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“Chinese Rehabilitation”
December 2022, Volume 37, Issue 12
Introduction
Autonomic nervous dysfunction is one of the common functional disorders after stroke, and its assessment and rehabilitation treatment are important parts of stroke rehabilitation. Despite a large amount of literature on autonomic nervous dysfunction after stroke, there is a lack of consensus on its diagnosis and assessment, and clinical treatment methods are limited, with insufficient attention. This article summarizes the clinical manifestations, neural mechanisms, assessment, conventional rehabilitation treatments, and neuromodulation-based intervention models related to autonomic nervous dysfunction after stroke, providing a basis and assistance for further exploration of its mechanisms and clinical rehabilitation treatment.
Clinical Manifestations of Autonomic Nervous Dysfunction After Stroke
The autonomic nervous system has a highly complex anatomical and functional organization in the brain and spinal cord, significantly affecting normal and abnormal cardiovascular functions through different networks. Autonomic nervous dysfunction after stroke manifests as unstable blood pressure, orthostatic hypotension, fever, and arrhythmias, with severe cases leading to brain-heart syndrome. Some studies suggest that post-stroke depression (PSD) is related to autonomic nervous dysfunction. Other studies indicate that bladder overactivity (urgency and frequency) or transient urinary retention may be related to transient autonomic nervous dysfunction caused by cerebral infarction, sensory disturbances during bladder filling, and insufficient detrusor activity during urination. Additionally, some studies have found that excessive sympathetic nerve activity may inhibit gastrointestinal motility, ultimately leading to constipation. Post-stroke shoulder-hand syndrome (SHS) is a chronic condition characterized by pain, sweating, hand swelling, vasomotor instability, and impaired motor function, with patients exhibiting limb autonomic nervous dysfunction and inflammation, including post-stroke complex regional pain syndrome (CRPS) or upper limb reflex sympathetic dystrophy.
Clinically, stroke patients with autonomic nervous dysfunction generally have a poor prognosis. It has been found that impaired heart rate variability (HRV) six months after acute ischemic stroke (AIS) is positively correlated with the severity of neurological dysfunction. Three months after AIS, patients with severe autonomic nervous dysfunction have a worse prognosis compared to those with mild dysfunction. Studies indicate that increased HRV and reduced vagal control in acute non-cardiac stroke patients are associated with a risk of delirium. Some scholars believe that stroke patients with autonomic nervous dysfunction may have a risk of cardiac complications, leading to adverse outcomes and increased mortality.
Neural Mechanisms of Autonomic Nervous Dysfunction After Stroke
Research shows that high HRV may increase the risk of stroke. For a long time, the “bottom-up” mechanism has been considered the main way of autonomic nervous regulation, relying on peripheral nerves, hormones, and endorphins. Changes in hormones and endorphins in the blood activate related brainstem structures (such as the ventrolateral medulla and the dorsomedial nucleus), which then regulate the heart and blood vessels through the peripheral nervous system to maintain normal cardiovascular homeostasis and reduce stroke risk. In contrast, the “top-down” mechanism involves the influence of the cerebral cortex on peripheral nerves, involving major brain areas such as the sensory-motor cortex, medial prefrontal cortex, and insular cortex. These brain areas activate sympathetic hyperactivity states that involve changes in skin conductance, pupil response, heart rate, and respiratory rate, either directly or by affecting the limbic system related to emotions. Many stroke patients have been found to have different skin conductance responses and HRV compared to healthy individuals, and both acute and six-month post-stroke periods show bilateral abnormalities in sympathetic skin reactions (SSR), supporting the conclusion that the cerebral cortex regulates the autonomic nervous system.
Abnormal blood pressure regulation after stroke includes central and peripheral mechanisms, such as reduced sympathetic nerve activity leading to persistent vasodilation. The regulation of pressure reflexes is mediated by the nucleus of the solitary tract and the ventrolateral medulla. Excitatory inhibition in brain areas such as the insular cortex (IC), thalamus, and medial prefrontal cortex (mPFC) can also trigger this symptom. Studies have found that the IC is a major regulatory center for cardiac autonomic nervous excitability. Additionally, in studies on the mechanisms of depression, deep brain stimulation (DBS) of the subgenual anterior cingulate cortex (sACC) has shown significant efficacy. Analyzing the anatomical connections of the prefrontal cortex (PFC), which is relatively superficial and closely related to the sACC, reveals that both the right and left PFC are closely connected to the sACC, but the peak anatomical connection coordinates between the two hemispheres differ slightly: the left PFC is directly connected to the sACC anatomically and functionally, while the right PFC is connected to the posterior cingulate cortex (PCC). The differences in anatomical connections suggest different mechanisms corresponding to different psychiatric symptoms. Given that earlier studies found that stress events activate the hypothalamus-pituitary-adrenal (HPA) axis, leading to a sharp increase in glucocorticoid secretion associated with anxiety and depression, the stress response is controlled by neural circuits connecting the prefrontal cortex (PFC) and the amygdala, where the dorsolateral prefrontal cortex (DLPFC) exerts an inhibitory effect on the amygdala, also affecting related hormone release. These mechanisms provide a preliminary theoretical basis for exploring and treating autonomic nervous dysfunction after stroke.
