The neurophysiological basis of the divergent sympathetic responses to long-lasting experimental muscle pain in humans

It is known that some individuals with chronic pain go on to develop high blood pressure. Indeed, patients with post-surgical chronic pain have nearly twice the prevalence of clinical hypertension than medical patients without pain (Bruehl, Chung, Jirjis, & Biridepalli, 2005). Accordingly, we could postulate that a person who consistently exhibited increases in muscle sympathetic nerve activity (MSNA), blood pressure and heart rate during experimental muscle pain may – if he or she developed chronic pain from an injury in the future – go on to develop hypertension (Bruehl et al., 2005). Interestingly, long-lasting experimental muscle pain induced by hypertonic saline solution in humans causes a sustained and consistent increase in muscle vasoconstrictor drive and blood pressure in some subjects, and a sustained decrease in others (Fazalbhoy, Birznieks, & Macefield, 2012, 2014). To further our understanding of the complex physiological changes that bring about these divergent responses, this thesis has explored the association of baseline physiological and psychological levels with the direction of the sympathetic response during tonic muscle pain. Furthermore, this project included combined microneurography and neuroimaging techniques to identify areas of the brain involved in generating sustained increases or decreases in sympathetic nerve activity to muscle, as well as changes in the brain associated with the generation of MSNA bursts during experimental muscle pain. The final chapter explored the effects of an audio-visual stimulus on the direction of the response. The results reported in this thesis highlight the fact that the muscle sympathetic responses to experimental muscle pain are not based on baseline physiological or psychological parameters but are associated with different signal intensity changes in important autonomic brain regions. Furthermore, distraction from the painful stimulus through audio-visual distraction does not influence the direction of the response. While this series of experiments has shed light on the neurophysiological mechanism through which the divergent sympathetic response to experimental muscle pain arises, many questions remain to be answered. For instance, it is unknown why such divergent responses would occur in humans. Furthermore, whether these responses remain sustained over a longer period of time needs to be determined

Inter-Individual Responses to Experimental Muscle Pain: Baseline Physiological Parameters Do Not Determine Whether Muscle Sympathetic Nerve Activity Increases or Decreases During Pain

We have previously reported that there are inter-individual differences in the cardiovascular responses to experimental muscle pain, which are consistent over time: intramuscular infusion of hypertonic saline, causing pain lasting ~60 minutes, increases muscle sympathetic nerve activity (MSNA) - as well as blood pressure and heart rate - in certain subjects, but decrease it in others. Here, we tested the hypothesis that baseline physiological parameters (resting MSNA, heart rate, blood pressure, heart rate variability) determine the cardiovascular responses to long-lasting muscle pain. MSNA was recorded from the common peroneal nerve, together with heart rate and blood pressure, during a 45-minute intramuscular infusion of hypertonic saline solution into the tibialis anterior of 50 awake human subjects (25 females and 25 males). Twenty-four subjects showed a sustained increase in mean amplitude of MSNA (160.9 ± 7.3 %), while 26 showed a sustained decrease (55.1 ± 3.5 %). Between the increasing and decreasing groups there were no differences in baseline MSNA (19.0 ± 1.5 vs 18.9 ± 1.2 bursts/min), mean BP (88.1 ± 5.2 vs 88.0 ± 3.8 mmHg), HR (74.7 ± 2.0 vs 72.8 ± 1.8 beats/min) or heart rate variability (LF/HF 1.8 ± 0.2 vs 2.2 ± 0.3). Furthermore, neither sex nor body mass index had any effect on whether MSNA increased or decreased during tonic muscle pain. We conclude that the measured baseline physiological parameters cannot account for the divergent sympathetic responses during tonic muscle pai

Resting regional brain activity and connectivity vary with resting blood pressure but not muscle sympathetic nerve activity in normotensive humans : an exploratory study

Blood pressure is tightly controlled by the central nervous system, particularly the brainstem. The aim of this study was to investigate the relationship between mean blood pressure (MBP), muscle sympathetic nerve activity (MSNA) and resting regional brain activity in healthy human subjects. Pseudocontinuous arterial spin labeling and functional magnetic resonance imaging of the brain were performed immediately following a laboratory microneurography recording of MSNA and BP measurement in 31 young, healthy normotensive subjects. Regional cerebral blood flow (CBF) correlated significantly with resting MBP levels in the region encompassing the rostroventrolateral medulla (RVLM), dorsolateral pons, and insular, prefrontal and cingulate cortices. Functional connectivity analysis revealed that the ventrolateral prefrontal cortex displayed greater resting connectivity strength within the RVLM in the lower compared with the higher MBP group. No significant differences in CBF were found when subjects were divided based on their MSNA levels. These results suggest that even subtle differences in resting MBP are associated with significant differences in resting activity in brain regions, which are well known to play a role in cardiovascular function. These data raise the question of the potential long-term consequences of differences in regional brain activity levels and their relationship with systemic blood pressure

Summary of Prime/Boost Immunizations with Truncated MSP1-42 (Construct 33-I) and Full Length MSP1-42s.

