Commentary: Are Postconcussive Symptoms and Exercise Testing Appropriate Tools to Identify Autonomic Impairment after Mild Traumatic Brain Injury?

Abstract

Objective:

After mild traumatic brain injury (mTBI), autonomic nervous system dysfunction is thought to contribute to exercise intolerance and self-reported postconcussive symptoms (e.g., dizziness, lightheadedness, brain fog) but little has been done to establish this relationship in the literature.

Methods:

Through recent literature review, it appears that few studies have assessed both autonomic function and exercise intolerance, and for those that have utilized varying methodologies making comparison across studies difficult. Some emerging research has identified potential impairment within the sympathetic nervous system after mTBI but no relationship between exercise tolerance testing and postconcussive symptoms has been established.

Conclusion:

For neuropsychologists, a physiologic understanding of the scope of autonomic dysfunction and appropriate assessment is vitally important, as autonomic nervous system impairment has the potential to impact sleep and mood, and subsequently cognitive function and mental health. When working in collaboration with other disciplines, referrals to exercise intolerance testing and laboratory based autonomic assessments may occur. However, given the lack of an established evidence, the use of exercise intolerance and/or related symptoms to clinically insinuate dysfunction of the autonomic nervous system function is likely premature, and a more thorough assessment of autonomic function via established batteries is more appropriate.

Introduction

Persistent self-reported symptoms after mTBI, defined as symptoms that persist for greater than 3 months post-injury, occur in 15-20% of individuals.^1,2 Persistent symptoms can contribute to a variety of other health care issues including a decline in mental health, difficulty with return to work or school, inability to participate in activities of daily life, and social strain.^3,4 Autonomic nervous system dysfunction is suspected to contribute to pathophysiology, with a growing link between autonomic nervous system dysfunction and both sleep and mood dysregulation.^5,6 Little is still known though about the extent to which autonomic dysfunction is present in mTBI, with only a single study estimating up to 28% of individuals demonstrating autonomic dysfunction post-mTBI.⁷

One reason little is known is that the measurement of the autonomic nervous system is not consistently performed and, when performed, assessment can be done using a variety of different methods, each conveying information about different aspects of overall autonomic control.^8-13 A second issue with post-mTBI autonomic testing is that studies have been performed at a variety of time periods post-injury. Current literature ranges from testing within the first 48-72hrs, to the first 2 weeks, and even as long as 6 months or more post-mTBI.^13-15 Given the lack of consistency, it is difficult to form any consensus on the impact that an mTBI has on the autonomic nervous system, localization of impairment within the autonomic nervous system, what the recovery of the autonomic nervous system looks like, and how to best assess autonomic dysfunction both in the laboratory and in the clinic.

This review provides an overview of the anatomy and physiology of the autonomic nervous system with the goal to help neuropsychologists, as clinicians and researchers, gain a better understanding of autonomic nervous system dysfunction in mTBI and available methods for assessment of such dysfunction by colleagues in allied disciplines. Importantly, identifying potential autonomic underpinnings of mood and sleep dysregulation may help explain subjective cognitive complaints frequently encountered in neuropsychological research and practice.^16,17

Anatomy and Physiology

The brainstem is an integral location in the control of the autonomic nervous system. Impact modeling studies have shown the maximum values of force during an mTBI to occur within the brainstem.¹⁸ Specifically, strain and strain rate, which are measures of deformation, have shown to significantly determine injury-induced nerve function alterations.¹⁹

The convergence of afferent input at the brainstem and subsequent efferent output creates a situation where any sort of damage or impairment can have widespread influence on autonomic nervous system control.^20-23 This includes, but is not limited to, blood flow to the brain, heart, skeletal muscles, and gastrointestinal system.²³ Cerebral blood flow is critical for day-to-day function and many symptoms associated with mTBI (e.g., fatigue, headaches, nausea, memory dysfunction, attention complaints, brain fog, anxiety, depression, and insomnia) that have been described in situations of alterations to cerebral blood flow.²⁴ The most important determinant for cerebral blood flow is arterial perfusion pressure, which depends on cardiac output and vascular peripheral resistance.²⁵ Carotid baroreceptors provide monitoring of arterial perfusion pressure and transmit afferent information to the cardiovascular autonomic control center within the brainstem. The subsequent efferent response to control parasympathetic and sympathetic output to the heart and vasculature may be altered after mTBI, resulting in poor cerebral blood flow control.^21,26,27