Main Assessment Indicators and Clinical Treatment
Main Assessment Indicators
There are many methods clinically used to assess autonomic nervous dysfunction after stroke, including HRV, changes in standing blood pressure, head-up tilt tests, isometric grip strength, quantitative sweating (evaporation measurement), pressure reflex sensitivity, Valsalva maneuver, deep breathing heart rate response, as well as plasma catecholamine levels, tumor necrosis factor α, interleukin-6, and high-sensitivity C-reactive protein testing. The autonomic response screening tool is a scale for assessing autonomic nervous dysfunction after stroke, quantifying autonomic nervous function assessment and having advantages in assessing sympathetic and parasympathetic autonomic nervous functions while considering pre- and post-ganglionic structures. It includes: assessing post-ganglionic sympathetic sweating function using quantitative sweating axon reflex tests (one upper limb and three lower limb sites); assessing cardiac vagal nerve function using deep breathing heart rate response and Valsalva ratio; and measuring cardiac adrenal function during Valsalva maneuver and head-up tilt tests. HRV, or heart rate variability, is an assessment indicator of autonomic nervous regulation of the heart and is one of the most widely used indicators clinically, reflecting the differences in frequency and timing of heartbeats between normal sinus beats. The ratio of low frequency (LF) to high frequency (HF) reflects the patterns of cardiac rhythmic changes and the influence of the autonomic nervous system on the cardiovascular system, where LF indicates sympathetic nervous function and HF is specific to parasympathetic nervous function; thus, a lower LF/HF ratio indicates a dominance of parasympathetic nervous function, and vice versa. Current HRV analysis methods include frequency domain, time domain, and nonlinear analysis, typically using dynamic electrocardiography for detection. Some scholars have also used SSR measurements clinically to assess autonomic nervous dysfunction caused by PSD. This is an electrophysiological test that records changes in skin conductance after sympathetic nervous system activation, with CRPS patients after stroke exhibiting excessive sympathetic nervous activity, potentially increasing SSR.
Rehabilitation Treatment
Respiratory Training, Aerobic Exercise, and Psychotherapy
Conventional respiratory training, psychotherapy, and aerobic exercise can regulate the autonomic nervous function of stroke patients. Studies have found that conventional rehabilitation interventions (including drug treatment) combined with progressive inspiratory muscle resistance training and breathing control training can effectively improve the daily living abilities, depressive emotional states, and HRV indicators of PSD patients. After psychological intervention combined with paroxetine treatment for PSD patients, it was found that the Hamilton Depression Rating Scale scores, Pittsburgh Sleep Quality Index scores, word fluency test results, SSR wave latency, and amplitude were all significantly better than before treatment, with increased serotonin levels in patients, leading to significant improvements in depressive states and autonomic nervous function. Using the self-generate physiological coherence system (SPCS) has been found to reduce fatigue and depression in patients and improve their HRV. The renin-angiotensin system in stroke patients presents a pathological state, and the processes of negative emotions such as anxiety and depression are related to the neural regulation mechanisms of the sympathetic and autonomic nervous systems. SPCS is a cardiopulmonary training system based on the theory of heart-brain interaction and decompression theory, dynamically displaying changes in HRV during patient training, helping to balance the autonomic nervous system, coordinate and improve HRV, alter brain wave activity, and promote connections between the bottom of the frontal lobe and the amygdala fiber bundles. Some studies have also shown that stroke patients exhibit lower LF/HF and overall variability at rest, with a dominance of parasympathetic nervous function, while during aerobic exercise, sympathetic nervous function dominates, and LF/HF does not return to baseline levels after 30 minutes of rest, consistent with responses in healthy elderly individuals. Previous HRV pattern analysis has been applied to develop exercise prescriptions for healthy populations, suggesting it can also serve as a simple and non-invasive assessment tool to help stroke patients formulate safe and effective exercise prescriptions.
