Alexander R. Burton

Effects of deep and superficial experimentally induced acute pain on muscle sympathetic nerve activity in human subjects

Human studies conducted more than half a century ago have suggested that superficial pain induces excitatory effects on the sympathetic nervous system, resulting in increases in blood pressure (BP) and heart rate (HR), whereas deep pain is believed to cause vasodepression. To date, no studies have addressed whether deep or superficial pain produces such differential effects on muscle sympathetic nerve activity (MSNA). Using microneurography we recorded spontaneous MSNA from the common peroneal nerve in 13 awake subjects. Continuous blood pressure was recorded by radial arterial tonometry. Deep pain was induced by intramuscular injection of 0.5 ml hypertonic saline (5%) into the tibialis anterior muscle, superficial pain by subcutaneous injection of 0.2 ml hypertonic saline into the overlying skin. Muscle pain, with a mean rating of 4.9 ± 0.8 (s.e.m.) on a 0–10 visual analog scale (VAS) and lasting on average 358 ± 32 s, caused significant increases in MSNA (43.9 ± 10.0%), BP (5.4 ± 1.1%) and HR (7.0 ± 2.0%) – not the expected decreases. Skin pain, rated at 4.9 ± 0.6 and lasting 464 ± 54 s, also caused significant increases in MSNA (38.2 ± 12.8%), BP (5.1 ± 2.1%) and HR (5.6 ± 2.0%). The high‐frequency (HF) to low‐frequency (LF) ratio of heart rate variability (HRV) increased from 1.54 ± 0.25 to 2.90 ± 0.45 for muscle pain and 2.80 ± 0.52 for skin pain. Despite the different qualities of deep (dull and diffuse) and superficial (burning and well‐localized) pain, we conclude that pain originating in muscle and skin does not exert a differential effect on muscle sympathetic nerve activity, both causing an increase in MSNA and an increase in the LF : HF ratio of HRV. Whether this holds true for longer lasting experimental pain remains to be seen.

Reduced Cardiac Vagal Modulation Impacts on Cognitive Performance in Chronic Fatigue Syndrome

Background Cognitive difficulties and autonomic dysfunction have been reported separately in patients with chronic fatigue syndrome (CFS). A role for heart rate variability (HRV) in cognitive flexibility has been demonstrated in healthy individuals, but this relationship has not as yet been examined in CFS. The objective of this study was to examine the relationship between HRV and cognitive performance in patients with CFS. Methods Participants were 30 patients with CFS and 40 healthy controls; the groups were matched for age, sex, education, body mass index, and hours of moderate exercise/week. Questionnaires were used to obtain relevant medical and demographic information, and assess current symptoms and functional impairment. Electrocardiograms, perceived fatigue/effort and performance data were recorded during cognitive tasks. Between–group differences in autonomic reactivity and associations with cognitive performance were analysed. Results Patients with CFS showed no deficits in performance accuracy, but were significantly slower than healthy controls. CFS was further characterized by low and unresponsive HRV; greater heart rate (HR) reactivity and prolonged HR-recovery after cognitive challenge. Fatigue levels, perceived effort and distress did not affect cognitive performance. HRV was consistently associated with performance indices and significantly predicted variance in cognitive outcomes. Conclusions These findings reveal for the first time an association between reduced cardiac vagal tone and cognitive impairment in CFS and confirm previous reports of diminished vagal activity.

The effects of experimental muscle and skin pain on the static stretch sensitivity of human muscle spindles in relaxed leg muscles

Animal studies have shown that noxious inputs onto γ‐motoneurons can cause an increase in the activity of muscle spindles, and it has been proposed that this causes a fusimotor‐driven increase in muscle stiffness that is believed to underlie many chronic pain syndromes. To test whether experimental pain also acts on the fusimotor system in humans, unitary recordings were made from 19 spindle afferents (12 Ia, 7 II) located in the ankle and toe extensors or peronei muscles of awake human subjects. Muscle pain was induced by bolus intramuscular injection of 0.5 ml 5% hypertonic saline into tibialis anterior (TA); skin pain was induced by 0.2 ml injection into the overlying skin. Changes in fusimotor drive to the muscle spindles were inferred from changes in the mean discharge frequency and discharge variability of spindle endings in relaxed muscle. During muscle pain no afferents increased their discharge activity: seven afferents (5 Ia, 2 II) showed a decrease and six (4 Ia, 2 II) afferents were not affected. During skin pain of 13 afferents discharge rate increased in one (Ia) and decreased in two (1 Ia, 1 II). On average, the overall discharge rate decreased during muscle pain by 6.1% (P < 0.05; Wilcoxon), but remained essentially the same during skin pain. There was no detectable correlation between subjective pain level and the small change in discharge rate of muscle spindles. Irrespective of the type of pain, discharge variability parameters were not influenced (P > 0.05; Wilcoxon). We conclude that, contrary to the ‘vicious cycle’ hypothesis, acute activation of muscle or skin nociceptors does not cause a reflex increase in fusimotor drive in humans. Rather, our results are more aligned with the pain adaptation model, based on clinical studies predicting pain‐induced reductions of agonist muscle activity.

