Abstract
The expanding application of spinal stimulation therapies in spinal cord injury (SCI) rehabilitation necessitates a critical reexamination of cardiovascular (CV) responses to these interventions. A key question arises: How should blood pressure (BP) responses to stimulation be interpreted, and does the conventional definition of autonomic dysreflexia (AD) adequately capture these phenomena? Researchers remain divided—some classify BP elevations during stimulation as AD, while others attribute them to intentional neuromodulation targeting sympathetic preganglionic neurons. This review scrutinizes the various AD definitions in the literature, including the conventional threshold (systolic BP increase >20 mmHg), revealing substantial limitations in research contexts. While symptomatic AD occurs in only 4-7% of stimulation study participants, asymptomatic BP increases are considerably more frequent. This established threshold lacks robust physiological rationale and creates significant interpretive challenges, particularly when evaluating interventions designed to modulate BP responses. The current limitations of guideline-based definitions of AD challenge research interpretation and clinical translation. Although several publications describe AD as “unregulated” or “uncontrolled,” it has not yet been incorporated into formal guideline definitions. This review underscores the need for a collaborative effort to refine AD definitions in research, particularly in the context of spinal stimulation. Future consensus development should address whether uniform thresholds should apply across different contexts, how to integrate heart rate dynamics and absolute BP values alongside symptomatic status, and how to meaningfully distinguish therapeutic BP modulation from adverse autonomic responses. This is essential for standardizing research approaches, optimizing stimulation parameters, and ensuring efficacy and safety as spinal stimulation technologies advance clinically.
Background
Restoring autonomic functions is a paramount recovery goal for individuals with spinal cord injury (SCI). 1 Specifically, addressing cardiovascular (CV) dysfunction is critical due to its prevalence in individuals with high-level SCI (T6 and above). It not only impedes daily activities and diminishes quality of life but also poses significant immediate and long-term health risks, including an increased likelihood of stroke and cardiac diseases.2-4 Post-SCI CV impairment is typically characterized by low resting blood pressure (BP) and difficulty maintaining stable and appropriate BP levels. Common complications include orthostatic hypotension (OH), a condition where BP drops upon moving to an upright position, and autonomic dysreflexia (AD), an elevation of BP triggered by noxious or non-noxious stimuli below the level of injury. 5
In 1996, the Consensus Committee of the American Autonomic Society and the American Academy of Neurology defined OH as a decrease of at least 20 mmHg in systolic BP (SBP) or 10 mmHg in diastolic BP (DBP) when transitioning from a supine to a standing position. 6 The threshold of a 20 mmHg drop in SBP is derived from epidemiological studies, which have identified it as a significant risk factor for falls and syncope and associated it with an increased 5-year mortality rate in diabetic patients with hypertension. 7 In the SCI population, a modified definition is used, where the standing position is adjusted to an upright position. Symptoms of OH may include dizziness, blurred vision, weakness, fatigue, nausea, headache, palpitations, and syncope. 8 OH is common in the early phases following SCI, frequently impeding essential rehabilitation efforts. One study demonstrated that OH persisted for at least 1 month in 74% of cervical and 20% of upper thoracic motor complete SCI patients. 9 In the chronic phase, while symptoms typically diminish, OH still clinically occurs in 50% of individuals with a cervical SCI, 10 leading to adverse outcomes and negatively impacting QOL.2-4 Daily fluctuations in BP along with persistent hypotension are associated with reduced cerebral blood flow velocity and cognitive impairments.11,12
Clinically, AD is defined as an increase in SBP, often accompanied by either bradycardia or tachycardia along with other signs or symptoms of autonomic overactivity, in response to noxious or non-noxious stimuli below the level of injury. The increase in BP is due to vasoconstriction from this sympathetic activity below the level of injury. AD typically develops between 2 and 6 months post-injury, but can occur at any time thereafter or before. 13 One estimate suggested that up to 91% of individuals with complete tetraplegia experience AD, and another estimated that 48% of individuals with a complete injury at or above T6 are affected.5,14,15 This variability is likely due to differences in the severity of the autonomic impairment across individuals and the varying criteria for the magnitude of BP increase required to diagnose AD across different studies over the years.