Other Traditional Physical Therapies
Research has shown that compared to transcutaneous electrical nerve stimulation (TENS) treatment, laser therapy on the deltoid muscle and long head tendon of the biceps in stroke patients with reflex sympathetic dystrophy can reduce shoulder pain, alleviate hand swelling, lower the incidence of depression, and improve daily living abilities. Many scholars have previously focused on functional impairment issues such as swelling, pain, and joint mobility in SHS treatment, while some have also treated by regulating the sympathetic nervous system. Mirror therapy for post-stroke upper limb sympathetic dystrophy has shown that compared to the control group, the experimental group receiving mirror therapy had more significant improvements in edema, pain intensity, and functional activity indicators. Improvements were sustained at the two-week follow-up. Lymphoid tissue contains sympathetic neurons, and the sympathetic nervous system is closely related to inflammation. Stroke patients exhibit weaker delayed sympathetic responses and sympathetic dysfunction, leading to skin vasoconstriction and poor circulation, resulting in inflammatory fluid accumulation in SHS patients’ limbs. Therefore, mirror therapy targeting motivation and awareness may induce anti-inflammatory responses, activating sympathetic nervous activity to correct edema. Studies have found that neural mobilization can effectively improve the decreased peripheral nerve activity and increased tension caused by post-stroke spastic patterns, alleviating sympathetic nervous symptoms associated with SHS and improving sympathetic nutritional status. Research indicates that conventional physical therapy combined with upper limb aerobic exercise is a good comprehensive method for treating CRPS, with significant improvements in patients’ pain, depression, and health status. The treatment mechanism is that neurogenic inflammation in CRPS is triggered by neuropeptides (such as substance P, vasoactive intestinal peptide, and bradykinin), and after sympathetic nerve intervention, pain and inflammation are alleviated. Dividing stroke patients into CRPS and non-CRPS groups, after contrast bath (CB) treatment, both groups showed significant reductions in SSR amplitude in the paralyzed hand, while the CRPS group showed reduced SSR amplitude in the healthy side hand, with no significant changes in the non-CRPS group. On one hand, extensive cortical activation has a cross-hemispheric effect, while on the other hand, CB utilizes increased excitability of the extensive sensory-motor cortex to influence multimodal sensory processing, indicating that CB has a depressor effect, reducing sympathetic nervous system tension, enhancing physical fitness, and decreasing myocardial oxygen consumption. Some studies have also shown that CB has a more pronounced effect on sympathetic nervous system tension at the end of cold water baths.
Acupuncture
Traditional acupuncture treatment in China also regulates the autonomic nervous system. Studies have found that acupuncture at the Quchi point increases logLF/HF compared to pre-treatment, while acupuncture at the Quchi and Tianjing points decreases LF and HF compared to pre-treatment, both bringing HRV frequency domain indicators to normal ranges, with acupuncture at the Quchi point better regulating patients’ autonomic nervous balance. Research has shown that compared to the non-acupoint group (1 cm below the left Dazhong point), the acupuncture group at the Dazhong point had lower LF, HF, LF%, HF%, and TP at all time points (before, during, retaining, after acupuncture) than the non-acupoint group, while LF/HF was higher at all time points in the Dazhong point group than in the non-acupoint group, suggesting that acupuncture at the left Dazhong point can reduce sympathetic nervous activity and vagal nervous activity in patients with right-sided cerebral infarction, improving the balance tension of sympathetic and autonomic nervous systems, and the treatment also has a certain residual effect. Acupuncture at points such as Neiguan, Qihai, Shuigou, Renying, and Xuehai has been found to significantly reduce cardiovascular and nervous system responses in patients with brain-heart syndrome caused by stroke, enhancing the cardioprotective effects, possibly related to the regulation of cardiac autonomic nervous states inhibiting stress responses and thus reducing catecholamine levels.
