Dorsal Column Research Articles

A novel therapeutic approach of ultrasound stimulation to restore forelimb functions following cervical cord injury in rats

Low-intensity pulsed ultrasound (LIPUS) stimulation has shown promising results in neurorehabilitation following a traumatic injury in brain and peripheral nerves. However, the effects of LIPUS stimulation in the injured neural circuit after spinal cord injury (SCI) are still unknown. We investigated the effects of LIPUS on forelimb functions in chronic cervical cord injured rats with and without a serotonergic agonist drug, Buspirone treatment. Twenty-six rats were trained for forelimb reaching and grasping followed by C4 dorsal funiculi crush injury. To deliver LIPUS, a silicon-coated ultrasound disc was implanted above the cervical cord and electromyography electrodes were implanted into forelimb muscles. In two cohorts (LIPUS and LIPUS + Buspirone combined) rats were tested pre-, with- and post-ultrasound stimulation. In LIPUS group rats, fore-limb reaching and grasping success rates first increased and then dropped after 3 weeks while for combination of drug and LIPUS stimulation the score continued to increase. Furthermore, LIPUS stimulation alone did not result in any significant improvement of grip strength compared to the control and combined groups. The findings of this study indicated the potential of LIPUS in SCI recovery and offer a future research direction of a new neuromodulation method.

Axon Fasciculation, Mediated by Transmembrane Semaphorins, Is Critical for the Establishment of Segmental Specificity of Corticospinal Circuits.

Axon fasciculation is thought to be a critical step in neural circuit formation and function. Recent studies have revealed various molecular mechanisms that underlie axon fasciculation; however, the impacts of axon fasciculation, and its corollary, defasciculation, on neural circuit wiring remain unclear. Corticospinal (CS) neurons in the sensorimotor cortex project axons to the spinal cord to control skilled movements. In rodents, the axons remain tightly fasciculated in the brain and traverse the dorsal funiculus of the spinal cord. Here we show that plexinA1 (PlexA1) and plexinA3 (PlexA3) receptors are expressed by CS neurons, whereas their ligands, semaphorin-5A (Sema5A) and semaphorin-5B (Sema5B) are expressed in the medulla at the decussation site of CS axons to inhibit premature defasciculation of these axons. In the absence of Sema5A/5B-PlexA1/A3 signaling, some CS axons are prematurely defasciculated in the medulla of the brainstem, and those defasciculated CS axons aberrantly transverse in the spinal gray matter instead of the spinal dorsal funiculus. In the absence of Sema5A/Sema5B-PlexA1/A3 signaling, CS axons, which would normally innervate the lumbar spinal cord, are unbundled in the spinal gray matter, and prematurely innervate the cervical gray matter with reduced innervation of the lumbar gray matter. In both Sema5A/5B and PlexA1/A3 mutant mice (both sexes), stimulation of the hindlimb motor cortex aberrantly evokes robust forelimb muscle activation. Finally, Sema5A/5B and PlexA1/A3 mutant mice show deficits in skilled movements. These results suggest that proper fasciculation of CS axons is required for appropriate neural circuit wiring and ultimately affect the ability to perform skilled movements.Significance Statement:Axon fasciculation is believed to be essential for neural circuit formation and function. However, whether and how defects in axon fasciculation affect the formation and function of neural circuits remain unclear. Here we examine whether the transmembrane proteins semaphorin-5A (Sema5A) and semaphorin-5B (Sema5B), and their receptors, plexinA1 (PlexA1) and plexinA3 (PlexA3) play roles in the development of corticospinal circuits. We find that Sema5A/Sema5B and PlexA1/A3 are required for proper axon fasciculation of corticospinal neurons. Furthermore, Sema5A/5B and PlexA1/A3 mutant mice show marked deficits in skilled motor behaviors. Therefore, these results strongly suggest that proper corticospinal axon fasciculation is required for the appropriate formation and functioning of corticospinal circuits in mice.

Deletion of Transferrin Receptor 1 in Parvalbumin Interneurons Induces a Hereditary Spastic Paraplegia-Like Phenotype.