Symptoms of AD can include sweating, piloerection (goosebumps), facial flushing, headaches, blurred vision, and nasal congestion, but it may also be asymptomatic. These episodes usually resolve once the underlying stimulus is removed. Severe AD, if left untreated, can cause a dramatic increase in SBP, with cases reported even above 300 mmHg. This poses serious risks such as cardiac arrhythmia, cardiac arrest, stroke, seizures, hypertensive encephalopathy, and even death.5,13,16,17 Symptoms of AD, as well as heart rate (HR) changes, are not typically a requirement in the definition of AD but have been used by several studies.13,18,19 Historically, bradycardia has been considered the classic HR pattern in AD. However, there are contradicting results, as some studies have shown that tachycardia is more prevalent.19-21
The current definition of AD centers on a seemingly straightforward criterion: an increase in SBP exceeding 20 mmHg stemming from a below-level stimulus. 22 However, this straightforward threshold presents significant challenges in research settings, particularly when studying interventions specifically designed to modulate BP responses. The research community has responded to these limitations by adopting various modified definitions, suggesting that the standard criterion may not fully capture the complexity of AD.16,23,24 A key concern is that while it serves as a useful clinical benchmark, this widely accepted definition appears to lack a solid physiological foundation or clear scientific rationale. This situation raises important questions about how we conceptualize and identify AD, especially in research contexts. This review will explore these concerns in detail, examining the implications of relying on such a simplified metric for a complex physiological phenomenon.
Despite various interventions, both pharmacological and non-pharmacological, CV dysfunction remains a persistent challenge without a definitive solution. 8 Epidural and transcutaneous spinal cord stimulation have emerged as promising interventions to address CV dysfunction post-SCI.25-27 Notably, stimulation has been shown to stabilize both the low and high BP episodes frequently experienced by individuals with SCI.28-33 The leading theory proposes that stimulation activates sensory afferent fibers, which, through interneurons, influence (via excitation or inhibition, respectively) sympathetic preganglionic neurons (SPNs) located in the T1-L2 region of the spinal cord, directly modulating BP. 27
Spinal cord stimulation has been shown to effectively address OH by increasing BP and alleviating orthostatic symptoms. This has been demonstrated in various epidural and transcutaneous stimulation studies, often including an orthostatic provocation such as a tilt test to induce OH.28-31 Furthermore, research suggests that repeated stimulation sessions (“training”) can result in an adaptive BP response; initially, participants experienced a significant symptomatic drop in BP during a tilt test, however, they no longer exhibited such drops after training and could better tolerate a tilt test, even without ongoing stimulation.34-37 On the other end of the spectrum, some reports have noted the ability of stimulation to mitigate or prevent AD episodes (in terms of both acute responses and longer-term modulation following repeated stimulation).32,33,38,39 These findings hint at the ability of stimulation to enhance autonomic regulation, whether in response to hypotension or hypertension, by augmenting physiological control mechanisms that may have been compromised due to injury.
This review critically examines the appropriateness of the >20 mmHg threshold and explores whether BP increases from spinal stimulation should be classified as AD. It is structured in 3 parts: Part 1 reviews AD occurrence across stimulation studies, highlighting a dichotomy of interpretations—CV-focused studies on orthostasis (Section 1A) view BP increases positively as improved regulation, while in contrast, motor-focused studies (Section 1B) classify them as adverse AD events. Part 2 examines the definition of AD, its complexities in the context of spinal stimulation, and whether updates are needed. Part 3 outlines future directions, offering a brief overview of clinical implications and mechanistic insights that underscore the complex interplay between spinal stimulation and blood pressure responses.