Remote Ischemic Preconditioning
Remote ischemic preconditioning (RIPostC) refers to the adaptation of target organs to a few rounds of brief ischemia and reperfusion cycles after a period of sustained ischemia, providing good endogenous protection to target organs. Researchers have found that AIS patients receiving four cycles of alternating inflation (inflating the cuff to 200 mmHg) and deflation on the healthy upper arm for 5 minutes each day for 30 days showed significant increases in all HRV parameters over time except for LF/HF. The RIPostC group had significantly higher values for all normal R-R intervals (SDNN standard deviation of heartbeats) and high-frequency standard deviation values on days 7 and 30, as well as significantly higher percentage difference values for adjacent normal R-R intervals (pNN50) on day 30 compared to the sham stimulation group. PNN describes the variability of heartbeats, with larger ratios indicating higher vagal nerve tension, suggesting that 30 days of RIPostC training can enhance overall autonomic nervous activity and vagal nerve activity in stroke patients, reducing the occurrence of disabilities, with the mechanisms mediating autonomic nervous function warranting further research. Evaluations using Ewing tests and HRV have also found similar conclusions regarding remote ischemic preconditioning.
Non-invasive Neuromodulation
The cerebral cortex is a key structure in the control of autonomic nervous functions such as cardiovascular regulation, so non-invasive neuromodulation techniques that can effectively regulate cortical function, such as transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS), can modulate heart rate, blood pressure, and autonomic nervous excitability through sustained, long-term effects on the cerebral cortex. These techniques are widely used in neurological diseases such as stroke, autism spectrum disorders, neurodegenerative diseases, movement disorders, tinnitus, chronic pain, and functional neurological disorders. In a study on central post-stroke pain (CPSP), it was found that using 10 Hz high-frequency rTMS on the affected primary motor cortex (M1) effectively alleviated upper limb pain in CPSP patients and lowered heat thresholds, improving cold sensations. However, the experiment could not confirm whether the reduction in heat thresholds related to the activation of the insula and anterior cingulate cortex (ACC) was a direct effect of M1 or an indirect effect through the primary sensory cortex (S1) or thalamus. Similarly, using 10 Hz rTMS on the M1 area of CPSP patients reduced their subjective pain sensations and increased pain thresholds, while analysis of patients’ neurophysiological indicators showed that compared to healthy individuals, indicators reflecting cortical-cortical excitability were suppressed bilaterally, and the duration of the inhibitory spinal reflex (iSP) was reduced, while the resting motor threshold (rMT) reflecting cortical-spinal excitability was not affected. The authors suggest that this result may be related to the selective inhibition of bilateral pathways by gamma-aminobutyric acid or to thalamic damage related to the assessment of pain sensation to modulate motor cortical excitability. In studies targeting central neuropathic pain (CNP), using true and sham 10 Hz deep repetitive transcranial magnetic stimulation (dTMS) on the posterior superior insula (PSI) or ACC of CNP patients caused by stroke or spinal cord injury found that only true stimulation on PSI reduced heat thresholds in CNP patients, supporting the selection of the insula as the primary target for CNP treatment. Studies have shown that using 10 mA anodal tDCS on the left temporal cortex (TC) of 10 athletes resulted in a decrease in LF/HF, while induced electric fields in the left TC were measured, and subjective fatigue scale scores decreased in the experimental group. Based on this, applying 2 mA anodal tDCS to the left TC before treadmill training in stroke patients also supported that tDCS can influence parasympathetic nervous modulation. In studies on autonomic nervous dysfunction in AIS, applying a 10 mA current at a frequency of 18 kHz using a percutaneous mastoid electrical stimulator (PMES) within 3 hours of onset in acute ischemic stroke patients successfully alleviated HRV abnormalities.
Conclusion and Outlook
Various stages of stroke are often accompanied by different autonomic nervous dysfunctions, significantly hindering patients’ functional recovery, mental health, and social and family reintegration. The occurrence and mechanisms involved involve multiple aspects, including body fluids, immunity, and nerves, and are still under exploration. The previous text summarizes the main theoretical mechanisms and methods of combined traditional Chinese and Western medicine physical rehabilitation treatments and non-invasive neuromodulation interventions for autonomic nervous dysfunction after stroke. However, despite high attention to autonomic nervous dysfunction after stroke both domestically and internationally, actual clinical efficacy remains poor, with short durations of effect and no unified assessment indicators. Domestic research has mostly focused on the sequelae phase after stroke, while interventions for the acute phase are scarce and singular. Therefore, further exploration of the mechanisms and new intervention methods for autonomic nervous dysfunction after stroke is warranted.
References
Zhang Lichao, Feng Tingyi, Li Yuanli, Shan Chunlei. Rehabilitation Treatment for Autonomic Nervous Dysfunction After Stroke [J]. Chinese Rehabilitation, 2022, 37(12): 755-759.
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