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Pathophysiology of Spinal Cord Injury (SCI)

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A special issue of Biology (ISSN 2079-7737). This special issue belongs to the section "Medical Biology".

Deadline for manuscript submissions: closed (31 January 2022) | Viewed by 54185

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Dr. Cédric Geoffroy

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Guest Editor

Department of Neuroscience & Experimental Therapeutics, College of Medicine, Texas A&M Health Science Center, Bryan, TX 77807, USA
Interests: axon growth; regeneration; spinal cord injury
Special Issues, Collections and Topics in MDPI journals

Dr. Warren Alilain

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Spinal Cord and Brain Injury Research Center, Department of Neuroscience, University of Kentucky, College of Medicine, Lexington, KY 40536, USA
Interests: spinal cord injury; neural control of breathing; plasticity; axonal regeneration and sprouting; personalized medicine

Special Issue Information

Dear Colleagues,

Spinal cord injury (SCI) leads to paralysis, sensory, and autonomic nervous system dysfunctions. However, the pathophysiology of SCI is complex, not limited to the nervous system. Indeed, several other organs and tissue are also affected by the injury, directly or not, acutely or chronically, which induces numerous health complications. While a lot of research has been performed to repair motor and sensory functions, SCI-induced health issues are less studied, although they represent a major concern among patients. There is a gap of knowledge in pre-clinical models studying these SCI-induced health complications that limits translational applications in humans.

In this Special Issue of Biology, we encourage the submission of manuscripts on any aspects of the pathophysiology of spinal cord injuries. This includes, but is not limited to, the impact of SCI on cardiovascular function, bladder and bowel function, risk of infections associated with SCI, liver pathology, metabolic syndrome, bones and muscles loss, and cognitive functions. We welcome original research articles, review articles, and short communications. This Special Issue will provide an overview of the pre-clinical models available to study the pathophysiology of SCI, and bring experts in the field to discuss what is needed to increase the research and translational potential of SCI-induced health complications.

Dr. Cédric G. Geoffroy
Dr. Warren Alilain
Guest Editors

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Keywords

spinal cord injury
cardiovascular function
bladder function
bowel function
infections
liver pathology
metabolic syndrome
bone loss
muscle loss
cognitive functions
sexual functions

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Published Papers (12 papers)

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Research

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28 pages, 8302 KiB

Open AccessArticle

The Inflammatory Response after Moderate Contusion Spinal Cord Injury: A Time Study

by Minna Christiansen Lund, Ditte Gry Ellman, Maiken Nissen, Pernille Sveistrup Nielsen, Pernille Vinther Nielsen, Carina Jørgensen, Ditte Caroline Andersen, Han Gao, Roberta Brambilla, Matilda Degn, Bettina Hjelm Clausen and Kate Lykke Lambertsen

Biology 2022, 11(6), 939; https://doi.org/10.3390/biology11060939 - 20 Jun 2022

Cited by 13 | Viewed by 3835

Abstract

Spinal cord injury (SCI) initiates detrimental cellular and molecular events that lead to acute and delayed neuroinflammation. Understanding the role of the inflammatory response in SCI requires insight into the temporal and cellular synthesis of inflammatory mediators. We subjected C57BL/6J mice to SCI and investigated inflammatory reactions. We examined activation, recruitment, and polarization of microglia and infiltrating immune cells, focusing specifically on tumor necrosis factor (TNF) and its receptors TNFR1 and TNFR2. In the acute phase, TNF expression increased in glial cells and neuron-like cells, followed by infiltrating immune cells. TNFR1 and TNFR2 levels increased in the delayed phase and were found preferentially on neurons and glial cells, respectively. The acute phase was dominated by the infiltration of granulocytes and macrophages. Microglial/macrophage expression of Arg1 increased from 1–7 days after SCI, followed by an increase in Itgam, Cx3cr1, and P2ry12, which remained elevated throughout the study. By 21 and 28 days after SCI, the lesion core was populated by galectin-3⁺, CD68⁺, and CD11b⁺ microglia/macrophages, surrounded by a glial scar consisting of GFAP⁺ astrocytes. Findings were verified in postmortem tissue from individuals with SCI. Our findings support the consensus that future neuroprotective immunotherapies should aim to selectively neutralize detrimental immune signaling while sustaining pro-regenerative processes. Full article