Hereditary spastic paraplegia (HSP) is a severe neurodegenerative movement disorder, the underlying pathophysiology of which remains poorly understood. Mounting evidence has suggested that iron homeostasis dysregulation can lead to motor function impairment. However, whether deficits in iron homeostasis are involved in the pathophysiology of HSP remains unknown. To address this knowledge gap, we focused on parvalbumin-positive (PV+) interneurons, a large category of inhibitory neurons in the central nervous system, which play a critical role in motor regulation. The PV+ interneuron-specific deletion of the gene encoding transferrin receptor 1 (TFR1), a key component of the neuronal iron uptake machinery, induced severe progressive motor deficits in both male and female mice. In addition, we observed skeletal muscle atrophy, axon degeneration in the spinal cord dorsal column, and alterations in the expression of HSP-related proteins in male mice with Tfr1 deletion in the PV+ interneurons. These phenotypes were highly consistent with the core clinical features of HSP cases. Furthermore, the effects on motor function induced by Tfr1 ablation in PV+ interneurons were mostly concentrated in the dorsal spinal cord; however, iron repletion partly rescued the motor defects and axon loss seen in both sexes of conditional Tfr1 mutant mice. Our study describes a new mouse model for mechanistic and therapeutic studies relating to HSP and provides novel insights into iron metabolism in spinal cord PV+ interneurons and its role in the regulation of motor functions.SIGNIFICANCE STATEMENT Iron is crucial for neuronal functioning. Mounting evidence suggests that iron homeostasis dysregulation can induce motor function deficits. Transferrin receptor 1 (TFR1) is thought to be the key component in neuronal iron uptake. We found that deletion of Tfr1 in parvalbumin-positive (PV+) interneurons in mice induced severe progressive motor deficits, skeletal muscle atrophy, axon degeneration in the spinal cord dorsal column, and alterations in the expression of hereditary spastic paraplegia (HSP)-related proteins. These phenotypes were highly consistent with the core clinical features of HSP cases and partly rescued by iron repletion. This study describes a new mouse model for the study of HSP and provides novel insights into iron metabolism in spinal cord PV+ interneurons.

A Prospective Evaluation of Percutaneous Vertebroplasty in Osteoporotic Vertebral Compression Fracture Patients.

Background Osteoporotic vertebral compression fracture (OVCF) is a common problem in old age, which causes incapacitating pain and leads to significant disability, morbidity, and mortality. Percutaneous vertebroplasty (PVP), a minimally invasive procedure, results in immediate pain relief with decreased morbidity. The primary aim of this study was to evaluate the quality of life (QOL), as denoted by the Roland-Morris Disability Questionnaire (RMDQ) score. In contrast, the secondary aims were determining pain relief using the 11-point Numeric Pain Rating Scale (NPRS) and vertebral height restoration and wedge angle measurements after PVP. Methodology This prospective, longitudinal, interventional study on the efficacy of PVP was conducted among patients with low back pain due to osteoporotic vertebral collapse in a tertiary care institute. Patients with OVCF were managed by PVP and followed at one week, one month, three months, and six months for improvement in QOL by the RMDQ score and pain relief using the NPRS. The pre and post-vertebroplasty wedge angle and vertebral height (anterior, middle, and posterior columns) at one week and six months were also compared by pre and post-vertebroplasty lateral view skiagrams. Results A total of 24 patients were included in this study based on the inclusion and exclusion criteria. The demographic data were comparable. The RMDQ score showed a statistically significant difference in post-PVP at one week (p = 0.044), one month (p = 0.031), three months (p = 0.022), and six months (p = 0.018). There was a statistically significant difference in the NPRS at six months compared to the pre-PVP status, showing drastic pain relief in patients after PVP. The mean wedge angle (20.5 ± 2.07) measurement was reduced with a statistically significant increase in anterior body height restoration from pre-PVP to six months. There was no significant change in height at the middle and posterior columns compared to the pre-PVP height. Conclusions PVP is an effective, safe, minimally invasive pain and spine intervention for OVCFs with improved QOL and restoration of vertebral height.

