JOURNAL CLUB: Quantifying needles in a haystack: the firing properties of single sympathetic vasoconstrictor neurones in chronic obstructive pulmonary disease

The technique of microneurography was first developed in Sweden in the late 1960s and subsequently used to document the first measurements of sympathetic neural activity in humans. Since these early recordings, microneurography has proven useful for measuring regional sympathetic activity under many different circumstances in healthy and pathological populations. However, the standard approach of rectification and integration of the sympathetic signal results in a loss of neural information. Recently, Macefield and colleagues (and others) have adapted the microneurographic technique to detect and quantify the firing patterns of single post-ganglionic sympathetic neurones not apparent in integrated multi-unit recordings (Macefield et al. 1994). Using high-impedance electrodes, large discharges from single neurones can be isolated against the background of multi-unit activity. With this approach these authors (and others) have expanded our understanding of sympathetic vasomotor regulation by demonstrating that, at rest, sympathetic vasomotor neurones fire predominately only once within a given burst of activity (∼70% of bursts) (Macefield et al. 1994; Macefield & Wallin, 1999) and that multiple firings of the same neurone, within a burst, increase with stress (Macefield & Wallin, 1999) and with certain pathologies (i.e. congestive heart failure (CHF) and obstructive sleep apnoea (OSA)) (Macefield et al. 1999; Elam et al. 2002). As a logical progression from these previous observations, a recent article by Ashley et al. in The Journal of Physiology sought to characterize the firing properties of single sympathetic vasomotor neurones in patients with chronic obstructive pulmonary disease (COPD) (Ashley et al. 2010). The authors hypothesized that similar to OSA patients, who experience repetitive bouts of hypoxic–hypercapnic stress, the concomitant hypoxaemia and hypercapnia with which COPD commonly present cause an elevated chemical drive and result in an increased firing probability of single sympathetic vasomotor neurones. To test their hypothesis, the authors compared unitary firing properties recorded from nine COPD patients to a group of four bronchiectasis (BE) patients. BE patients exhibit similar airflow limitation and airway inflammation as COPD patients but have normal blood gases. Data from COPD and BE patients were further contrasted with a group of seven normal healthy subjects exhibiting high levels of resting sympathetic activity and a group of eight OSA patients, both described previously (Macefield & Wallin, 1999; Elam et al. 2002). Compared to healthy controls with high levels of sympathetic activity, BE patients exhibited similar burst incidence (bursts/100 heart beats; as determined from the integrated neurogram) and single-unit firing probability (percentage of cardiac cycles in which a given neurone was active). In contrast, COPD patients exhibited higher burst incidence and elevated single-unit firing probability with respect to both the high activity controls and BE patients. However, despite apparently different sympathetic drives in the BE and COPD subjects, both patient groups had a significant shift towards multiple within-burst firing and higher mean firing frequencies compared to the high activity controls, suggesting an altered central sympathetic regulation with pulmonary pathology. The inclusion of previous data from healthy control subjects with high multi-unit burst incidence and OSA patients provides a supplemental review of the unitary firing properties of sympathetic neurones in healthy and pathological states as well as context for the broader interpretation of the results as presented. Here we can also consider data previously obtained from CHF patients (Macefield et al. 1999). Comparisons across these varied groups demonstrate a complex pattern of alterations in the unitary firing characteristics of sympathetic vasomotor neurones not evident in the integrated neurogram. While integrated burst incidence in each of the high activity control (75 bursts per 100 heart beats), BE (78 bursts per 100 heart beats), OSA (77 bursts per 100 heart beats), CHF (88 bursts per 100 heart beats) and COPD (85 bursts per 100 heart beats) groups was arguably elevated compared to a normative value of ∼20–40 bursts per 100 heart beats (Macefield et al. 1994, 1999), single unit firing probability was greater in the OSA, CHF and COPD subjects compared to the high activity and BE controls. Further, whereas the BE, OSA and COPD patients all exhibited a shift towards multiple within-burst firing, as also observed in healthy subjects during voluntary apnoea (Macefield & Wallin, 1999), this shift appears to be absent in CHF patients. From these data there is no clear pattern immediately linking these varied measures of sympathetic drive. As hypothesized by Ashley et al. (2010), chronic chemoreceptor stimulation and augmented chemosensitivity may be important factors contributing to the increased firing probability of vasomotor neurones in COPD and other pathologies. To this end, the authors highlight the known impact of hypoxaemia in COPD on respiratory drive and resting sympathetic outflow, as well as the reduction in integrated sympathetic activity observed with acute oxygen administration in this population. In conjunction with the pH compensation observed in COPD patients (Ashley et al. 2010, Table 1), this suggests that hypoxaemia is the primary regulator of altered sympathetic drive in COPD. Supporting this premise is their previous data from OSA (Elam et al. 2002) and CHF (Macefield et al. 1999) patients, which both exhibit heightened peripheral chemosensitivity, as well as from healthy subjects performing volitional apnoea (Macefield & Wallin, 1999). However, without directly testing their hypothesis (with the simple administration of a hyperoxic gas mixture) it remains to be determined if there is a fundamental neural dysregulation in central sympathetic drive in COPD or whether the observed alterations in single-unit firing characteristics are the result of heightened chemoreflex mediated sympathoexcitation. Further, the mechanisms that lead to elevated within-burst firing across populations are not currently known. These data, from a research group that has pioneered this area of study, provide additional, intriguing information regarding sympathetic neural plasticity in healthy and diseased populations. Indeed, single-unit analysis of sympathetic activity provides a detailed characterization of underlying neural regulation not obvious from multi-unit recordings. However, caution must be taken in interpreting these results as this reductionist approach may be intrinsically limited in the information which it provides. A clear example of this is the data presented in Table 2 (Ashley et al. 2010). In isolation, firing probability was elevated similarly in both OSA and COPD patients. Yet, when burst incidence is also considered, the increase in firing probability in OSA patients is even more striking (i.e. a given neurone is more active with respect to the background level of activity). By contrasting burst incidence and action potential firing probability the authors also indirectly demonstrate: (a) independent activation of separate populations of neurones (i.e. a given neurone fires in only 47–66% of bursts) and (b) that increased action potential firing probability is not a fixed function of increased burst incidence, such that the ability to recruit populations of neurones is likely to differ with certain pathologies. Thus the power of the single-unit approach is its potential to complement and extend our understanding of sympathetic neural regulation. If integrated sympathetic nerve activity and single-unit unit firing characteristics represent differing aspects of central sympathetic control, then it is yet to be determined if the unitary firing characteristics in pathological states are also corrected by treatments known to influence measures of integrated sympathetic activity (i.e. CPAP therapy in OSA patients) or whether there is a more fundamental change in sympathetic regulation in these patients. In the context of the study by Ashley et al. (2010), a description of the relationship between subject specific chemosensitivity and the firing probability of vasomotor neurones in healthy and pathological populations is currently lacking from the literature. These data could help determine the role of chemosensitivity and chemoreflex-mediated excitation in increased sympathetic drive. Nonetheless, the data presented by Ashley et al. (2010) clearly demonstrate heightened sympathetic drive in COPD patients and altered single-unit vasomotor firing characteristics not evident from integrated recordings. How these differences in neural regulation impact on the broader cardiovascular health of COPD patients is yet to be determined. The author would like to acknowledge Dr J. Kevin Shoemaker for his supervision and Dr Gary J. Hodges for his critical review of the manuscript. The author is funded by a NSERC CGS Doctoral Scholarship. Due to the abbreviated Journal Club format the author regretfully omits reference to other important work in the area of single-unit sympathetic recordings.

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