(This article belongs to the Special Issue Pathophysiology of Spinal Cord Injury (SCI))

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14 pages, 14366 KiB

Open AccessArticle

Diaphragmatic Activity and Respiratory Function Following C3 or C6 Unilateral Spinal Cord Contusion in Mice

by Afaf Bajjig, Pauline Michel-Flutot, Tiffany Migevent, Florence Cayetanot, Laurence Bodineau, Stéphane Vinit and Isabelle Vivodtzev

Biology 2022, 11(4), 558; https://doi.org/10.3390/biology11040558 - 6 Apr 2022

Cited by 2 | Viewed by 2500

Abstract

The majority of spinal cord injuries (SCIs) are cervical (cSCI), leading to a marked reduction in respiratory capacity. We aimed to investigate the effect of hemicontusion models of cSCI on both diaphragm activity and respiratory function to serve as preclinical models of cervical SCI. Since phrenic motoneuron pools are located at the C3–C5 spinal level, we investigated two models of preclinical cSCI mimicking human forms of injury, namely, one above (C3 hemicontusion—C3HC) and one below phrenic motoneuron pools (C6HC) in wild-type swiss OF-1 mice, and we compared their effects on respiratory function using whole-body plethysmography and on diaphragm activity using electromyography (EMG). At 7 days post-surgery, both C3HC and C6HC damaged spinal cord integrity above the lesion level, suggesting that C6HC potentially alters C5 motoneurons. Although both models led to decreased diaphragmatic EMG activity in the injured hemidiaphragm compared to the intact one (−46% and −26% in C3HC and C6HC, respectively, both p = 0.02), only C3HC led to a significant reduction in tidal volume and minute ventilation compared to sham surgery (−25% and −20% vs. baseline). Moreover, changes in EMG amplitude between respiratory bursts were observed post-C3HC, reflecting a change in phrenic motoneuronal excitability. Hence, C3HC and C6HC models induced alteration in respiratory function proportionally to injury level, and the C3HC model is a more appropriate model for interventional studies aiming to restore respiratory function in cSCI. Full article

(This article belongs to the Special Issue Pathophysiology of Spinal Cord Injury (SCI))

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24 pages, 6573 KiB

Open AccessArticle

Evaluation of the Cardiometabolic Disorders after Spinal Cord Injury in Mice

by Adel B. Ghnenis, Calvin Jones, Arthur Sefiani, Ashley J. Douthitt, Andrea J. Reyna, Joseph M. Rutkowski and Cédric G. Geoffroy

Biology 2022, 11(4), 495; https://doi.org/10.3390/biology11040495 - 24 Mar 2022

Cited by 2 | Viewed by 4116

Abstract

Changes in cardiometabolic functions contribute to increased morbidity and mortality after chronic spinal cord injury. Despite many advancements in discovering SCI-induced pathologies, the cardiometabolic risks and divergences in severity-related responses have yet to be elucidated. Here, we examined the effects of SCI severity on functional recovery and cardiometabolic functions following moderate (50 kdyn) and severe (75 kdyn) contusions in the thoracic-8 (T8) vertebrae in mice using imaging, morphometric, and molecular analyses. Both severities reduced hindlimbs motor functions, body weight (g), and total body fat (%) at all-time points up to 20 weeks post-injury (PI), while only severe SCI reduced the total body lean (%). Severe SCI increased liver echogenicity starting from 12 weeks PI, with an increase in liver fibrosis in both moderate and severe SCI. Severe SCI mice showed a significant reduction in left ventricular internal diameters and LV volume at 20 weeks PI, associated with increased LV ejection fraction as well as cardiac fibrosis. These cardiometabolic dysfunctions were accompanied by changes in the inflammation profile, varying with the severity of the injury, but not in the lipid profile nor cardiac or hepatic tyrosine hydroxylase innervation changes, suggesting that systemic inflammation may be involved in these SCI-induced health complications. Full article

(This article belongs to the Special Issue Pathophysiology of Spinal Cord Injury (SCI))