Part 1
Stimulation Studies Aimed at Improving CV Function During Orthostasis
Focusing on individuals with a high-level SCI (above T6), CV-focused stimulation studies usually involve an orthostatic provocation to evaluate the CV response to stimulation during a significant OH episode (see Table 1). Most studies incorporate epidural stimulation, with 1 study thus far employing transcutaneous stimulation. 28 Combined, there were 30 participants in the CV-focused stimulation studies, 25 of whom had demonstrated autonomic dysfunction manifested by low baseline BP and OH, and 5 who did not.30,40
Reports of BP Response and Occurrence of AD in CV-focused Spinal Cord Stimulation Studies (Aiming to Increase BP and Resolve Orthostasis) in Individuals With SCI. a
Abbreviations: scES, spinal cord epidural stimulation; scTS, spinal cord transcutaneous stimulation; CV, cardiovascular; BP, blood pressure; SBP, systolic blood pressure; DBP, diastolic blood pressure; HR, heart rate; AD, autonomic dysreflexia; SCI, spinal cord injury; NLI, Neurological level of injury; AIS, ASIA impairment scale; LE, lower extremity; EMG, electromyography; UTI, urinary tract infection; OH, orthostatic hypotension.
All studies used continuous beat-to-beat blood pressure monitoring.
Subgroups that did not demonstrate OH during the tilt and did not have a significant response to stimulation. Individuals that are likely without (or minimal) autonomic dysfunction.
Baseline SBP values in supine position prior to the orthostatic test (typically a tilt) ranged between 90 to 120 mmHg, dropping to 65 to 80 mmHg during the test (as expected), often accompanied by orthostatic symptoms.28-31,40-42 With the addition of stimulation (before or during the stress test), symptoms were alleviated and SBP was restored (and at times even further increased beyond baseline). The increase in SBP caused by stimulation, sometimes as high as 60 mmHg, was considered a positive outcome. Among all the studies, out of a total of 30 participants, only 2 individuals were reported to have experienced symptomatic AD events, both within the same study, accounting for 7% of the total. Notably, these participants likely had a relatively high SBP (>120 mmHg) in the supine position and during the tilt, as indicated by the data in Table 1. One of these events coincided with a urinary tract infection (UTI), which may have further increased susceptibility to AD. 41
In the studies included in this review, during tilt-test provocations (without stimulation), HR initially increased as expected based on physiological responses. 43 In comparison, in tilt-tests that included stimulation, HR typically remained elevated compared to the supine position,30,41,42 but to a lesser extent than during tilt without stimulation.
Although tilt-testing remains the standard method for demonstrating impaired sympathetic activation and its potential improvement through stimulation in individuals with SCI, numerous testing variables that can significantly impact hemodynamic outcomes often go underreported. For example, critical factors include the presence or absence of foot support, the occurrence of lower extremity spasticity, how securely straps are fastened below the injury level, the specific angle of tilt (typically 70°) and the protocol for reaching it, including whether intermediate angles were tested. Given these variables’ potential influence on results, researchers have proposed additional assessment methods that provide more controlled testing conditions, including the use of Valsalva maneuver and (above-level) hand cold pressor tests, as well as lower body negative pressure.44,45
Of note, several of these studies included an evaluation of lower extremity muscles to identify stimulation configurations that modulate BP without eliciting motor activity. This was either in the form of an EMG assessment, muscle observation or manual palpation. Results were variable, with some describing increased activity of lower extremity with increasing stimulation voltage 30 and others reporting no activity.28,31,41,42
Stimulation Studies Targeting Motor (or Respiratory) Functions, Reporting on BP Increases or AD
This section of the review analyzed 10 studies (Table 2) that documented CV changes during spinal stimulation interventions, despite their primary focus on other therapeutic outcomes. The interventions targeted diverse functional improvements, including upper and lower extremity performance,18,24,46-48 postural control for sitting and standing,47,49 and respiratory function.50-52 Various stimulation mechanisms were involved including scES, 50 percutaneous scES,18,52 scTS24,46,47,49,53 and posteroanterior scTS. 48 CV measurements were collected (sometimes anecdotally) across various functional contexts, from supine assessments to more complex activities such as respiratory testing, upper extremity exercises, and standing. This range of physical activities introduced additional variables that could independently influence CV responses in either direction, highlighting the complexity of interpreting BP and HR changes in these studies. Although there may be some differences, we included 2 studies involving children because SCI manifestations, including CV dysfunction, are generally similar.
Spinal Cord Stimulation Studies (for Motor Function) Reporting on BP or AD in Individuals With an SCI.
