Jordan Squair
Doctor of Medicine and Doctor of Philosophy (MDPhD)
Research Topic
Autonomic dysfunction following spinal cord injury: mechanisms, novel treatments, and clinical reality
Andrei Krassioukov
Professor
Relevant Thesis-Based Degree Programs
Affiliations to Research Centres, Institutes & Clusters
Open Research Positions
This list of possible research projects is non-exhaustive. It only shows positions that are specifically advertised in the G+PS website.
Great Supervisor Week Mentions
Each year graduate students are encouraged to give kudos to their supervisors through social media and our website as part of #GreatSupervisorWeek. Below are students who mentioned this supervisor since the initiative was started in 2017.
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.
Graduate Student Supervision
Doctoral Student Supervision
Dissertations completed in 2010 or later are listed below. Please note that there is a 6-12 month delay to add the latest dissertations.
A translational approach to understanding and treating autonomic dysfunction after spinal cord injury (2023)
No abstract available.
Cardiac consequences and effects of exercise interventions following spinal cord injury in humans (2021)
Individuals with chronic motor-complete spinal cord injury experience reduced cardiac function compared to non-injured individuals. Findings of cardiac deconditioning are not uncommon in this unique population and contribute to the increased risk of developing cardiovascular disease. In addition, disruption of descending autonomic pathways can cause abnormalities in cardiac function due to an intact parasympathetic (vagal) control and decreased sympathetic activity. The lack of research assessing cardiac outcomes during the first year following spinal cord injury limits the knowledge of time course changes and effective clinical therapies. Further investigation using different modalities of exercise as a therapeutic strategy are warranted, as the benefits of aerobic exercise to mitigate health complications associated with spinal cord injury have been well documented. In this thesis, I initially used a cross-sectional design assessing echocardiographic measures for left ventricular structure, systolic function, diastolic function, and mechanics, in individuals with sub-acute (i.e., three months) and chronic (i.e., > one year) cervical spinal cord injury to a non-injured control group. The results showed no differences between the non-injured group and the sub-acute group, though there was a decline in left ventricular indices for the chronic group. Upon further investigation of cardiac consequences, Holter monitoring showed the occurrences of arrhythmias up to six months post-injury in individuals with cervical and thoracic spinal cord injury. Next, echocardiography was used in a longitudinal design to track the changes in left ventricular structure, function, and mechanics within a six-month period for individuals with cervical and thoracolumbar injuries. The results show changes in left ventricular volumes and function occur only months after cervical injury. Finally, to explore cardiac rehabilitation through exercise strategies for this population, echocardiography was used to show that arm cycle ergometry may be more beneficial than body weight supported treadmill training for individuals with cervical or high-thoracic spinal cord injury to improve cardiac mechanics. Overall, the work presented in this thesis explored clinically relevant data that 1) increases our understanding of cardiac function in the months following a spinal cord injury and 2) investigates the efficacy of therapeutic exercise interventions to mitigate the long-term cardiac consequences of spinal cord injury.
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The impact of exercise on cardiorespiratory fitness and cardiovascular health in individuals with cervical and upper-thoracic spinal cord injury (2021)
Spinal cord injury (SCI) leads to motor, sensory, and autonomic dysfunctions. Cardiovascular disease (CVD) is the leading cause of mortality and morbidity following SCI, higher level of injury and more severe SCI increases this risk. Individuals with SCI experience multiple CVD risk factors including reduced cardiorespiratory fitness (CRF), physical inactivity, and cardiometabolic syndrome. In uninjured individuals, evidence supports the positive effects of exercise on these CVD risk factors. This thesis examined the effect of exercise modalities on CVD risk factors after SCI. Adult participants with motor complete SCI between the fourth cervical and sixth thoracic spinal segments were assigned to 24 weeks of active arm exercise or passive leg exercise training three times per week. Outcome measures were collected before and after training completion; with arterial stiffness measured following 12 weeks of training. Research results are presented in four studies. First, a scoping review of the SCI literature investigated and critiqued common peak oxygen uptake (V̇O2peak) averaging strategies and V̇O2peak attainment criteria. The time-interval method was the most common averaging strategy, and 52% of studies reported 30-second averaging. Second, I examined the association between V̇O2peak and echocardiographic measures and found no association between these measures. Third, in a multicenter randomised clinical trial, I examined the effect of the above-mentioned exercise modalities on arterial stiffness, CRF, and cardiometabolic measures. Arm exercise improved CRF; whereas neither exercise modality affected arterial stiffness or cardiometabolic measures. Fourth, a crossover design examined the effect of the same exercise modalities on multiple cardiovascular measures following at least a 6-month washout period. Arm exercise improved CRF, increased left ventricular (LV) mass, and improved free fat mass.Overall, results from the scoping review highlighted the importance of standardized exercise testing methodology to ensure comparability between studies. The findings emphasized on the importance of performing structured exercise to improve CRF. Apart from the underpowered trials secondary to small sample sizes, arterial stiffness, cardiometabolic measures, LV functions may have limited responses to exercise in the SCI population. This may suggest that the exercise training employed in this thesis was insufficient to provide enough stimulus to induce changes in these measures.
