Circulating blood levels of catecholamines

The original standard for measuring sympathetic activity involved the measurement of circulating catecholamines. Epinephrine serves as a measure of sympathoadrenal activation, but since epinephrine functions primarily as a hormone circulating throughout the cardiovascular system to have wide-ranging effects at multiple sites, it does not serve well as a measure of sympathetic neural activity. Norepinephrine (NE) is the primary neurotransmitter at sympathetic nerve terminals and is released in proportion to the neural activity. Deactivation of norepinephrine primarily involves reuptake into nerve terminals and other non-neuronal cells in the region; however, a portion of the norepinephrine released at sympathetic nerve terminals spills over into the vascular bed and determines the circulating concentration within the plasma. Therefore, venous samples of norepinephrine from a given vein represent the global sympathetic activity specific to the tissues from that vein, combined with the background level of overall sympathetic activity within the system. Consequently, it is at best a ‘ball park’ measure of sympathetic activity. Nevertheless, changes in peripheral venous norepinephrine concentrations do reflect changes associated with changes in sympathetic activation accompanying physical or mental stress, pain, reflex responses, and other modulatory inputs (Esler et al. 1990, Goldstein 1995). Alternatively, a central venous sample from a great vein (superior or inferior vena cava or right atrium) provides a true mixed venous sample representing activity throughout the system. This is a better measure than a peripheral venous sample, but it is also more invasive and lacks specificity with respect to the target tissues. A peripheral arterial sample provides a similar measure of general sympathetic activity under most circumstances; however, it requires arterial cannulation and the associated increased risk and discomfort.

An alternative measure of sympathetic activity from plasma samples is the norepinephrine spillover technique (Goldstein 1995). This involves the infusion of a known amount of tritiated norepinephrine into a peripheral artery and sampling from the associated regional vein. Assessment of the ratio of tritiated to non-tritiated NE and blood flow rate allows an estimation of the spillover rate of NE from the nerve terminals in this particular vascular bed. This is a more accurate measure of regional sympathetic activity than a venous sample.

Using blood samples to assess the effects of manual medicine on sympathetic activity is a practical option if the goal is to determine the longer-term (minutes to hours) steady-state effects of a given therapy. It can also have some value when making comparisons across days if care is taken to establish a basal state when the measures are obtained. Mixed venous samples are preferred; however, peripheral samples from the arm can be used with most applications as long as the arm is not stressed (e.g., exercise or temperature fluxes). If the effect of a treatment on a regional tissue is to be studied, the norepinephrine spillover can be used if venous and arterial sampling can be achieved for that region.

Skin physiology

Several different techniques can be used to assess skin physiology based on measuring changes in either skin blood flow or sweat rate (Lima & Bakker 2005, Rossi et al. 2006). The traditional measurement of a galvanic skin response or skin conductance is reflective of sweat gland activity and the associated sympathetic nerve activity controlling these sweat responses (Rossi et al. 2006). The standard measurement of skin blood flow uses laser Doppler technology and is very sensitive to small changes in superficial blood flow (Lima & Bakker 2005, Rossi et al. 2006). Each of these measures is limited by the fact that basal quantization cannot be readily compared across measurement sites or between individuals. Therefore, they are used primarily to assess responses to a given intervention. Although these measures have been used in manual medicine research as noted below, for most applications their utility is limited by the physiological nature of the responses. Changes in skin blood flow and sweat rate are predominantly under the control of thermoregulatory mechanisms or as part of a psychological response. In some regions of the body there may be local reflex responses; however, the physiological purposes of these responses are unclear and thus, the utility of these measurements is equally uncertain. Further investigations into the meaning and utility of changes in skin conductance or blood flow associated with regional manipulative treatments merits consideration.

Microneurography (directly measured sympathetic activity)

Directly measured efferent sympathetic nerve activity can be obtained for sympathetic nerves that innervate either the skin or muscle vascular beds of the leg or arm (Grassi & Esler 1999, Mancia & Grassi 1991, Wallin 1984). These measures are most commonly obtained at the peroneal nerve (at either the fibular head or the popliteal fossa), but are also obtained from the radial or ulnar nerves. The recordings are from unmyelinated fibers that have burst patterns which are distinctive for the skin efferent and muscle efferent nerves; thus, recordings can be obtained that are specific to the type of fiber that is desired. The nerve is identified via surface stimulation and then a microelectrode similar to an acupuncture needle is inserted percutaneously into the nerve and advanced and adjusted until an acceptable recording is obtained. The integrated activity and frequency of sympathetic bursts are used to quantify the sympathetic activity from a given recording. The recording is a multiunit recording (multiple postganglionic axons), therefore, all quantization involving the activity must be normalized to either a maximum response (such as during a cold pressor stimulus) or a controlled baseline period.

The measurement of skin sympathetic activity is limited for the same reasons as those described for the measures of skin blood flow and sweat rate: it is responsive primarily to thermoregulatory and emotional stimuli. On the other hand, muscle sympathetic nerve activity tends to respond in parallel to other branches of the sympathetic nervous system, such as cardiac and renal, when provoked by stressors. Thus, it can be used as a ‘global’ index of sympathetic activity.

The use of microneurography for investigations involving manual medicine can be quite limited owing to the sensitivity of the recording to movement. The subject or patient must remain relatively still and cannot move the limb from which the recording is obtained. Thus, the types of manipulative intervention that can be assessed are limited. One approach to circumvent this limitation is to obtain recordings before and after a treatment; however, this is also limited by the inherent challenges of obtaining a recording. If this approach is used, only the burst frequency can be used to quantify the sympathetic activity, because the signal from different recording sites cannot be compared owing to the differing ‘quality’ of the multiunit recordings from different sites. Similarly, if a recording is lost and then re-obtained, only the burst frequency can be compared, or the change in total activity in response to an intervention.