Abbreviations: scES, spinal cord epidural stimulation; scTS, spinal cord transcutaneous stimulation; BP, blood pressure; SBP, systolic blood pressure; DBP, diastolic blood pressure; HR, heart rate; AD, autonomic dysreflexia; SCI, spinal cord injury; NLI, Neurological level of injury; AIS, ASIA impairment scale; UE, upper extremity; LE, lower extremity; EMG, electromyography; UTI, urinary tract infection; N/A, not available; MAP, mean arterial pressure.
The severity of autonomic dysfunction in participants (if present) is unknown, as this was not a primary outcome measure in the studies. The baseline SBP described in some of the studies was approximately 100 mmHg, and responses to stimulation varied widely, ranging from modest elevations to increases by up to 60 mmHg, reaching levels as high as 175 mmHg.46,49,52 HR response was reported in only a few studies and generally decreased with stimulation. However, there was significant variability, with fluctuations ranging from increases of 5 bpm to decreases by 40 bpm.
The definition of AD varied across these studies, with some using specific thresholds like the current standard SBP increases above 20 mmHg18,24,49 or absolute SBP exceeding 140 to 150 mmHg,24,50-52 while others rely on qualitative descriptions. Symptomatic AD occurred in 4% of participants (6/139).18,24,47,48 When including asymptomatic cases with significant BP increases (defined by the respective studies as adverse events or an increase in SBP > 60 mmHg above baseline or an absolute SBP 140 to 170 mmHg that led to session termination), the incidence rose to 18% (14/79).49-52 Given the disparate definitions, the true incidence is unknown. Additionally, some studies, particularly those with a higher number of sessions, reported AD incidence (using the 20 mmHg cutoff) per session rather than per participant. One study noted occurrences in 12% to 27% of trials, while another reported AD in approximately 11% of sessions.18,24
In contrast to CV-focused stimulation studies, many of these studies did not involve continuous BP monitoring, with BP in some cases measured only once during stimulation. As a result, certain episodes of elevated BP may have gone undetected.
A Comparison: The Frequency of Substantial BP Increases and AD Events in CV and Motor Stimulation Studies
Comparing BP responses between CV and motor-focused spinal stimulation studies presents several methodological challenges. First, the stimulation protocols differ significantly—CV-focused studies typically use lower amplitudes and stimulation is often applied in the lower thoracic or lumbosacral spinal segments, while motor activation requires higher intensities and sites vary from high cervical to sacral segments. Both amplitude and stimulation site, and possibly other stimulation parameters such as pulse-width and frequency (and potentially, their interplay), have a significant effect on the BP response. 46 Additionally, the nature of activities performed during stimulation, such as tilt testing versus seated upper extremity exercises, inherently produces different BP responses. Monitoring protocols also vary considerably between study types. CV-focused research employs continuous BP monitoring, while motor-focused studies often rely on periodic measurements or symptom-triggered monitoring, making it difficult to establish consistent comparisons of high BP events.
Another difference between CV and motor stimulation studies lies in the population. While both primarily included individuals with cervical injuries, and occasionally thoracic SCI, the CV-focused studies involved participants with motor-complete injuries (ASIA Impairment Scale [AIS] A-B). In contrast, motor-focused studies included a range of injury severities, from AIS A to D. While severity of injury does not always align with severity of autonomic dysfunction, there is a correlation.54,55
Both the initiation and withdrawal of stimulation—including factors like ramping speed and increment size—significantly impact BP responses, though these parameters are seldom discussed in published studies. All the aforementioned factors render comparing stimulation studies, and specifically the BP responses, exceptionally challenging. Efforts to establish standards for reporting stimulation studies in SCI are ongoing, with a recent standard having been recommended. 56
Analyzing the frequency of events classified as AD in these studies is also challenging due to inconsistent AD definitions across studies. Moreover, an SBP increase deemed AD in a motor-focused study might not be classified as such in a CV-focused study. Overall, symptomatic AD events were reported in approximately 4% to 7% of participants across all reviewed stimulation studies (CV and motor). However, the inclusion of asymptomatic BP elevations shifts this percentage significantly. In motor studies, at least 18% of participants experienced substantial asymptomatic BP increases, although this figure likely underestimates the true frequency due to intermittent BP monitoring. In contrast, CV stimulation studies showed substantial BP increases in nearly all participants with low BP or OH—an expected and desired outcome.