Use of the iliac-outlet and iliac-inlet combined views in percutaneous posterior column retrograde screw fixation

Posterior column fractures are common acetabular injuries. Although displaced fractures require open reduction and fixation, undisplaced patterns may benefit from percutaneous screw fixation. The combination of iliac oblique with inlet and outlet views offers an intuitive and panoramic rendering of the bony corridor into the posterior column; lateral cross table view completes the sequence of fluoroscopic projections. Herein we describe the use of outlet/inlet iliac views and a detailed procedure for percutaneous retrograde posterior column screw fixation.

Simulated full weight bearing following posterior column acetabular fracture fixation: a biomechanical comparability study

PurposeThe incidence of acetabular fractures (AFs) is increasing in all industrial nations, with posterior column fractures (PCFs) accounting for 18.5–22% of these cases. Treating displaced AFs in elderly patients is a known challenge. The optimal surgical strategy implementing open reduction and internal fixation (ORIF), total hip arthroplasty (THA), or percutaneous screw fixation (SF), remains debated. Additionally, with either of these treatment methods, the post-surgical weight bearing protocols are also ambiguous. The aim of this biomechanical study was to evaluate construct stiffness and failure load following a PCF fixation with either standard plate osteosynthesis, SF, or using a screwable cup for THA under full weight bearing conditions.MethodsTwelve composite osteoporotic pelvises were used. A PCF according to the Letournel Classification was created in 24 hemi-pelvis constructs stratified into three groups (n = 8) as follows: (i) posterior column fracture with plate fixation (PCPF); (ii) posterior column fracture with SF (PCSF); (iii) posterior column fracture with screwable cup fixation (PCSC). All specimens were biomechanically tested under progressively increasing cyclic loading until failure, with monitoring of the interfragmentary movements via motion tracking.ResultsInitial construct stiffness (N/mm) was 154.8 ± 68.3 for PCPF, 107.3 ± 41.0 for PCSF, and 133.3 ± 27.5 for PCSC, with no significant differences among the groups, p = 0.173. Cycles to failure and failure load were 7822 ± 2281 and 982.2 ± 428.1 N for PCPF, 3662 ± 1664 and 566.2 ± 366.4 N for PCSF, and 5989 ± 3440 and 798.9 ± 544.0 N for PCSC, being significantly higher for PCPF versus PCSF, p = 0.012.ConclusionStandard ORIF of PCF with either plate osteosynthesis or using a screwable cup for THA demonstrated encouraging results for application of a post-surgical treatment concept with a full weight bearing approach. Further biomechanical cadaveric studies with larger sample size should be initiated for a better understanding of AF treatment with full weight bearing and its potential as a concept for PCF fixation.

Evaluation of the effect of pelvis type in percutaneous acetabular column fixation: a computed tomography study.

This study aimed to evaluate the effect of pelvis type in percutaneous acetabular column fixation. What is the effect of pelvis type in percutaneous acetabular colon fixation? The available pelvic computed tomography (CT) scans which were obtained in the diagnostic imaging center with a 1 mm slice width were evaluated. The pelvic type was classified with the help of MPR (Multiplanar Reformat) and 3D (Three Dimensional) imaging modes. All evaluated bony pelvic structures were anatomically intact. 40 types of android, gynecoid, anthropoid, and platypelloid pelvis were determined. CT sections were created in MPR imaging mode. Anterior obturator oblique (AOO) and inlet images were created for anterior column evaluation, while iliac oblique (IO) and outlet images were created for posterior column evaluation. The possibility of obtaining a linear corridor for acetabular columns was investigated by measuring corridor width and lengthon images of pelvic CTs. A linear corridor could not be obtained between the pubic tubercle and the supraacetabular region of 12 (30%) CTs in the anterior column of gynecoid pelvis group. The diameter of the anterior column corridor was below 5.5 mm in 10 (25%) of Gynecoid pelvis group, 5 (12.5%) of Anthropoid pelvis group, and 10 of Platypelloid pelvis group, , and all those scans belonged to the female gender. There was a statistically significant difference between pelvis types in terms of anterior and posterior column diameters (p <0.001). While the android pelvis type had the highest diameter and corridor length in both anterior column and posterior column measurements, the gynecoid pelvic type had the lowest diameter and corridor length. In the evaluations made according to gender, both anterior and posterior column diameters were larger and longer in males than in females (p <0.001). Pelvis type is an important factor which can affect anterior and posterior column diameter and length of acetabulum. Pelvic typing before acetabular surgery can help the surgeon determining the most appropriate patient position, surgical approach, and implant selection. Level of Evidence: Level 2.