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18 pages, 3058 KiB

Open AccessArticle

Effects of Chronic High-Frequency rTMS Protocol on Respiratory Neuroplasticity Following C2 Spinal Cord Hemisection in Rats

by Pauline Michel-Flutot, Isley Jesus, Valentin Vanhee, Camille H. Bourcier, Laila Emam, Abderrahim Ouguerroudj, Kun-Ze Lee, Lyandysha V. Zholudeva, Michael A. Lane, Arnaud Mansart, Marcel Bonay and Stéphane Vinit

Biology 2022, 11(3), 473; https://doi.org/10.3390/biology11030473 - 19 Mar 2022

Cited by 11 | Viewed by 3407

Abstract

High spinal cord injuries (SCIs) lead to permanent diaphragmatic paralysis. The search for therapeutics to induce functional motor recovery is essential. One promising noninvasive therapeutic tool that could harness plasticity in a spared descending respiratory circuit is repetitive transcranial magnetic stimulation (rTMS). Here, we tested the effect of chronic high-frequency (10 Hz) rTMS above the cortical areas in C2 hemisected rats when applied for 7 days, 1 month, or 2 months. An increase in intact hemidiaphragm electromyogram (EMG) activity and excitability (diaphragm motor evoked potentials) was observed after 1 month of rTMS application. Interestingly, despite no real functional effects of rTMS treatment on the injured hemidiaphragm activity during eupnea, 2 months of rTMS treatment strengthened the existing crossed phrenic pathways, allowing the injured hemidiaphragm to increase its activity during the respiratory challenge (i.e., asphyxia). This effect could be explained by a strengthening of respiratory descending fibers in the ventrolateral funiculi (an increase in GAP-43 positive fibers), sustained by a reduction in inflammation in the C1–C3 spinal cord (reduction in CD68 and Iba1 labeling), and acceleration of intracellular plasticity processes in phrenic motoneurons after chronic rTMS treatment. These results suggest that chronic high-frequency rTMS can ameliorate respiratory dysfunction and elicit neuronal plasticity with a reduction in deleterious post-traumatic inflammatory processes in the cervical spinal cord post-SCI. Thus, this therapeutic tool could be adopted and/or combined with other therapeutic interventions in order to further enhance beneficial outcomes. Full article

(This article belongs to the Special Issue Pathophysiology of Spinal Cord Injury (SCI))

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19 pages, 2227 KiB

Open AccessArticle

Osteopenia in a Mouse Model of Spinal Cord Injury: Effects of Age, Sex and Motor Function

by Michelle A. Hook, Alyssa Falck, Ravali Dundumulla, Mabel Terminel, Rachel Cunningham, Arthur Sefiani, Kayla Callaway, Dana Gaddy and Cédric G. Geoffroy

Biology 2022, 11(2), 189; https://doi.org/10.3390/biology11020189 - 26 Jan 2022

Cited by 3 | Viewed by 4045

Abstract

After spinal cord injury (SCI), 80% of individuals are diagnosed with osteopenia or osteoporosis. The dramatic loss of bone after SCI increases the potential for fractures 100-fold, with post-fracture complications occurring in 54% of cases. With the age of new SCI injuries increasing, we hypothesized that a SCI-induced reduction in weight bearing could further exacerbate age-induced bone loss. To test this, young (2–3 months) and old (20–30 months) male and female mice were given a moderate spinal contusion injury (T9–T10), and recovery was assessed for 28 days (BMS, rearing counts, distance traveled). Tibial trabecular bone volume was measured after 28 days with ex vivo microCT. While BMS scores did not differ across groups, older subjects travelled less in the open field and there was a decrease in rearing with age and SCI. As expected, aging decreased trabecular bone volume and cortical thickness in both old male and female mice. SCI alone also reduced trabecular bone volume in young mice, but did not have an additional effect beyond the age-dependent decrease in trabecular and cortical bone volume seen in both sexes. Interestingly, both rearing and total activity correlated with decreased bone volume. These data underscore the importance of load and use on bone mass. While partial weight-bearing does not stabilize/reverse bone loss in humans, our data suggest that therapies that simulate complete loading may be effective after SCI. Full article