This interpretative difference becomes more complex when examining the absolute changes in SBP. A 50 to 60 mmHg increase (as seen in various stimulation studies) can result in markedly different final SBP values depending on the initial values. In CV studies, which often employ an orthostatic provocation, stimulation is typically applied when SBP is low, resulting in final SBP values within the normotensive range of 110 to 120 mmHg. In contrast, motor-focused stimulation studies may see BP escalating to problematic levels approaching or exceeding 160 mmHg, more likely to be associated with clinical symptoms, possibly due to a combined effect of stimulation and motor activity. This also highlights the importance of nuanced interpretation when evaluating BP responses across different research paradigms.
The inconsistencies in AD definitions and BP measurement practices underscore the need to reevaluate how AD is defined, particularly in the context of spinal stimulation research.
Part 2
Background on the Definition of AD and Current BP Thresholds of AD
AD was first described in 1860 in a patient with cervical SCI who presented with pallor, chills, and later flushing and heat, during defecation and micturition. 57 By 1890, clinical reports expanded the symptom profile to include facial sweating and transient rash following urinary catheterization. 58 In 1947, Sir Ludwig Guttmann established the link between these symptoms and cardiovascular changes, specifically elevated BP and decreased HR, in individuals with cervical and upper thoracic SCI. 59 Although the specific origin of the current diagnostic threshold (SBP increase >20 mmHg) is not definitively documented, Guttmann’s early work documented SBP rises of 20-40 mmHg in patients at or near T6, which later informed the widely accepted diagnostic criteria, also for individuals with higher spinal level injuries.
Building upon the initial ranges documented by Guttmann, the Consortium for Spinal Cord Medicine incorporated specific BP criteria in their 1997 and 2001 clinical practice guidelines (CPG) for Acute Management of AD. These guidelines identified that “a (systolic) blood pressure of 20 mm to 40 mmHg above baseline may be a sign of autonomic dysreflexia.”60,61 This definition was subsequently refined in the 2012 International Standards to document remaining Autonomic Function after Spinal Cord Injury (ISAFSCI), 62 which established the current threshold of >20 mmHg elevation for SBP. This criterion has been maintained in more recent guidelines, including the 2021 CPG. 22
While the >20 mmHg threshold for SBP increase was established to provide clinical clarity, it lacks robust evidence-based validation and remains largely arbitrary. The research community has employed various alternative definitions of AD, reflecting different clinical experiences and perspectives. These alternate criteria include an SBP increase of at least 30 or 40 mmHg,5,63 a 20% elevation from baseline,13,16 or the achievement of specific absolute SBP values (between 140-160 mmHg)—aligning with current clinical guidelines for initiating pharmacological intervention (150 mmHg).5,19,41,51,64 Additional proposed measures have included consideration of symptoms, DBP and HR in the definition of AD. 23 Further, the definition of AD has sometimes been limited to “uncontrolled” elevations in BP to differentiate it from well-controlled therapeutic interventions intended to increase BP.23,29,41,42 While this terminology has gained traction in recent years, with some groups in the field operationalizing AD as “unregulated” or “uncontrolled,”19,32,65-68 it has not yet been formally incorporated into existing clinical guidelines and may benefit from clearer definitional consensus. This conceptual distinction, reflected in recent work,19,32,65-68 highlights the need for continued discussion around what such a definition implies and how it might be operationalized in both research and clinical contexts.
