer recommends a 50.00 g peak force and 5.0 s ramp time.²¹ All animals were allowed a minimum of a one-hour acclimation period in the aesthesiometer booths. Paw withdrawal thresholds were collected in grams. This was repeated six times with a two-minute intertrial period and averaged for each individual animal’s functional sensory assessment session. Functional sensory assessment testing was carried out as described at the pre-injury timepoint (baseline) and at the 2-, 4-, 6-, 8-, 10-, and 12-week timepoints post-injury.

Randomization

All subjects that completed the pre-injury training and baseline functional sensory assessment were blocked randomized into one of four groups: (1) sham surgery and sham TNS (positive control), (2) PNI with sham PNS and sham TNS (negative control), (3) PNI with active PNS and sham TNS, and (4) PNI with sham PNS and active TNS. An overview schematic of allocation and treatments for all subjects can be found in Fig. 1.

Injury Surgery

Injury-repair surgeries were performed under sterile conditions with isoflurane anesthesia via nosecone. Post-operative anesthesia was maintained with weight-based dosing of sustained released buprenorphine at 1.0 mg/kg. A longitudinal incision was made in the upper right forelimb from pectoralis insertion to the medial epicondyle of the humerus. In the sham surgery group, a mixture of sharp and blunt dissection was used to carefully isolate the median and ulnar nerve within the upper forelimb. In the PNI groups, the median and ulnar nerves were transected using microscissors 1.0 cm proximal to the medial epicondyle of the humerus. The nerves were repaired individually using a 4 mm silastic conduit (1 mm internal diameter). A single vertical mattress, epineurial suture (9 − 0 nylon) was used to fix the nerves within the conduits, generating a 2 mm gap repair.

In the active peripheral stimulation group, compound motor activation potential (CMAP) was measured using a custom-fabricated bipolar nerve cuff prior to nerve transection. After nerve transection, one hour of continuous electrical stimulation was delivered to the proximal nerve stumps en bloc, using a custom fabricated bipolar nerve cuff (1.85 mm internal diameter). Stimulation parameters were selected based on prior literature (biphasic, cathode leading, charge balanced pulses; 20 Hz; 100 µs pulse width) (Fig. 2).²² All active peripheral stimulation subjects were stimulated at a current that was 80% of their recorded CMAP (median 24 µA, minimum 12 µA, maximum 64 µA).

In the sham peripheral stimulation groups, a sham nerve cuff (1.85 mm internal diameter silastic tube without wire leads) was placed around the proximal nerve stumps for one hour. All subjects were closed in a single layer using a simple running suture (5 − 0 Vicryl). All subjects were allowed five weeks of recovery with ad libitum food.

Trigeminal Cuff Implant Surgery

At the 5-week timepoint post-injury, all animals underwent implantation of a trigeminal nerve stimulation electrode under sterile conditions with isoflurane anesthesia via nosecone. A longitudinal incision was made from the base of the cranium to the glabellum. The periosteum and scalp were raised in a single layer to expose the cranium. Four screws were placed between the coronal and lambdoid sutures. The left supraorbital nerve was dissected free of surrounding frontalis muscle. A custom-fabricated bipolar nerve cuff (0.6 mm internal diameter) was placed around the nerve. The leads were fed through subcutaneous tissue and the pin connector was placed between the screws. This construct was reinforced with bone cement and dental resin. The wound was closed in a single layer using 5 − 0 Vicryl. All subjects were allowed a 1-week recovery period with ad libitum food.

Functional Rehabilitation

Six weeks post-injury, all subjects returned to perform the isometric pull task in two 30-minute sessions daily. The rehabilitation stage consisted of an adaptative force threshold (minimum 10 g, maximum 120 g) and the lever 2.0 cm outside the chamber. The median peak force and percent success were collected for each session and aggregated in weekly epochs. All animals were tethered by their headcap to the commutator for the first five weeks of rehabilitation. Subjects in the active TNS group were stimulated automatically each time they had a successful lever interaction (constant current, biphasic, cathode leading, charge balanced pulses; 30 Hz; 200 µs pulse width; 500 ms pulse duration) (Tucker Davis Technologies, Alachua, FL, USA) (Fig. 3). To minimize aversion to the lever, current was titrated from 0 µA to 10 µA lower than aversion response in the animal in 10 µA increments per session for the first two weeks of rehabilitation (median 25 µA, minimum 10 µA, maximum 80 µA). Aversion response in the animal was defined as a startle response or aggressive grooming of the left forehead post-stimulation. In the final week of rehabilitation (week 12 post-injury), all subjects were allowed to interact with the lever untethered and the active TNS group was not stimulated.