<p>Summary of Prime/Boost Immunizations with Truncated MSP1-42 (Construct 33-I) and Full Length MSP1-42s.</p

Inter-individual responses to experimental muscle pain : baseline anxiety ratings and attitudes to pain do not determine the direction of the sympathetic response to tonic muscle pain in humans

We have recently shown that intramuscular infusion of hypertonic saline, causing pain lasting ~. 60. min, increases muscle sympathetic nerve activity (MSNA) in one group of subjects, yet decreases it in another. Across subjects these divergent sympathetic responses to long-lasting muscle pain are consistent over time and cannot be foreseen on the basis of baseline MSNA, blood pressure, heart rate or sex. We predicted that differences in anxiety or attitudes to pain may account for these differences. Psychometric measures were assessed prior to the induction of pain using the State and Trait Anxiety Inventory (STAI), Pain Vigilance and Awareness Questionnaire (PVAQ), Pain Anxiety Symptoms Scale (PASS) and Pain Catastrophising Scale (PCS); PCS was also administered after the experiment. MSNA was recorded from the common peroneal nerve, before and during a 45-minute intramuscular infusion of hypertonic saline solution into the tibialis anterior muscle of 66 awake human subjects. Forty-one subjects showed an increase in mean burst amplitude of MSNA (172.8. ±. 10.6%) while 25 showed a decrease (69.9. ±. 3.8%). None of the measured psychological parameters showed significant differences between the increasing and the decreasing groups. We conclude that inter-individual anxiety or pain attitudes do not determine whether MSNA increases or decreases during long-lasting experimental muscle pain in healthy human subjects

Antibody responses against MSP1-19 and antigen-specific T cell responses in reciprocal prime/boost immunizations in SW mice.

<p>Panel A, antibody titers of mice primed with Construct 33-I and boosted with MSP1-42; and antibody titers of mice primed with MSP1-42 and boosted with Construct 33-I. Filled circles represent the experimental groups with Construct 33-I. Open circles represent the control groups. The percent (%) of animals responding is shown above for each immunization group. Results of secondary bleeds are presented. Horizontal bars indicate mean antibody titers. Antibody titers were determined and analyzed for each individual responding animal. Panel B, antigen specific T cell responses as determined by ELISPOTs. IL-4/IFN-γ responses in mice primed with Construct 33-I, then boosted with MSP1-42; and IL-4/IFN-γ responses in mice primed with MSP1-42, then boosted with Construct 33-I. Asterisks indicate a significant difference between groups by the Mann-Whitney test; 33-I×33-I versus 33-I×MSP1-42 for IL-4 (<i>p = </i>0.0476) and IFN-γ (<i>p</i> = 0.0077). Filled circles represent the experimental groups with Construct 33-I. Open circles represent the control groups. The horizontal line in each bar indicates the mean SFU.</p

The effects of audiovisual distraction on the muscle sympathetic responses to experimental muscle pain

Pain elicited by intramuscular infusion of hypertonic saline solution causes muscle sympathetic nerve activity (MSNA) to increase in some subjects, yet decrease in others. Although the direction of the response is not predictable based on baseline physiological and psychological parameters, we know that it results from sustained functional changes in specific brain regions that are responsible for the behavioral and cardiovascular responses to psychological stressors, as well as those involved in attention. The aim of this study was to investigate whether MSNA responses to experimental muscle pain in humans could be altered with an audiovisual stimulus that served to distract them from the pain. MSNA was recorded from the left common peroneal nerve of 20 young healthy individuals during a 45-min intramuscular infusion of hypertonic saline solution into the ipsilateral tibialis anterior muscle. The distracting stimulus commenced 15 min after the start of the infusion and lasted for 15 min. Fifteen subjects showed an increase in mean burst amplitude of MSNA (to 176.4 ± 7.9% of baseline), while five showed a decrease (to 73.1 ± 5.2% of baseline); distraction had no effect on these profiles. These results indicate that even though the subjects were attending to the audiovisual stimulus, and were presumably distracted from the pain, it failed to alter the MSNA responses to muscle pain

Aligned amino acid sequences of the truncated MSP1-42 protein, Construct 33-I, compared to full length MSP1-42.