Challenges in the Definition and Classification of Autonomic Dysreflexia
The current definition of AD as an increase in SBP of >
A relatively modest SBP increase of 20 mmHg is common throughout the day, even without identifiable stimuli or symptoms, in individuals with a high SCI. 21 An asymptomatic rise in SBP, even beyond the 20 mmHg threshold, in this population is often referred to as “silent AD.”21,64,69 For individuals with SCI and low baseline BP, such an increase may still result in normotensive values and might lack clinical significance. 23 This increase is generally well-tolerated, as symptoms typically correlate more closely with absolute SBP values rather than with specific increases from baseline. Conversely, the effects of small, repeated BP increases (even by 20 mmHg) on accelerated CV disease and immunosuppression remain an active area of research.70,71 Addressing these complexities necessitates a pathophysiological approach rather than relying exclusively on predefined thresholds. Due to the arbitrary nature of the cutoff, this definition risks misclassifying beneficial interventions such as stimulation designed to raise BP to treat OH as having negative outcomes.
Baseline measurement itself presents another challenge, particularly in the SCI population, where resting BP can vary dramatically between individuals and even within the same person across different days or moments. This variability makes it difficult to establish reliable baseline values. 23 The nuance in the measurement of baseline values also depends on clinical vs. research settings. 72
Early investigations into CV changes associated with AD primarily focused on BP elevation, but researchers consistently noted another significant physiological response: a concurrent HR decrease. 59 During an AD episode, bradycardia often emerges, reflecting the body’s compensatory regulatory mechanisms. 67 This characteristic HR change was delineated in the first CPG for AD, which explicitly included bradycardia as a diagnostic symptom. 60 Recognizing the diagnostic potential of this HR characteristic, some researchers have proposed incorporating an HR criterion into the AD definition.18,23,73
Contradicting findings exist, as several studies have reported that tachycardia is more prevalent during AD episodes,19-21 with some suggesting a physiological basis.16,72 Due to the observed variations in HR, 16 the most recent (2021) CPG acknowledges that both bradycardia and tachycardia may accompany BP elevation during AD. 22
Part 3
Future Directions: Refining Definitions, Clinical Implications, and Our Understanding of the Interplay Between Stimulation and AD
The nuanced and heterogeneous CV responses observed in SCI underscore the complexity of physiological mechanisms and demand a more sophisticated approach to understanding these dynamics, particularly in the context of interventional research. Researchers have increasingly advocated for a comprehensive revision of the AD definition,16,23 a perspective we support based on the evidence presented. Current diagnostic criteria may benefit from multiple refinements, and a classification framework for BP response in SCI research should consider not only the magnitude and rate of BP elevation but also baseline BP, symptom presence, HR dynamics, and the nature of the stimulus. For instance, establishing both an absolute SBP threshold (such as 140 or 150 mmHg) and a relative increase from baseline (potentially exceeding 20 mmHg) could provide more precise diagnostic parameters. Additionally, incorporating symptomatic criteria and HR measurements might enhance the definition’s diagnostic accuracy and clinical utility. However, these recommended modifications should be grounded in rigorous, mechanistic physiological studies that can systematically address the critical questions raised in this review, ultimately improving our understanding and clinical management of this complex condition.
The relationship between AD and spinal cord stimulation presents a complex physiological puzzle that warrants careful examination. While some researchers attribute BP increases during stimulation to an AD response, others suggest these changes reflect direct neuromodulation influencing SPNs’ regulation. Several key observations illuminate this relationship’s complexity. While each of the following observations could warrant its own detailed investigation, we present them here as part of a brief discussion.
First, while ongoing work continues to refine our understanding, several key mechanisms by which spinal stimulation modulates CV function have been described in detail. Preclinical and clinical evidence support activation of somatoautonomic reflexes, sensory afferent inputs that alter autonomic function, as well as facilitation of neuroplasticity within spinal autonomic pathways. While this is beyond the scope of the current manuscript, it is reviewed in detail by Samejima et al. 27 In preclinical models, Squair et al 29 identified several key components underlying pressor responses to epidural spinal stimulation: effective modulation requires targeting spinal segments rich in sympathetic preganglionic neurons projecting to splanchnic targets; stimulation engages sympathetic circuitry through afferent fibers in the posterior roots; and activation of splanchnic sympathetic ganglia leads to vasoconstriction and subsequent increases in blood pressure. Understanding the mechanisms and neuronal architecture underlying the response to spinal stimulation remains a priority, particularly given its partial overlap with pathways involved in AD, as highlighted in a recent work published by Soriano et al. 74 This overlap exists alongside distinct physiological and clinical differences that warrant further investigation.