Selective activation of muscle and skin nociceptors does not trigger exaggerated sympathetic responses in spinal-injured subjects.

Study design:Measurement of sympathetic effector organ responses to selective activation of muscle and skin nociceptors below lesion in spinal cord-injured (SCI) subjects.Objectives:To test whether selective noxious stimulation below lesion causes exaggerated sympathetic responses in human SCI.Setting:Prince of Wales Medical Research Institute, Australia.Methods:Twelve subjects (C5-T10, ASIA A-C), none of whom had sensation below the lesion, were included in the study. Selective stimulation of muscle or cutaneous nociceptors was produced by bolus injection of hypertonic (5%) saline into the tibialis anterior muscle or overlying skin and compared with non-noxious electrical stimulation of the abdominal wall. Cutaneous vasoconstrictor (photoelectric plethysmography) and sudomotor (skin conductance) responses, in addition to respiration, heart rate and continuous arterial pressure were monitored.Results:Electrical stimulation of the abdominal wall caused a significant increase in arterial pressure (31.8±6.1%). Conversely, intramuscular or subcutaneous injection of hypertonic saline caused no significant changes in blood pressure (−3.0±2.4%; −1.4±3.4%) heart rate, skin blood flow or sweat release.Conclusions:While hypertonic saline injected into muscle or skin induces strong pain, cutaneous vasoconstriction and sweat release in able-bodied subjects, we saw no evidence of exaggerated sympathoexcitation when these same noxious stimuli were delivered below lesion in subjects with SCI. This suggests that certain types of somatic noxious input may not trigger autonomic dysreflexia, and questions the concept that any painful stimuli originating below lesion can reliably trigger dysreflexia.

Autonomic hyper-vigilance in post-infective fatigue syndrome

This study examined whether post-infective fatigue syndrome (PIFS) is associated with a disturbance in bidirectional autonomic signalling resulting in heightened perception of symptoms and sensations from the body in conjunction with autonomic hyper-reactivity to perceived challenges. We studied 23 patients with PIFS and 25 healthy matched control subjects. A heartbeat discrimination task and a pressure pain threshold test were used to assess interoceptive sensitivity. Cardiac response was assessed over a 4-min Stroop task. PIFS was associated with higher accuracy in heartbeat discrimination and a lower pressure pain threshold. Increased interoceptive sensitivity correlated strongly with current symptoms and potentiated differences in the cardiac response to the Stroop task, which in PIFS was characterized by insensitivity to task difficulty and lack of habituation. Our results provide the first evidence of heightened interoceptive sensitivity in PIFS. Together with the distinct pattern in cardiac responsivity these findings present a picture of physiological hyper-vigilance and response inflexibility.

Sympathetic Responses to Noxious Stimulation of Muscle and Skin

Acute pain triggers adaptive physiological responses that serve as protective mechanisms that prevent continuing damage to tissues and cause the individual to react to remove or escape the painful stimulus. However, an extension of the pain response beyond signaling tissue damage and healing, such as in chronic pain states, serves no particular biological function; it is maladaptive. The increasing number of chronic pain sufferers is concerning, and the associated disease burden is putting healthcare systems around the world under significant pressure. The incapacitating effects of long-lasting pain are not just psychological – reflexes driven by nociceptors during the establishment of chronic pain may cause serious physiological consequences on regulation of other body systems. The sympathetic nervous system is inherently involved in a host of physiological responses evoked by noxious stimulation. Experimental animal and human models demonstrate a diverse array of heterogeneous reactions to nociception. The purpose of this review is to understand how pain affects the sympathetic nervous system by investigating the reflex cardiovascular and neural responses to acute pain and the long-lasting physiological responses to prolonged (tonic) pain. By observing the sympathetic responses to long-lasting pain, we can begin to understand the physiological consequences of long-term pain on cardiovascular regulation.