Terminal Surgeries

At the conclusion of the rehabilitation period, subjects were anesthetized with isoflurane and euthanized with intracardiac injection of pentobarbital.

Statistical Analysis

Twelve subjects per treatment group were justified by power analysis (statistical power of 0.8). A two-sample t-test was performed to detect a difference in median peak force, assuming an effect size of 20g mean difference between the active TNS group and sham stimulation groups based on a prior study in similar circumstances.¹⁵

All statistical methods of comparison were determined prior to the start of data collection. To compare the functional motor and sensory data between groups, a repeated measures analysis of variance (ANOVA) was used for the averaged median peak force, percent success, and paw withdrawal thresholds for each aggregated weekly timepoint. Post-hoc analysis was performed using differences of least square means. Significance was set 0.05 type I error for all statistical tests. A group was considered to reach functional recovery for median peak force, percent success, or paw withdrawal threshold when the aggregated value for the week post-injury was not statistically different than the pre-injury baseline timepoint. All values for functional motor and sensory outcomes are represented as mean difference from pre-injury baseline ± standard error. A positive or negative mean difference denotes a value that was greater than or less than the pre-injury baseline value, respectively.

Equivalence of Pre-injury Baseline Functionality and Injury Severity Between Groups

There was no difference in performance between all groups at the pre-injury baseline timepoints for median peak force, percent success, and paw withdrawal thresholds (P > 0.05, respectively) (Figs. 4 and 5). Additionally, all injury groups demonstrated comparable reductions in motor functional outcomes – median peak force and percent success – at week 6 post-injury compared to their pre-injury baselines (Fig. 4). The sham ES group demonstrated a 72.20±5.48 g reduction in median peak force (P < 0.0001) and a 71.72±4.78% reduction in percent success (P < 0.0001). The PNS group demonstrated a 71.37±5.25 g reduction in median peak force (P < 0.0001) and a 69.33±4.58% reduction in percent success (P < 0.0001). The TNS group demonstrated a 74.58±5.48 g reduction in median peak force (P < 0.0001) and a 67.66±4.78% reduction in percent success (P < 0.0001). The sham surgery group performed similarly in median peak force (mean difference − 10.87±6.06 g, P > 0.05) but demonstrated a 13.82±5.29% reduction in percent success (P = 0.0095) between pre-injury baseline and week 6 post-injury.

Functional Motor Recovery

The sham ES group did not recover their pre-injury baseline median peak force (mean difference − 12.36±5.48 g, P = 0.0252) or percent success (mean difference − 15.54±4.78%, P = 0.0013) by the final week of recovery. The PNS group reached functional recovery for median peak force (mean difference − 5.383±5.25 g, P > 0.05) and percent success (mean difference − 3.992±4.58%, P > 0.05) at week 9 of rehabilitation (Fig. 4). The TNS group reached functional recovery for median peak force (mean difference − 3.873±5.48 g, P > 0.05) and percent success (mean difference − 8.509±4.78%, P > 0.05) at the final week of rehabilitation (Fig. 4). The sham surgery group outperformed their pre-injury baseline for median peak force (mean difference + 22.19±6.06 g, P = 0.0003) at the final week of recovery and reached functional recovery of percent success (mean difference − 1.311±5.29, P > 0.05) at the week 7 timepoint.

Functional Sensory Recovery

The sham ES group did not recover their pre-injury baseline paw withdrawal threshold by the final timepoint of the rehabilitation period (mean difference + 4.177±1.59 g, P = 0.0092). The PNS group made a functional sensory recovery at week 8 post-injury (mean difference + 1.019±1.52 g, P > 0.05) (Fig. 5). The TNS group recovered their pre-injury baseline paw withdrawal threshold at the week 6 post-injury timepoint (mean difference + 1.08±1.59 g, P > 0.05) (Fig. 5). The sham surgery group demonstrated no difference between their pre-injury baseline paw withdrawal thresholds and any subsequent week (Ps > 0.05).

The proposed mechanism for this therapy is similar to that of vagus nerve stimulation (i.e., TNS, repetitively coupled with a motor task, evokes a targeted neuroplasticity in the portion of the cerebral cortex associated with the task performed).¹⁴ The trigeminal nerve has projections to key deep brain nuclei which govern the release of neuromodulators like dopamine and norepinephrine to the cerebral cortex.¹⁷ The presence of these neuromodulators with glutamate induce dendritic sprouting and pruning, effectively reorganizing the motor cortex to better perform the learned task. When analyzing the data, the TNS group reached functional motor and sensory recovery, whereas the sham ES group did not. Additionally, the TNS group demonstrated the earliest sensory recovery of any injury group. Vagal nerve stimulation has been explored as a treatment for neuropathic pain,²³ and it is possible that TNS has similar effects which normalized the paw withdrawal thresholds of this group sooner than the sham stimulation and PNS groups.