ID: 222778 Spinal ECAP Morphology: Decoding the Spinal Cord With an Indicator of Lead Position

The spinal evoked compound action potential (ECAP) is a biopotential originating from the synchronous activation of dorsal column fibers in response to spinal cord stimulation (SCS). However, the factors contributing to the unique morphology of the ECAP waveform in humans have not been well elucidated. We examine whether the ECAP morphology is related to the medial-to-lateral placement of the SCS lead. Morphometry of the spinal cord, as well as recent studies in sheep,2 indicates that the superficial dorsal columns in humans have largest fiber types located more laterally3. We hypothesize, that laterally placed contacts may be associated with shorter ECAP latency.

ID: 202712 Loss of Conduction Fidelity in Dorsal Column Axons During Spinal Cord Stimulation With Conventional Frequencies

Epidural spinal cord stimulation (SCS) is an effective therapy for chronic pain, but there remains an opportunity to increase efficacy and response rates. Conventional paresthesia-producing SCS delivers pulse repetition frequencies < 200 Hz. SCS produces analgesia by activating large dorsal column axons which innervate inhibitory interneurons in the dorsal horn (Gate control theory). This understanding and contemporary research presume that dorsal column (DC) axons propagate faithfully every time a stimulation pulse is delivered. However, recent computational studies suggested that there may be a loss of conduction fidelity, or faithful propagation of an action potential for each stimulation pulse, depending on the stimulation frequency. We measured the response of single dorsal column axons to epidural SCS in healthy urethane-anesthetized Sprague-Dawley rats.

ID: 204152 Single Versus Dual Lead Spinal Cord Stimulation Trials

Spinal cord stimulation (SCS) has been used to treat chronic low back pain (LBP) since it was first proposed by Shealy et al. (1). SCS required placing electrodes in the posterior epidural space near the dorsal columns with electrical stimulation delivered at low-frequency 30-60 Hz (LFSCS) with concordant paresthesia elicited in the areas of pain (2). 10 kHz high-frequency spinal cord stimulation (HF10) was introduced and required no paresthesia mapping and used standardized reproducible epidural lead placement. Several studies have shown the clinical superiority of HF10 over LFSCS, including the two SENZA-RCTs(4,5). Since no paresthesia mapping is needed, we wanted to see if single lead trial would be comparable to standard dual lead trial.

Role of Fibrinogen in Type-2 Diabetes Mellitus with Diabetic Neuropathy and its Preliminary Mechanism.

Diabetic peripheral neuropathy (DN) is the most common complication of type 2 diabetes mellitus (T2DM). This study aimed to explore the role of fibrinogen (FIB) in T2DM neuropathy and its preliminary mechanism. Ten male Sprague-Dawley rats were divided into a normal control group (NC group) and a T2DM neuropathy model group (DN group). The DN group was given a high-energy diet and streptozotocin, while the NC group was given a normal diet and a citric acid buffer. The expression levels of related proteins were analysed. Electrophysiology: Compared with the NC group, the conduction latency of the somatosensory-evoked potential and nerve conduction velocity was prolonged in the DN group, while the motor nerve action potential was decreased. As seen under a light microscope, the peripheral nerve fibres in the DN group were swollen, and the nerve fibres in the posterior funiculus of the spinal cord were loose or missing. Moreover, as seen under an electron microscope, the peripheral nerve demyelination of the DN group was severe, with microvascular blood coagulation, luminal stenosis, and collapse. Compared with the NC group, in the DN group, the expression of FIB was positively correlated with the expression of both ionised calcium-binding adaptor molecule-1 and glial fibrillary acidic protein. Compared with the NC group, in the DN group, the expression of platelet/endothelial cell adhesion molecule-1 and B-cell lymphoma 2 was negatively correlated. The increased concentration of FIB may be the cause of neuropathy, and its mechanism may be related to its promotion of inflammatory response, blood coagulation, and vascular stenosis.

