Doctor of Medicine and Doctor of Philosophy (MDPhD)
Autonomic dysfunction following spinal cord injury: mechanisms, novel treatments, and clinical reality
Very knowledgeable in his field of autonomic function and spinal cord injury. Busy in dedicating his time to research and clinical work. In between his time spent presenting at conferences and maintaining his various responsibilities, including as president of the American Spinal Injury Association, he makes time for his students, post-docs, and staff providing various levels of guidance in their pre-clinical and clinical work.
The outcome of spinal cord injury (SCI) is still commonly described in terms of motor andsensory function, despite increasing awareness that there is also damage to the autonomicnervous system (ANS). The purpose of this thesis was to examine the integrity of spinalautonomic pathways among individuals with sub-acute and chronic SCI. The selection ofappropriate tests to assess autonomic function is challenging since the ANS is complex.Examining reliability and comparability among measures provides a comprehensiveunderstanding of the validity of specific tools. This doctoral thesis is comprised of three separateinvestigations that focus on determining the integrity of spinal autonomic pathways followingSCI. In the first study (Chapter 2), the focus was on the reliability of heart rate variability (HRV),sympathetic skin responses (SSRs) and an orthostatic challenge (sit-up test). Measures of HRV,SSRs and blood pressure changes during the sit-up test were found to be reliable. Additionally,the sit-up test was compared with the gold standard orthostatic challenge (tilt-table test), whichrevealed that the sit-up test provokes an orthostatic response comparable to the tilt-table test. Inthe last two studies (Chapters 3 and 4) HRV and changes in blood pressure (BP) during anorthostatic challenge, SSRs and the Valsalva manoeuvre (VM) were used to examine spinalautonomic integrity. The novel focus on integrity of spinal autonomic pathways revealed that itis affected by lesion level, neurologic severity of injury, and time post-injury. As expected basedon extensive existing research on cardiovascular autonomic function following SCI, higherlesion levels produced greater cardiovascular impairments. That is, there is greater compromiseto spinal autonomic integrity in high-level compared to low-level SCI. However, the associationbetween neurologic and autonomic “completeness” of injury is unclear. Our findings suggest thattime post-injury may affect the latter. During the sub-acute stage, autonomic tests revealedcardiovascular changes in patients in a one-month follow-up after admission to a rehabilitationhospital. The exact time course of alterations to integrity is unknown. Not acknowledging changeto spinal autonomic integrity is inherently problematic since it is unclear what neurologicseverity of injury infers about autonomic dysfunction.
Cardiovascular problems create life-long challenges for people living with spinal cord injury (SCI). When SCI occurs above the sixth thoracic segment (T6), it isolates spinal circuitry governing the critical splanchnic vascular bed, and creates the conditions for autonomic dysreflexia (AD), episodic hypertension instigated by sensory stimulation below the level of SCI. Most experiments investigating mechanisms of AD describe plasticity in the injured spinal cord. In this dissertation, I examined injury-induced changes at two peripheral loci critical to AD, the dorsal root ganglion (DRG) and mesenteric arteries. I used adult Wistar rats and performed complete transection SCI at T3 or T10: while both injuries produce hind limb paralysis, only the former is accompanied by AD.In the DRG, I found that T3 SCI triggered somatic hypertrophy in a specific subset of nociceptors, those expressing the capsaicin receptor (TRPV1). SCI-induced hypertrophy occurred in DRGs caudal to SCI and was most pronounced in lumbosacral ganglia. Intriguingly, SCI-induced hypertrophy was much more pronounced after T3 than T10 SCI. Importantly, when I used capsaicin to selectively eliminate TRPV1-positive projections to the lumbosacral spinal cord, the severity of AD was dramatically reduced. Next I examined glial, immune and vascular constituents of the lumbar DRG following SCI. I found that T3, but not T10 SCI activated satellite cells and macrophages in the DRG, and provoked mast cell accumulation in the adjacent spinal nerve. SCI at both levels promoted angiogenesis in the DRG and ingrowth of sympathetic ganglionic axons.In the superior mesenteric artery (SMA), I used in vitro myography to examine the role of cyclooxygenase (COX) enzymes in phenylephrine (PE) hyper-responsiveness after T3 SCI. I found that PE hypersensitivity was reversed by specific inhibitors of COX-2 and that COX-2 was upregulated in the SMA after T3 SCI. In an additional set of experiments, I found that recurrent episodes of AD, induced intentionally during recovery from SCI, exacerbated PE hyper-responsiveness in the SMA. These findings identify SCI-induced changes in the periphery that may contribute to AD by augmenting sensory input to the spinal cord or sympathetically-mediated vasoconstriction. These SCI-provoked effects may represent new therapeutic targets to treat AD.