(This article belongs to the Special Issue Pathophysiology of Spinal Cord Injury (SCI))

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16 pages, 1767 KiB

Open AccessArticle

Development of a Spinal Cord Injury Model Permissive to Study the Cardiovascular Effects of Rehabilitation Approaches Designed to Induce Neuroplasticity

by Liisa Wainman, Erin L. Erskine, Mehdi Ahmadian, Thomas Matthew Hanna and Christopher R. West

Biology 2021, 10(10), 1006; https://doi.org/10.3390/biology10101006 - 7 Oct 2021

Cited by 1 | Viewed by 3668

Abstract

As primary medical care for spinal cord injury (SCI) has improved over the last decades there are more individuals living with neurologically incomplete (vs. complete) cervical injuries. For these individuals, a number of promising therapies are being actively researched in pre-clinical settings that seek to strengthen the remaining spinal pathways with a view to improve motor function. To date, few, if any, of these interventions have been tested for their effectiveness to improve autonomic and cardiovascular (CV) function. As a first step to testing such therapies, we aimed to develop a model that has sufficient sparing of descending sympathetic pathways for these interventions to target yet induces robust CV impairment. Twenty-six Wistar rats were assigned to SCI (n = 13) or naïve (n = 13) groups. Animals were injured at the T3 spinal segment with 300 kdyn of force. Fourteen days post-SCI, left ventricular (LV) and arterial catheterization was performed to assess in vivo cardiac and hemodynamic function. Spinal cord lesion characteristics along with sparing in catecholaminergic and serotonergic projections were determined via immunohistochemistry. SCI produced a decrease in mean arterial pressure of 17 ± 3 mmHg (p < 0.001) and left ventricular contractility (end-systolic elastance) of 0.7 ± 0.1 mmHg/µL (p < 0.001). Our novel SCI model produced significant decreases in cardiac and hemodynamic function while preserving 33 ± 9% of white matter at the injury epicenter, which we believe makes it a useful pre-clinical model of SCI to study rehabilitation approaches designed to induce neuroplasticity. Full article

(This article belongs to the Special Issue Pathophysiology of Spinal Cord Injury (SCI))

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22 pages, 4238 KiB

Open AccessArticle

What Makes a Successful Donor? Fecal Transplant from Anxious-Like Rats Does Not Prevent Spinal Cord Injury-Induced Dysbiosis

by Emma K. A. Schmidt, Pamela J. F. Raposo, Karen L. Madsen, Keith K. Fenrich, Gillian Kabarchuk and Karim Fouad

Biology 2021, 10(4), 254; https://doi.org/10.3390/biology10040254 - 24 Mar 2021

Cited by 9 | Viewed by 3149

Abstract

Spinal cord injury (SCI) causes gut dysbiosis and an increased prevalence of depression and anxiety. Previous research showed a link between these two consequences of SCI by using a fecal transplant from healthy rats which prevented both SCI-induced microbiota changes and the subsequent development of anxiety-like behaviour. However, whether the physical and mental state of the donor are important factors in the efficacy of FMT therapy after SCI remains unknown. In the present study, rats received a fecal transplant following SCI from uninjured donors with increased baseline levels of anxiety-like behaviour and reduced proportion of Lactobacillus in their stool. This fecal transplant increased intestinal permeability, induced anxiety-like behaviour, and resulted in minor but long-term alterations in the inflammatory state of the recipients compared to vehicle controls. There was no significant effect of the fecal transplant on motor recovery in rehabilitative training, suggesting that anxiety-like behaviour did not affect the motivation to participate in rehabilitative therapy. The results of this study emphasize the importance of considering both the microbiota composition and the mental state of the donor for fecal transplants following spinal cord injury. Full article

(This article belongs to the Special Issue Pathophysiology of Spinal Cord Injury (SCI))