ID: 199708 Significant Pain Relief Using an SCS System Delivering Novel Fast-Acting Sub-Perception Therapy

Sub-perception Spinal Cord Stimulation (SCS) is now a commonly used treatment approach in the treatment of chronic pain.1-3 Fast-Acting Sub-Perception Therapy (FAST) is a new SCS method that utilizes precise stimulation field location and optimal neural dosing. Computational modeling suggests that FAST-SCS activates dorsal column axons and inhibits dorsal horn projection neurons via the surround inhibition mechanism. Recently published reports suggested that FAST-SCS is capable of provide profound pain relief with rapid onset of analgesia within minutes.4 Here, we present a single-center experience with the use of FAST and other therapies in the treatment of chronic pain.

ID: 222711 Fast-Acting Sub-Perception SCS for Lower Back Pain in an Individual With Incomplete Spinal Cord Injury

Spinal cord stimulation (SCS) has been utilized for decades to manage different pain conditions, particularly, those with a neurogenic origin. However, its usefulness and mechanism of action in treating neurogenic pain in individuals with spinal cord injuries remain unclear. Neuropathic pain in SCI is difficult to treat with modalities like dorsal column stimulation due to loss of efficacy over time, incomplete coverage of painful areas, and undesirable paresthesias in unaffected areas.

ID: 208638 Evoked Compound Action Potentials and Closed-Loop Spinal Cord Stimulation in Neuropathic Rats: Feasibility Study

Evoked compound action potentials (ECAPs) identified during spinal cord stimulation (SCS) in humans have been observed to closely correlate with the activation of the stimulation-induced sensory perception perceived as paresthesia1. We recently demonstrated feasibility of recording ECAPs from the spinal cord in naïve rats using uniquely designed equipment2. Here, we extended our experiments to provide electrophysiological characteristics of the response of dorsal column axons to SCS based on ECAPs recording in rats with neuropathic pain. Moreover, we demonstrate the ability to deliver ECAP-controlled closed-loop SCS in neuropathic pain rats, which has been proven superior to open-loop stimulation in humans3,4.

ID: 213534 Early Outcomes With the Medtronic Closed-Loop Spinal Cord Stimulation Study

Spinal cord stimulation (SCS) is a therapy for the treatment of chronic pain that relies on the application of mild electrical stimulation delivered to the dorsal column fibers of the spinal cord via lead(s) implanted in the epidural space. Most of the current SCS systems do not adjust the stimulation to reflect changes in distance between the SCS lead and the cord during activities of daily living. Hence, the net energy delivered varies dynamically resulting in inconsistent therapy delivery i.e., open-loop (OL) SCS.1 Closed-Loop SCS (CL SCS), where the therapy is titrated by the physiologic response of the spinal cord to stimulation – known as evoked compound action potential (ECAPs),2 can be used to address this limitation of OL SCS systems. The objective of this study is to evaluate patient experience and therapy durability with CL SCS. Primary study objective is to demonstrate the reduction in overstimulation sensation with the CL feature in subjects implanted with the CL SCS system. Secondary objectives include characterizing therapy efficacy in reducing overall, back or leg pain as measured by the proportion of subjects with ≥50% reduction in pain score, at the time of the 3-month visit. Consistency of dosing and long-term durability of therapy will also be characterized.

ID: 210002 A Novel Spinal Cord Stimulation Waveform Targeting the Dorsal Horn: 12-Month Clinical Trial Results

Conventional spinal cord stimulation (SCS) targets the dorsal columns, an indirect target of nociceptive transmission, and utilizes large pulse amplitudes to activate more nerve fibres and produce paresthesia. This approach can provide reliable pain relief, however, there appears to be a limit to its effectiveness. An appealing, alternative target for the treatment of chronic neuropathic low back pain (CNLBP) are dorsal horn dendrites. There is evidence for their involvement in neuropathic pain and their neurophysiological response to stimulation has been documented. With this information, a novel dorsal horn activation strategy (“Subwave”) was devised consisting of a T9/10-disc bipole, 100Hz stimulation frequency, 1000μs pulse width, and amplitude set to 80% of the patient’s stimulation perception threshold or lower. The 6-month results of a clinical trial evaluating this strategy have been presented previously. The 12-month results will be presented here.