Lactation dysfunction following spinal cord injury has been previously documented. However, the extent of lactation dysfunction and influence of spinal cord injury on breastfeeding ability and behaviour is not well understood. The research aim was to identify major barriers to lactation and breastfeeding related to spinal cord injury, specifically comparing injuries above and below the T6 spinal cord segment. A retrospective survey design was used to evaluate breastfeeding barriers in an international cohort of women who gave birth following their spinal cord injury. In the pilot study, 52 women participated in two online questionnaires. The follow-up study evaluated 102 participants with one questionnaire. An expert panel of clinicians and mothers with spinal cord injury systematically developed and reviewed all questionnaires. Exclusive breastfeeding duration significantly differed between women with spinal cord injury above versus below T6. Women with cervical spinal cord injury were less likely to breastfeed for at least 6 months (as recommended by the World Health Organization). Breastfeeding difficulties rated most severe were insufficient milk production and impaired milk ejection. Breastfeeding barriers also included autonomic dysreflexia (particularly with cervical and upper thoracic injuries), impaired access to the infant and balancing breastfeeding with personal care and tasks of daily living. A considerable proportion of women did not receive education specific to breastfeeding with spinal cord injury. Postpartum depression and anxiety were self-reported by this population at a higher incidence than is reported in the general population. The prevalence of self-reported postpartum depression was greater than prevalence of clinical diagnosis, indicating a greater need for early screening and postpartum mental health support.This research provides novel insight into the breastfeeding barriers presented by spinal cord injury, which differ based on level of injury. Multidisciplinary care is recommended to address these barriers, which range from physiological (i.e. impaired milk production and autonomic dysreflexia) to psychological (i.e. postpartum depression) to fundamental functioning (i.e. functional independence and personal care) in order to improve the chance of successful breastfeeding. These findings provide the impetus for further research into motherhood after spinal cord injury to improve breastfeeding outcomes and quality of life for this population.
Spinal cord injury (SCI) is a devastating condition that not only results in motor and sensory loss, but also autonomic dysfunctions. Individuals with SCI experience a 3-4 fold increased risk of cardiovascular disease (CVD), the leading cause of mortality in this population. Endothelial dysfunction is among the earliest markers of CVD progression. This thesis aims to: 1) clarify previous reports showing a counterintuitive improvement in endothelial function after SCI, 2) examine the effect of autonomic dysreflexia (AD) on conduit vasculature, and 3) assess the efficacy of passive exercise (PE) to reverse vascular dysfunction. In uninjured controls (CON), T3-complete spinal cord transected Wistar rats (SCI), T3-transected with induced AD by colorectal distension (SCI+CRD), and T3-transected with PE (SCI+PE), we assessed endothelium-dependent vasodilation and specific mechanisms for relaxation in brachial (BA) and femoral artery (FA) using wire-myography. Sympathetic innervation, mechanotransducer expression [transient receptor potential channel V4 (TRPV4)], arterial morphology, and profibrotic markers were assessed using immunohistochemistry. Impaired reactivity to acetylcholine was seen in FA after SCI via decreased contribution of endothelium dependent hyperpolarizing factor (EDHF) mediated pathways, while BA showed preserved endothelial function. Moreover, FA in SCI exhibited inward remodelling, 37.7% less sympathetic nerve fiber density, and increased collagen I expression (53.0%). Chronic repetitive AD resulted in a shift in vasodilatory mechanisms away from nitric oxide and towards EDHF, hypersensitivity to phenylephrine, and reduced elastin expression (13.9%). Passive hind-limb exercise after SCI led to improved sensitivity of FA to acetylcholine, through an increase in TRPV4 and prostacyclin-mediated pathways for vasodilation. Outward remodelling, as well as decreased expression of transforming growth factor beta (47.7%) and collagen I (39.0%) was seen in FA after PE. We have shown, for the first time, the expected endothelial dysfunction in the inactive/supraspinally disrupted FA after SCI and that chronic repetitive AD resulted in exacerbation of vascular dysfunction caudal to injury. Furthermore, PE was effective in reversing endothelial dysfunction and provided atheroprotective benefit, indicating PE may be a viable therapeutic intervention for preventing CVD after SCI. The observed changes provide insight into the mechanisms of endothelial dysfunction and possible directions on improvement of vascular health after SCI.