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16 pages, 1383 KiB

Open AccessArticle

Delivery of the 5-HT_2A Receptor Agonist, DOI, Enhances Activity of the Sphincter Muscle during the Micturition Reflex in Rats after Spinal Cord Injury

by Jaclyn H. DeFinis, Jeremy Weinberger and Shaoping Hou

Biology 2021, 10(1), 68; https://doi.org/10.3390/biology10010068 - 19 Jan 2021

Cited by 3 | Viewed by 3113

Abstract

Traumatic spinal cord injury (SCI) interrupts spinobulbospinal micturition reflex pathways and results in urinary dysfunction. Over time, an involuntary bladder reflex is established due to the reorganization of spinal circuitry. Previous studies show that manipulation of serotonin 2A (5-HT_2A) receptors affects recovered bladder function, but it remains unclear if this receptor regulates the activity of the external urethral sphincter (EUS) following SCI. To elucidate how central and peripheral serotonergic machinery acts on the lower urinary tract (LUT) system, we employed bladder cystometry and EUS electromyography recordings combined with intravenous or intrathecal pharmacological interventions of 5-HT_2A receptors in female SCI rats. Three to four weeks after a T10 spinal transection, systemic and central blockage of 5-HT_2A receptors with MDL only slightly influenced the micturition reflex. However, delivery of the 5-HT_2A receptor agonist, DOI, increased EUS tonic activity and elicited bursting during voiding. Additionally, subcutaneous administration of DOI verified the enhancement of continence and voiding capability during spontaneous micturition in metabolic cage assays. Although spinal 5HT_2A receptors may not be actively involved in the recovered micturition reflex, stimulating this receptor subtype enhances EUS function and the synergistic activity between the detrusor and sphincter to improve the micturition reflex in rats with SCI. Full article

(This article belongs to the Special Issue Pathophysiology of Spinal Cord Injury (SCI))

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Review

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16 pages, 2488 KiB

Open AccessReview

Inflammation and Oxidative Stress as Common Mechanisms of Pulmonary, Autonomic and Musculoskeletal Dysfunction after Spinal Cord Injury

by Cristián Rosales-Antequera, Ginés Viscor and Oscar F. Araneda

Biology 2022, 11(4), 550; https://doi.org/10.3390/biology11040550 - 1 Apr 2022

Cited by 9 | Viewed by 3484

Abstract

One of the etiopathogenic factors frequently associated with generalized organ damage after spinal cord injury corresponds to the imbalance of the redox state and inflammation, particularly of the respiratory, autonomic and musculoskeletal systems. Our goal in this review was to gain a better understanding of this phenomenon by reviewing both animal and human studies. At the respiratory level, the presence of tissue damage is notable in situations that require increased ventilation due to lower thoracic distensibility and alveolar inflammation caused by higher levels of leptin as a result of increased fatty tissue. Increased airway reactivity, due to loss of sympathetic innervation, and levels of nitric oxide in exhaled air that are similar to those seen in asthmatic patients have also been reported. In addition, the loss of autonomic control efficiency leads to an uncontrolled release of catecholamines and glucocorticoids that induce immunosuppression, as well as a predisposition to autoimmune reactions. Simultaneously, blood pressure regulation is altered with vascular damage and atherogenesis associated with oxidative damage. At the muscular level, chronically elevated levels of prooxidants and lipoperoxidation associated with myofibrillar atrophy are described, with no reduction or reversibility of this process through antioxidant supplementation. Full article

(This article belongs to the Special Issue Pathophysiology of Spinal Cord Injury (SCI))

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37 pages, 1047 KiB

Open AccessReview

Role of Descending Serotonergic Fibers in the Development of Pathophysiology after Spinal Cord Injury (SCI): Contribution to Chronic Pain, Spasticity, and Autonomic Dysreflexia