ID: 205748 A Case of Open Surgical Dorsal Root Ganglion Stimulator Implantation: A Novel Approach

Neuromodulation at the Dorsal Root Ganglion (DRG) has been used to treat chronic neuropathic pain conditions including CRPS of the lower extremity and pelvic pain syndromes1. It is particularly useful in cases where traditional dorsal column stimulation may not provide optimal efficacy and can provide a more targeted treatment2. DRG stimulators are typically inserted percutaneously under fluoroscopic guidance. In certain populations, however, this approach may prove to be challenging and open surgical approaches may be more feasible, while limiting the risk of long-term lead fracture or migration.

ID: 217375 Dorsal Root Ganglion Stimulation: An Off-Label Indication for Targeted Coverage of Chronic Pelvic Pain

Chronic pelvic pain (CPP) is a treatment-resistant, complex neuropathic pain state which encompasses a number of painful pelvic disorders affecting women in a range of reproductive ages including inguinal and pudendal neuralgia, coccydynia, and vulvodynia. A majority of the sensory neuroinnervation to the pelvis is derived from the sacral plexus, specifically the pudendal nerve. In contrast to traditional dorsal column stimulation, dorsal root ganglion (DRG) stimulation offers more targeted therapy to focal areas of pain.

The effect of dorsal column lesions in the primary somatosensory cortex and medulla of adult rats

Spinal cord injury is a devastating condition that haunts human lives. Typically, patients experience referred phantom sensations on the hand when they are touched on the face. In adult monkeys, massive deafferentations such as chronic dorsal column lesions at higher cervical levels result in the large-scale expansion of face inputs into the deafferented hand cortex of area 3b. However, adult rats with thoracic dorsal column lesions do not demonstrate such large-scale reorganization. The large-scale face expansion in area 3b of monkeys is driven by the reorganization of the cuneate nucleus in the medulla. The sprouting of afferents from the trigeminal nucleus to the adjacent deafferented cuneate nucleus is facilitated by close proximity and compactness of the medulla in primates. Previously, in adult rats with thoracic lesions, the cuneate nucleus was not deafferented and its functional organization was not explored. The extent of the deafferentation and the duration of the recovery period are two major factors that determine the extent of reorganization. Hence, higher cervical (C3-C4) dorsal column lesions were performed, which cause massive deafferentations, and physiological maps were obtained after prolonged recovery periods (3 weeks -18 months). In spite of the above, the expansion of the intact face inputs was not observed in the deafferented zones of the primary somatosensory cortex (SI) and medulla of adult rats. The deafferented forelimb and hindlimb representations in SI were unresponsive to cutaneous stimulation of any part of the body. The cuneate and gracile nuclei in rats with complete dorsal column lesions remained mostly inactive except for a few sites which responded to stimulation of the spared upper arm. Hence, dorsal column lesions have different effects on the adult primate and rodent somatosensory systems. Appreciating this inter-species difference can aid in identifying the underlying neural substrates and restrict maladaptive reorganizations to cure phantom sensations.

ID: 208864 EMG Component and Use in Prediction for Target Engagement During Spinal Cord Stimulation

Dorsal column responses (DCR) recorded from spinal cord stimulation (SCS) leads represent a promising method of improving effectiveness of SCS. DCR may include evoked compound action potentials (ECAP), late response component and others. Late response component in the DCR has been demonstrated in intraoperative neuromonitoring (IONM) to represent the nearby muscle activation. Quantitative analysis between the ECAP and EMG components in DCR could reveal important information about target engagement. In this study, we intend to quantify the DCR with intermuscular EMG recordings to understand how to properly use the EMG components to better inform spinal cord stimulation.