Individuals with high-level (>T₆) spinal cord injury (SCI) are prone to the development of a dangerous episodic hypertensive condition called autonomic dysreflexia (AD). The urinary bladder is the number one trigger of AD and is attributed to a condition called neurogenic detrusor overactivity (NDO). Intravesical injections of OnabotulinumtoxinA (Botox) into the detrusor muscle of the bladder in a dose of 200 Units (U) provides effective treatment for NDO. Following Botox, a few studies observed a reduction in AD during urodynamic studies (UDS). In this dissertation, I quantitatively assessed the efficacy of 200 U of intravesical injected Botox into 20 sites of the detrusor muscle on reducing AD severity, frequency and impact on AD-related quality of life (QoL) and bladder-related QoL. A total of 14 individuals (11 male; 3 female), mean age 45 ± 11 years, injury duration of 21 ± 12 years with a traumatic, chronic (> 1 year) SCI at ≥T₆ level underwent arterial blood pressure (BP) and heart rate (HR) monitoring according to an AD cut-off criteria of an increase in systolic BP (SBP) by ≥20 mm Hg above baseline SBP during UDS and 24-hr ambulatory BP monitoring (ABPM). Visit #1 consisted of a UDS pre-screening assessment with BP and HR monitoring. Participants who met the AD cut-off criteria were enrolled and completed 24-hr ABPM, the AD questionnaire, and bladder questionnaire. During Visit #2 (one week later), participants received the Botox injections by the urologist. During Visit #3 (one month later), participants repeated all components of Visit #1. During post-Botox UDS #2, there was a significant reduction in AD severity as per average SBP change (∆) (P =
Spinal cord injury (SCI) is a devastating condition that not only leads to paralysis, but also causes dramatic changes in cardiovascular function. Individuals with cervical or high thoracic SCI commonly suffer from a life threatening condition known as autonomic dysreflexia (AD). AD is characterized by episodic hypertension─ an exaggerated sympathetic response triggered by irritating stimulus below the level of injury e.g. distended bladder. As a lifespan of SCI patients increases, cardiovascular-related illnesses become more prevalent. Recent studies suggest marked vascular dysfunction within the critical splanchnic vascular bed. Mesenteric arteries from rats with chronic high-thoracic SCI are hypersensitive to the α₁-adrenoceptor agonist PE. The hypersensitivity of splanchnic vascular bed in response to PE develops over time after SCI and may contribute to the development of AD. In this dissertation, I examined the morphological changes in peripheral vasculature following repetitive episodes of AD in animals with high SCI. I hypothesized that recurrent episodes of AD will trigger an inward eutrophic remodeling in peripheral resistance arteries of SCI rats. In this study, male Wistar rats with complete spinal cord transection at third (T3) thoracic segment were utilized. At 2 weeks after the injury, AD was induced in rats with T3 SCI using CRD. 4 weeks following injury superior mesenteric (SMA) arteries and primary branches (PMA) were collected from T3 SCI-only, T3+CRD and control uninjured rats. Morphological characteristics such as media thickness, lumen diameter, wall-to-lumen ratio and wall cross sectional area (CSA) of the arteries were evaluated. Results suggest that AD induced through CRD lead to structural remodeling of PMAs, but no changes were observed in SMAs of CRD group. Media thickness, wall-to-lumen ratio significantly increased in PMAs of CRD group; lumen diameter and CSA of PMAs in CRD did not change when compared to T3 SCI-only and uninjured groups. The data support eutrophic (no change in CSA) remodeling of PMAs in CRD group, but failed to show a reduction in lumen diameter (inward changes) of these arteries. The findings of the study highlight the underlying effect of AD on structural remodeling of vasculature following an injury.