Assessment of Autonomic Function

No single test can reflect the complex function of the autonomic nervous system. The Ewing Battery is a collection of clinically useful laboratory based tests that challenge baroreflex function (i.e., the body’s mechanism that helps maintain blood pressure) while measuring continuous heart rate (HR) and blood pressure (BP) recording.²⁸ The Ewing Battery is primarily validated for the diagnosis of autonomic failure; however the sensitivity and specificity of the battery is unknown relative to the mTBI population.^29,30 The battery includes, heart rate variability, change to deep breathing, the Valsalva maneuver, and the head-up tilt table test. See Table 1 for a description of these procedures.

Table 1.

Categorization of Parasympathetic and Sympathetic Output into Type of Assessment and Description.

OUTPUT	ASSESSMENTS	DESCRIPTION
Parasympathetic	Deep Breathing	Inspiration results in an increase in HR while expiration results in a decrease in HR.40
Parasympathetic & Sympathetic	Valsalva Maneuver	The Valsalva maneuver elicits an abrupt increase in intrathoracic pressure, which causes a decrease in venous return and cardiac output. These changes cause a change in both HR and BP.41
	Head-Up Tilt	The head-up tilt test evaluates sympathetic function of the cardiopulmonary and carotid arterial baroreceptors through an orthostatic stress that causes a shift in blood volume out of thoracic cavity and into the lower extremities. This triggers vasoconstriction and increased HR.27,41

Abbreviations: HR – Heart Rate, BP – Blood Pressure

Exercise tolerance testing is not part of the Ewing Battery but is a common clinical test performed by assessing symptom provocation during exercise. Such testing is often considered an assessment of autonomic function; however, this has not yet been extensively supported in the literature, and there are many body system impairments post-mTBI that may contribute to an overall state of exercise intolerance.

Exercise tolerance testing often involves graded exertion via bike or treadmill while recording of a patient’s symptoms and/or heart rate and has been performed in multiple studies.^10,31-33 This type of testing provides valuable information on the ability to exert oneself and the intensity of exertion at which post-mTBI symptoms might be provoked. This information is highly valuable in individuals who are looking to return to an active lifestyle or are participating in athletic competition. The prevalence of exercise intolerance has been found to be around 50% in the post-mTBI population but confounding elements that are introduced during bike or treadmill testing limit localizing capacity of exertional testing.³⁴ Examples include head motion during treadmill testing, which can create vestibular and visual stimulation, emotional responses, and stress responses.

Even if these variables are controlled for, exercise testing still results in increased sympathetic nerve activity and decreased parasympathetic nerve activity via two distinct neural mechanisms outside of baroreceptor control (i.e., cortical control and the exercise pressor reflex), which provides further barrier to localization of pathophysiology.³⁵ Specifically, cortical control functions through a feed-forward neural mechanism that transmits excitatory impulses to descending motor neurons for locomotion and in a parallel fashion activates cardiovascular control circuits within the brainstem;³⁵ and the exercise pressor reflex responds to mechanical distortion and the metabolic by-products of exercising skeletal muscle and induces elevations in heart rate and blood pressure.^35-38

Current Literature

Studies that have claimed to parse out autonomic function and exercise testing were reviewed in a recent scoping review by Pelo et al.³⁹ Due to methodological differences and a wide range in testing timeline, limited actionable conclusions could be drawn, though several key themes and opportunities for future research were identified.³⁹

Testing across all studies demonstrated little standardization and the testing methods could be methodologically questioned in many of the studies. None of the identified studies performed a comprehensive autonomic testing battery, such as the widely used Ewing’s Battery.^40-43 Formalized symptom driven exercise intolerance testing varied widely across studies, and was lacking assessment of symptoms in some studies, which presents an issue given that symptom provocation is a hallmark of exercise intolerance testing.

The most problematic variability across studies was that of inconsistent timelines. Studies in the review ranged from evaluation within 72 hours, up to 7 months post-mTBI, and two studies included participants if they had “any” lifetime history of mTBI. While several studies did utilize a longitudinal assessment approach, the variability of time since mTBI and time to follow-up evaluation represents a critical gap.