Reliability revisited: Autonomic responses in the context of everyday well-being

Vishal Patel , Sabine Giesebrecht , Alexander R. Burton , Erin Cvejic , Jim Lemon , Dusan Hadzi-Pavlovic , Stephen Dain , Andrew Lloyd , Ute Vollmer-Conna a,⁎ a School of Psychiatry, University of New South Wales, Sydney, NSW 2052, Australia b Optics and Radiometry Laboratory, School of Optometry and Vision Science, University of New South Wales, Sydney, NSW 2052, Australia c Inflammation and Infection Research Centre, School of Medical Sciences, University of New South Wales, Sydney, NSW 2052, Australia

Somatosympathetic vasoconstrictor reflexes in human spinal cord injury: responses to innocuous and noxious sensory stimulation below lesion

It is known that the sudden increases in blood pressure associated with autonomic dysreflexia in people with spinal cord injury (SCI) are due to a spinally mediated reflex activation of sympathetic vasoconstrictor neurons supplying skeletal muscle and the gut. Apart from visceral inputs, such as those originating from a distended bladder, there is a prevailing opinion that autonomic dysreflexia can be triggered by noxious stimulation below the lesion. However, do noxious inputs really cause an increase in blood pressure in SCI? Using microelectrodes inserted into a peripheral nerve to record sympathetic nerve activity we had previously shown that selective stimulation of small-diameter afferents in muscle or skin, induced by bolus injection of hypertonic saline into the tibialis anterior muscle or the overlying skin, evokes a sustained increase in muscle sympathetic nerve activity and blood pressure and a transient increase in skin sympathetic nerve activity and decrease in skin blood flow in able-bodied subjects. We postulated that these sympathetic responses would be exaggerated in SCI, with a purely noxious stimulus causing long-lasting increases in blood pressure and long-lasting decreases in skin blood flow. Surprisingly, though, we found that intramuscular or subcutaneous injection of hypertonic saline into the leg caused negligible changes in these parameters. Conversely, weak electrical stimulation over the abdominal wall, which in able-bodied subjects is not painful and activates large-diameter cutaneous afferents, caused a marked increase in blood pressure in SCI but not in able-bodied subjects. This suggests that it is activation of large-diameter somatic afferents, not small-diameter afferents, that triggers increases in sympathetic outflow in SCI. Whether the responses to activation of large-diameter afferents reflect plastic changes in the spinal cord in SCI is unknown.

Viscerosympathetic reflexes in human spinal cord injury: relationships between detrusor pressure, blood pressure and skin blood flow during bladder distension.

•  What is the central question of this study? Dangerous increases in blood pressure (autonomic dysreflexia) can be caused by visceral stimuli in spinal cord injury, but it is not known how cutaneous vasoconstriction is related to increases in bladder and blood pressures during bladder distension. •  What is the main finding and its importance? We show that an increase in bladder pressure causes cutaneous vasoconstriction in the fingers that is inversely related to the bladder pressure. Skin blood flow was inversely related to the increase in blood pressure in nine of 15 patients. Monitoring finger blood flow therefore provides a useful, supplementary, non‐invasive means of assessing sympathetic outflow below the lesion in high thoracic or cervical spinal cord injury.

Autonomic dysreflexia: Somatosympathetic and viscerosympathetic vasoconstrictor responses to innocuous and noxious sensory stimulation below lesion in human spinal cord injury

Autonomic dysreflexia is a dangerous elevation in blood pressure in people with spinal cord injury (SCI), produced by a spinally-mediated reflex activation of sympathetic vasoconstrictor neurones supplying skeletal muscle and the gut. Current dogma states that, apart from visceral inputs - such as those originating from a distended bladder or impacted colon - autonomic dysreflexia is triggered by noxious inputs below the lesion. However, while selective stimulation of small-diameter afferents in muscle or skin evokes a sustained increase in muscle sympathetic nerve activity and blood pressure, and a transient increase in skin sympathetic nerve activity and decrease in skin blood flow in able-bodied subjects, such noxious inputs have no effects on blood pressure and skin blood flow in SCI individuals. Conversely, weak electrical stimulation over the abdominal wall, which in able-bodied subjects is not painful and activates large-diameter cutaneous afferents, causes a marked increase in blood pressure in SCI but not in able-bodied subjects. Moreover, vibration of the penis in spinal-injured men, which is not noxious, caused marked vasoconstriction and increases in blood pressure, similar to those produced by non-noxious distension of the bladder during urodynamics procedures. This suggests that activation of large-diameter somatic afferents, not small-diameter afferents, triggers the increases in vasoconstrictor drive that lead to autonomic dysreflexia, arguing against current dogma on the importance of noxious inputs in triggering autonomic dysreflexia.