Evidence from both animal and human models demonstrates that spinal stimulation can directly prevent and mitigate AD while stabilizing BP, indicating that stimulation cannot be reduced to merely an AD-triggering intervention.32,33 Further research is needed to confirm the inhibitory effect of stimulation on AD as recent studies included only a small number of participants.32,33 Additionally, the procedure used to elicit AD was digital anorectal stimulation (DARS), while typically major studies have used a urodynamic procedure to provoke AD.15,73
Furthermore, animal and human studies have demonstrated that repeated stimulation sessions provide lasting changes for both OH34,36,37 and AD,33,39,74 with changes persisting even in the absence of ongoing stimulation. These lasting effects suggest the mechanism involves more than temporary symptom relief, pointing to an underlying adaptation. Notably, these findings warrant closer examination, as the long-term cardiovascular consequences of repeated stimulation remain largely unexplored. 29 A key question is whether such interventions ultimately improve CV morbidity and mortality in this population, or whether the manipulation of BP, and specifically, the increases in BP that are often associated with stimulation, could pose risks akin to those seen in AD such as stroke, arrhythmia, and an accelerated CV disease.70,71,75
The stimulation site plays a crucial role in determining physiological responses. Evidence suggests that stimulating the lumbosacral and thoracic regions of the spinal cord may lead to a more robust sympathetic activation compared to cervical stimulation, potentially also increasing susceptibility to AD.24,46,74 However, while recent research indicates variable effects based on stimulation location, the impact of specific sites continues to be subject to investigation and debate within the field.29,46,74,76
Adding another layer of complexity, a recent study indicated that stimulation generates tonic frequency-dependent sympathoexcitation. 44 This sympathoexcitation normalized impaired responses to Valsalva, mirroring results from orthostatic challenge. However, the tonic sympathoexcitation further exacerbated already impaired sympathinhibitory testing (resulting in significantly greater mean arterial pressure increase with the same phenylephrine doses compared to baseline), and increased incidence of AD with below-level noxious stimuli. This suggested that spinal cord stimulation may not have led to improved autonomic regulation after SCI. 44
Conventional understanding holds that epidural and transcutaneous stimulation primarily activates large-diameter sensory axons (group I and II afferent fibers) in the posterior roots, as supported by computational models,29,77,78 mechanistic neuroscience, 74 and electrophysiological studies.79,80 Traditional theory associates AD with small-diameter C-fibers and aδ afferents rather than large-diameter fibers, which are typically thought to inhibit small fiber signals (“gate control theory”). 81 However, some evidence suggests large-diameter fibers may play a more significant role in AD than previously recognized, either supplementing or potentially replacing small fiber involvement, keeping this an area of ongoing investigation.82,83
The role of lower limb muscle contractions in stimulation-induced BP responses represents another area requiring further investigation. While some CV-focused studies use EMG or muscle palpation to identify stimulation configurations that can increase BP without engaging the skeletal muscle pump,28,31,41,42 achieving this separation may be challenging. At high stimulation amplitudes, lower extremity muscle activation seems likely, even though parameters like frequency and pulse-width may be potentially adjusted to minimize it. Indeed, there are reports of increased lower extremity muscle EMG activity during stimulation primarily targeting CV function. 30
Conclusions
The relationship between AD and spinal cord stimulation represents a critical area that demands refined understanding and standardization. The current clinical definition of AD, based primarily on a >20 mmHg increase in SBP, requires reconsideration when applied to research to better reflect the complexities observed. This is particularly important given the expanding applications of spinal stimulation therapies, where similar BP changes can be interpreted as either therapeutic or adverse depending on the context and study focus.
Additionally, further research is needed to fully understand the neural mechanisms underlying stimulation-induced CV changes and their relationship to AD. This enhanced understanding will be crucial for optimizing stimulation protocols and improving patient outcomes while ensuring appropriate monitoring and safety measures.
Footnotes
Author Contributions
Declaration of Conflicting Interests
The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding
The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was supported by the Tim Reynolds Foundation.