by Gizelle N. K. Fauss, Kelsey E. Hudson and James W. Grau

Biology 2022, 11(2), 234; https://doi.org/10.3390/biology11020234 - 1 Feb 2022

Cited by 15 | Viewed by 8010

Abstract

As the nervous system develops, nerve fibers from the brain form descending tracts that regulate the execution of motor behavior within the spinal cord, incoming sensory signals, and capacity to change (plasticity). How these fibers affect function depends upon the transmitter released, the receptor system engaged, and the pattern of neural innervation. The current review focuses upon the neurotransmitter serotonin (5-HT) and its capacity to dampen (inhibit) neural excitation. A brief review of key anatomical details, receptor types, and pharmacology is provided. The paper then considers how damage to descending serotonergic fibers contributes to pathophysiology after spinal cord injury (SCI). The loss of serotonergic fibers removes an inhibitory brake that enables plasticity and neural excitation. In this state, noxious stimulation can induce a form of over-excitation that sensitizes pain (nociceptive) circuits, a modification that can contribute to the development of chronic pain. Over time, the loss of serotonergic fibers allows prolonged motor drive (spasticity) to develop and removes a regulatory brake on autonomic function, which enables bouts of unregulated sympathetic activity (autonomic dysreflexia). Recent research has shown that the loss of descending serotonergic activity is accompanied by a shift in how the neurotransmitter GABA affects neural activity, reducing its inhibitory effect. Treatments that target the loss of inhibition could have therapeutic benefit. Full article

(This article belongs to the Special Issue Pathophysiology of Spinal Cord Injury (SCI))

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17 pages, 1508 KiB

Open AccessEditor’s ChoiceReview

Plasticity in Cervical Motor Circuits following Spinal Cord Injury and Rehabilitation

by John R. Walker and Megan Ryan Detloff

Biology 2021, 10(10), 976; https://doi.org/10.3390/biology10100976 - 28 Sep 2021

Cited by 11 | Viewed by 5108

Abstract

Neuroplasticity is a robust mechanism by which the central nervous system attempts to adapt to a structural or chemical disruption of functional connections between neurons. Mechanical damage from spinal cord injury potentiates via neuroinflammation and can cause aberrant changes in neural circuitry known as maladaptive plasticity. Together, these alterations greatly diminish function and quality of life. This review discusses contemporary efforts to harness neuroplasticity through rehabilitation and neuromodulation to restore function with a focus on motor recovery following cervical spinal cord injury. Background information on the general mechanisms of plasticity and long-term potentiation of the nervous system, most well studied in the learning and memory fields, will be reviewed. Spontaneous plasticity of the nervous system, both maladaptive and during natural recovery following spinal cord injury is outlined to provide a baseline from which rehabilitation builds. Previous research has focused on the impact of descending motor commands in driving spinal plasticity. However, this review focuses on the influence of physical therapy and primary afferent input and interneuron modulation in driving plasticity within the spinal cord. Finally, future directions into previously untargeted primary afferent populations are presented. Full article

(This article belongs to the Special Issue Pathophysiology of Spinal Cord Injury (SCI))

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19 pages, 1495 KiB

Open AccessEditor’s ChoiceReview

Peripheral Immune Dysfunction: A Problem of Central Importance after Spinal Cord Injury

by Marisa A. Jeffries and Veronica J. Tom

Biology 2021, 10(9), 928; https://doi.org/10.3390/biology10090928 - 17 Sep 2021

Cited by 19 | Viewed by 6465

Abstract

Individuals with spinal cord injuries (SCI) exhibit increased susceptibility to infection, with pneumonia consistently ranking as a leading cause of death. Despite this statistic, chronic inflammation and concurrent immune suppression have only recently begun to be explored mechanistically. Investigators have now identified numerous changes that occur in the peripheral immune system post-SCI, including splenic atrophy, reduced circulating lymphocytes, and impaired lymphocyte function. These effects stem from maladaptive changes in the spinal cord after injury, including plasticity within the spinal sympathetic reflex circuit that results in exaggerated sympathetic output in response to peripheral stimulation below injury level. Such pathological activity is particularly evident after a severe high-level injury above thoracic spinal cord segment 6, greatly increasing the risk of the development of sympathetic hyperreflexia and subsequent disrupted regulation of lymphoid organs. Encouragingly, studies have presented evidence for promising therapies, such as modulation of neuroimmune activity, to improve regulation of peripheral immune function. In this review, we summarize recent publications examining (1) how various immune functions and populations are affected, (2) mechanisms behind SCI-induced immune dysfunction, and (3) potential interventions to improve SCI individuals’ immunological function to strengthen resistance to potentially deadly infections. Full article

(This article belongs to the Special Issue Pathophysiology of Spinal Cord Injury (SCI))

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