<p>Sequences shown are for the N- terminal MSP1-33 fragment. All proteins contain the MSP1-19 fragment (not shown) at the C-terminal end. Amino acid sequences of the two dimorphic alleles of MSP1-42, represented by the FUP (MAD 20 equivalent) and the FVO (K1 equivalent) strains, are also shown.</p

Muscle sympathetic nerve activity-coupled changes in brain activity during sustained muscle pain

Introduction: Long-lasting experimental muscle pain elicits divergent muscle sympathetic responses, with some individuals exhibiting a persistent increase in muscle sympathetic nerve activity (MSNA), and others a decrease. These divergent responses are thought to result from sustained functional changes in specific brain regions that modulate the cardiovascular responses to pain. Aim: The aim of this study was to investigate brain regions that are functionally coupled to the generation of an MSNA burst at rest and to determine their behavior during tonic muscle pain. Methods: Functional magnetic resonance imaging of the brain was performed concurrently with microelectrode recording of MSNA from the common peroneal nerve during a 40 min infusion of hypertonic saline into the ipsilateral tibialis anterior muscle of 37 healthy human subjects. Results: At rest, blood oxygen level-dependent signal intensity coupled to bursts of MSNA increased in the rostral ventrolateral medulla, insula, dorsolateral prefrontal cortex, posterior cingulate cortex, and precuneus and decreased in the region of the midbrain periaqueductal gray. During pain, MSNA-coupled signal intensity was greater in the region of the nucleus tractus solitarius, midbrain periaqueductal gray, dorsolateral prefrontal, medial prefrontal, and anterior cingulate cortices, than at rest. Conversely, MSNA-coupled signal intensity decreased during pain in parts of the prefrontal cortex. Conclusions: These results suggest that multiple brain regions are recruited in a burst-to- burst manner, and the magnitude of these signal changes is correlated to the overall change in MSNA amplitude during tonic muscle pain

Obstructive sleep apnoea and 12-month weight loss in adults with class 3 obesity attending a multidisciplinary weight management program.

BACKGROUND Although there is a strong association between obesity and obstructive sleep apnoea (OSA), the effects of OSA and CPAP therapy on weight loss are less well known. The aim of this study in adults with class 3 obesity attending a multidisciplinary weight management program was to assess the relationship between OSA and CPAP usage, and 12-month weight change. METHODS A retrospective cohort study of all patients commencing an intensive multidisciplinary publicly funded weight management program in Sydney, Australia, between March 2018 and March 2019. OSA was diagnosed using laboratory overnight sleep studies. Demographic and clinical data, and use of CPAP therapy was collected at baseline and 12 months. CPAP use was confirmed if used ≥4 h on average per night on download. RESULTS Of the 178 patients who joined the program, 111 (62.4 %) completed 12 months in the program. At baseline, 63.1 % (n=70) of patients had OSA, of whom 54.3 % (n=38) were using CPAP. The non-OSA group had more females compared to the OSA with CPAP group and OSA without CPAP group (90.2 % vs. 57.9 % and 62.5 %, respectively; p=0.003), but there were no significant baseline differences in BMI (50.4±9.3 vs. 52.1±8.7 and 50.3±9.5 kg/m, respectively; p=0.636). There was significant weight loss across all three groups at 12 months. However, there were no statistically significant differences across groups in the percentage of body weight loss (OSA with CPAP: 6.3±5.6 %, OSA without CPAP: 6.8±6.9 %, non-OSA: 7.2±6.5 %; p=0.844), or the proportion of patients who achieved ≥5 % body weight loss (OSA with CPAP: 57.9 %, OSA without CPAP: 59.4 %, non-OSA: 65.9 %; p=0.743). In patients with T2DM, there was a significant reduction in HbA1c from baseline to 12 months (7.8±1.7 % to 7.3±1.4 %, p=0.03), with no difference between groups (p=0.997). CONCLUSIONS This multidisciplinary weight management program resulted in significant weight loss at 12 months, regardless of OSA diagnosis or CPAP use in adults with class 3 obesity. Larger studies are needed to further investigate the effects of severity of OSA status and CPAP use in weight management programs. Until completed, this study suggests that the focus should remain on implementing lifestyle changes and weight management regardless of OSA status