Overall, while symptoms of exercise intolerance are frequently accepted as clinical signs of autonomic dysfunction following a mTBI, to date, few studies have directly tested this relationship and within those that have attempted to test this relationship little consensus can be drawn, largely due to the lack standardized methodology.³⁹

Emerging Research

Through ongoing research by the author and colleagues, current studies have attempted to reduce variability and gain an understanding of autonomic function through measures that are largely capable of localizing baroreflex function and have compared these results with exercise tolerance testing as well as patient reported symptoms. Results from these studies have started to provide insight into potential alterations in baroreflex function after mTBI and lay a foundation for future studies.

Specifically, preliminary results have found a blunted sympathetic nervous system response along with reduced variability in HR and BP in an acute (<2 weeks) mTBI group compared to a healthy control group when tilt-table testing was utilized to provide a stressor to cardiovascular autonomic nervous system control.⁴⁴ When the mTBI group was then tested for performance on exercise tolerance testing, little to no relationship was found between performance on exercise tolerance and tilt-table testing, suggesting that mechanisms other than the orthostatic challenge itself likely contribute to the former.⁴⁴ The assessment of a relationship between concussion related symptom burden and autonomic testing was also performed and again, little relationship was found. Additionally, a recent study that assessed the prevalence of exercise intolerance across mTBI symptom profiles found exercise intolerance equally pervasive across five mTBI symptom subtypes and recommended that comprehensive assessment should include evaluation for exercise intolerance regardless of the primary clustering of symptoms after mTBI.³⁴

Taken together, the findings suggest that autonomic impairment is not the lone contributor to exercise intolerance or specific symptom profiles and that the broad range of system impairments post-mTBI have the ability to contribute to an individual’s tolerance to exercise and overall symptom profile. Therefore, the utilization of exercise tolerance testing alone or symptoms alone to diagnoses autonomic impairment should be discouraged.

Role of the Clinician and Researcher

For neuropsychologists, an understanding of the autonomic nervous system and how sympathetic and parasympathetic imbalance may impair mood and sleep and subsequently impact cognitive function and mental health is critical in providing the appropriate treatment and recommendations for an individual after mTBI. Provided the current literature and emerging research, a few keys concepts can be taken and applied to current practice and further research within the field of mTBI.

First, symptom report is often utilized in the assessment of impairment after mTBI but localizing capacity of symptom report to pathophysiology has continued to come into question.⁶ Therefore, utilization of symptom report remains important but does not provide the sensitivity or specificity to stand on its own and is in need of additional testing to provide direction as to pathophysiology post-mTBI.

Second, the use of exercise tolerance testing can have significant value in an mTBI population but a deeper understanding of the capabilities of exercise tolerance testing is needed. Although exercise may not typically fall within a clinical neuropsychologists practice, the performance of exercise testing and rehabilitation is common clinical practice for both sport and non-sport related concussion. Stress, anxiety, performance expectations, and overall involvement of the limbic system represent significant factors in an individual’s activity tolerance and overall level of cognitive function.

Third, although it is not feasible to perform laboratory based autonomic testing on every individual after mTBI, allied qualified professionals may assess orthostatic vital signs (e.g., conduct the Active Stand Test) as a screening tool. Such an approach may be more clinically feasible and more appropriate to guide referral to laboratory based autonomic testing than exercise tolerance testing.^45,46 In cases with a prolonged recovery of symptoms both related and unrelated to exercise intolerance, and where other methods of assessment have been unable to determine the cause of impairment, it may be beneficial to refer all such patients for a laboratory-based autonomic testing through neurology colleagues.

Conclusions

Cardiovascular autonomic dysfunction is thought to contribute to exercise performance, symptom profile, mood, and sleep dysfunction after mTBI, although current literature has not established a solid connection. This has led to clinical assumptions of specific physiologic impairment when performing measures of exercise intolerance and symptom report. These assumptions may be misguided as the current literature has yet to supported this. While emerging evidence supports the likelihood that sympathetic output is altered after mTBI, how this relates to physiological demands of exercise testing and symptom burden remains to be resolved. For neuropsychologists, when working in collaboration with other disciplines, referrals to exercise intolerance testing and laboratory based autonomic assessments may occur. A physiologic understanding of the scope of autonomic dysfunction and limitations of certain assessments is vitally important, as autonomic nervous system impairment has the potential to impact sleep and mood, and subsequent cognitive function and mental health.