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Integrity of spinal autonomic pathways in sub-acute and chronic spinal cord injuries (2013)
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.
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Peripheral Platicity After Spinal Cord Injury and Ramifications of Cardiovascular Function (2012)
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.
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Master's Student Supervision
Theses completed in 2010 or later are listed below. Please note that there is a 6-12 month delay to add the latest theses.
Vascular-cognitive impairment after chronic high-thoracic spinal cord injury (2020)
Individuals living with chronic spinal cord injury (SCI) often exhibit impairments in cognitive function, which impedes their rehabilitation and possible transition into community. While a number of clinical studies have demonstrated the impact of impaired cardiovascular control on cognitive impairment, the mechanistic understanding of this deleterious relationship is still lacking. The present study investigates whether chronic disruption of cardiovascular control following experimental SCI results in cerebrovascular decline and vascular cognitive impairment. Fourteen weeks following a high thoracic SCI (at 3rd thoracic segment), rats were subjected to a battery of in vivo and in vitro physiological assessments, cognitive-behavioral tests, and immunohistochemical approaches to investigate changes in cerebrovascular structure and function in middle cerebral artery (MCA). We show that in MCA of rats with SCI, there is 55% reduction in the maximal vasodilator response to carbachol, which is associated with reduced expression of endothelial marker cluster of differentiation 31 (CD31) and transient receptor potential cation channel 4 (TRPV4) channels. Compared to controls, MCAs in rats with SCI were found to have 50% more collagen I in the media of vascular wall and 37% less distensibility at physiological intralumenal pressure. Furthermore in SCI group, the cerebral blood flow (CBF) in the hippocampus was reduced by 32% in association with impairment in short-term memory based on a novel object recognition test. There were no changes in the sympathetic innervation of the vasculature and passive structure in the SCI group. Chronic experimental SCI is associated with structural alteration and endothelial dysfunction in cerebral arteries that likely contributes to significantly reduced CBF and vascular cognitive impairment.
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Motherhood after spinal cord injury: lactation, breastfeeding, autonomic dysreflexia and postpartum considerations (2018)
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.
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Above and below: Changes in conduit artery after spinal cord injury, autonomic dysreflexia, and passive exercise (2016)
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.
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Examination of Preserved Motor Pathways in Persons with Motor-Complete Spinal Cord Injury (2014)
Previous work has demonstrated that mobility is consistently one of the most, if not the most important function persons with a spinal cord injury (SCI) desire following their injury. By increasing functional mobility, even slightly, there may be improved independence, leading to improved quality of life. While the current clinical examination for determining the level and severity of an SCI has proven to be very reliable and useful for standardizing SCI classification, it still has significant limitations that may limit a patient’s future mobility. For example, the measures used to assess motor function in the limb following a SCI may not be sensitive enough to detect minimal levels of preserved motor function, as they are limited to manual palpation and/or visual inspection. Furthermore, the extent of preservation of trunk musculature and the vestibulospinal pathway following an SCI remains unclear. Therefore, there is a need for more sensitive measures of remaining motor activity and a need to examine the integrity of individual motor pathways. Using transcranial magnetic stimulation (TMS) and vestibular evoked myogenic potentials (VEMPs), this thesis examined the integrity of the cortico- and vestibulospinal pathways in 16 persons with a motor-complete SCI and 16 able-bodied (AB) matched controls. Despite being clinically classified as motor-complete, persons with an SCI showed some observable muscle activity to cortico- and vestibulospinal stimulation, as well as in response to voluntary contractions. In general, the corticospinal responses in the SCI group were delayed compared to their AB matched controls. The muscle activity detected using TMS related to voluntary activation; however, TMS appears to detect preserved muscle activity below that which can be voluntarily activated. Overall, the results from this thesis provide evidence for the use of TMS and VEMPs to assist in determining the neurophysiological integrity of various motor pathways in persons with a motor-complete SCI. Using these techniques may provide clinicians with more accurate information about the state of various motor pathways and may offer a method to more accurately target rehabilitation.
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OnabotulinumtoxinA Treatment for Neurogenic Detrusor Overactivity and the Prevention of Autonomic Dysreflexia Following Spinal Cord Injury (2014)
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 =
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Vascular changes in spinal cord injured animals with repetitive episodes of autonomic dysreflexia (2012)
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.
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