With a growing body of literature on the therapeutic effects of cranial nerve stimulation for epilepsy, stroke rehabilitation, complex task learning, and nerve injury, developing facile methods of interfacing with these nerves becomes increasingly important. In comparison to the vagus nerve, the trigeminal nerve is superficial and carries out a relatively benign function physiologically. It has been demonstrated that the trigeminal nerve may be stimulated transcutaneously in humans with a simple and cost-effective capacitively coupled skin electrode. This broadens access to cranial nerve stimulation for a wider range of indications.

Another advantage to TNS is that therapeutic current applied is not limited by autonomic effects on visceral organs like the vagus nerve. However, one limitation to TNS noted when conducting the present study is that because the trigeminal nerve is predominantly somatosensory in nature, subjects may have developed an aversion to the lever. That is, TNS may have elicited a pain response in the animals, and they may have given submaximal effort when engaging in the isometric pull task. This is evidenced by the fact that when the current was titrated too quickly or above tolerance for the individual animal, they did not engage in the motor task. Additionally, the TNS group performed similarly to the sham ES group until the final rehabilitation week when the headcap was removed. When the animals in the TNS group were allowed to perform the task untethered and without stimulation, they demonstrated a marked improvement in both median peak force and percent success. Finally, the functional sensory data for the TNS group demonstrated that they had the earliest recovery of paw withdrawal thresholds of any of the injury groups, but motor functional recovery was delayed. These anecdotal findings necessitate further research into developing a better understanding of the minimum activation thresholds of TNS and pain responses in animal subjects.

There is a strong body of evidence in support of PNS for the treatment of nerve injuries in both preclinical and randomized controlled human studies. In the present study, the PNS group demonstrated an earlier return of motor function when compared to both the TNS and sham stimulation groups. These findings are in agreement with the other studies which demonstrate that PNS induces an early and supraphysiologic upregulation of RAGs, resulting in more axons crossing an injury site earlier than normal circumstrances.²⁴ However, the TNS and PNS groups performed similarly for both motor and sensory functional outcomes at the final week of rehabilitation. This finding is compelling for future studies to combine these two therapies because PNS and TNS act by entirely separate proposed mechanisms.

The trigeminal nerve is a viable target to improve functional outcomes of peripheral nerve injury, and in the present study appears to have a similar effect size when compared to PNS. These data demonstrated that TNS resulted in the quickest return of normal sensory function of any of the treatment groups. Further research is required to better refine TNS for this purpose and to understand its mechanisms. Finally, combination therapy of PNS and TNS may have additive benefit for functional outcomes of PNI, and this is being explored in the model used in the present study.

Authors Competing Interesting Statement: The authors declare no competing interests.

Author Contributions

PJN contributed to study design, data collection, statistical analysis, manuscript drafting and manuscript revision.

DTD contributed to data collection, statistical analysis, manuscript drafting, and manuscript revision

WZ contributed to study design, data collection, and manuscript revision

AJS contributed to figure design and manuscript revision

SOP contributed to study design, statistical analysis, and manuscript revision

AJS contributed to study design, statistical analysis, and manuscript revision

AMD contributed to study design, statistical analysis, and manuscript revision

Data Availability Statement: Data used to support the findings of this study are available from the corresponding author upon request.

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No competing interests reported.

Download PDF

Journal Publication

published 01 Jan, 2024

Read the published version in Journal of Plastic, Reconstructive & Aesthetic Surgery →

Version 1

posted

You are reading this latest preprint version

Peripheral and Trigeminal Nerve Stimulation Improve Functional Outcomes of Nerve Recovery in a Rodent Forelimb Gap Repair Model

Status:

Journal Publication

Version 1

Abstract

Figures

Introduction

Methods

Subjects

Behavioral Apparatus

Pre-Injury Training

Functional Sensory Assessment

Randomization

Injury Surgery

Trigeminal Cuff Implant Surgery

Functional Rehabilitation

Terminal Surgeries

Statistical Analysis

Results

Equivalence of Pre-injury Baseline Functionality and Injury Severity Between Groups

Functional Motor Recovery

Functional Sensory Recovery

Discussion

Conclusions

Declarations

References

Additional Declarations

Status:

Journal Publication

Version 1