Articular inflammation is a major clinical burden in multiple inflammatory diseases, especially in rheumatoid arthritis. Biological anti-rheumatic drug therapies are expensive and increase the risk of systemic immunosuppression, infections, and malignancies. Here, we report that vagus nerve stimulation controls arthritic joint inflammation by inducing local regulation of innate immune response. Most of the previous studies of neuromodulation focused on vagal regulation of inflammation via the efferent peripheral pathway toward the viscera. Here, we report that vagal stimulation modulates arthritic joint inflammation through a novel "afferent" pathway mediated by the locus coeruleus (LC) of the central nervous system. Afferent vagal stimulation activates two sympatho-excitatory brain areas: the paraventricular hypothalamic nucleus (PVN) and the LC. The integrity of the LC, but not that of the PVN, is critical for vagal control of arthritic joint inflammation. Afferent vagal stimulation suppresses articular inflammation in the ipsilateral, but not in the contralateral knee to the hemispheric LC lesion. Central stimulation is followed by subsequent activation of joint sympathetic nerve terminals inducing articular norepinephrine release. Selective adrenergic beta-blockers prevent the effects of articular norepinephrine and thereby abrogate vagal control of arthritic joint inflammation. These results reveals a novel neuro-immune brain map with afferent vagal signals controlling side-specific articular inflammation through specific inflammatory-processing brain centers and joint sympathetic innervations.

The heart rate variability analysis could be used as a complementary non-invasive tool for the early diagnosis and better prognosis of autonomic dysfunction, and survival in BC patients. There are many potential clinical applications of heart rate variability analysis in BC patients, and the employment of such approaches could lead to lower impairment of autonomic function in this individuals.

Frailty has been defined as a geriatric syndrome that results in high vulnerability to health adverse outcomes. This increased vulnerability state results from dysregulation of multiple physiological systems and its complex interactions. Thus, assessment of physiological systems integrity and of its dynamic interactions seems to be useful in the context of frailty management. Heart rate variability (HRV) analysis provides information about autonomic nervous system (ANS) function, which is responsible to control several physiologic functions. This study investigated the cardiac autonomic modulation by HRV analysis in community-dwelling elderly women classified as non-frail, pre-frail and frail. Twenty-three elderly women were assigned to the following groups: non-frail (n = 8), pre-frail (n = 8) and frail (n = 7). HRV assessment was performed through linear and non-linear analysis of cardiac interval variability. It was observed a higher sympathetic and lower parasympathetic modulation in frail when compared with non-frail and pre-frail groups (p < 0.05) as indicated by frequency domain indices. Additionally, frail group had a decreased 2LV % pattern (that reflects parasympathetic modulation) in the symbolic analysis in comparison with non-frail group. These findings suggest that frail elderly women present an autonomic imbalance characterized by a shift towards sympathetic predominance. Thus, monitoring ANS function in the context of frailty management may be an important strategy to prevention, diagnosis and treatment of this syndrome and its consequences.

The baroreflex is a critical physiological mechanism controlling cardiovascular function by modulating both the sympathetic and parasympathetic activities. Here, we report that electrical activation of the baroreflex attenuates joint inflammation in experimental arthritis induced by the administration of zymosan into the femorotibial cavity. Baroreflex activation combined with lumbar sympathectomy, adrenalectomy, celiac subdiaphragmatic vagotomy or splenectomy dissected the mechanisms involved in the inflammatory modulation, highlighting the role played by sympathetic inhibition in the attenuation of joint inflammation. From the immunological standpoint, baroreflex activation attenuates neutrophil migration and the synovial levels of inflammatory cytokines including TNF, IL-1β and IL-6, but does not affect the levels of the anti-inflammatory cytokine IL-10. The anti-inflammatory effects of the baroreflex system are not mediated by IL-10, the vagus nerve, adrenal glands or the spleen, but by the inhibition of the sympathetic drive to the knee. These results reveal a novel physiological neuronal network controlling peripheral local inflammation.

Electrical carotid baroreflex activation has been used to treat patients with resistant hypertension. It is hypothesized that, in conscious rats, combined activation of carotid baro- and chemoreceptors afferences attenuates the reflex hypotension. Rats were divided into 4 groups: 1) control group, with unilateral denervation of the right carotid chemoreceptors; 2) chemoreceptor denervation group, with bilateral ligation of the carotid body artery; 3) baroreceptor denervation group, with unilateral denervation of the left carotid baroreceptors and right carotid chemoreceptors; 4) carotid bifurcation denervation group, with denervation of the left carotid baroreceptors and chemoreceptors, plus denervation of the right carotid chemoreceptors. Animals were subjected to 4 rounds of electrical stimulation (5 V, 1 ms), with 15 Hz, 30 Hz, 60 Hz, and 90 Hz applied randomly for 20 s. Electrical stimulation caused greater hypotensive responses in the chemoreceptor denervation group than in the control group, at 60 Hz (−37 mmHg vs −19 mmHg) and 90 Hz (−33 mmHg vs −19 mmHg). The baroreceptor denervation group showed hypertensive responses at all frequencies of stimulation. In contrast, the carotid sinus denervation group showed no hemodynamic responses. The control group presented no changes in heart rate, whereas the chemoreceptor denervation group and the baroreceptor denervation group showed bradycardic responses. These data demonstrate that carotid chemoreceptor activation attenuates the reflex hypotension caused by combined electrical stimulation of the carotid sinus and the carotid sinus nerve in conscious rats. These findings may provide useful insight for clinical studies using Baroreflex Activation Therapy in resistant hypertension and/or heart failure.

We previously reported that activation of the baroreflex, a critical physiological mechanism controlling cardiovascular homeostasis, through electrical stimulation of the aortic depressor nerve attenuates joint inflammation in experimental arthritis. However, it is unknown whether baroreflex activation can control systemic inflammation. Here, we investigate whether baroreflex activation controls systemic inflammation in conscious endotoxemic rats. Animals underwent sham or electrical aortic depressor nerve stimulation initiated 10 min prior to a lipopolysaccharide (LPS) challenge, while inflammatory cytokine levels were measured in the blood, spleen, heart and hypothalamus 90 min after LPS treatment. Baroreflex activation did not affect LPS-induced levels of pro-inflammatory (tumor necrosis factor, interleukin 1β and interleukin 6) or anti-inflammatory (interleukin 10) cytokines in the periphery (heart, spleen and blood). However, baroreflex stimulation attenuated LPS-induced levels of all these cytokines in the hypothalamus. Notably, these results indicate that the central anti-inflammatory mechanism induced by baroreflex stimulation is independent of cardiovascular alterations, since aortic depressor nerve stimulation that failed to induce hemodynamic changes was also efficient at inhibiting inflammatory cytokines in the hypothalamus. Thus, aortic depressor nerve stimulation might represent a novel therapeutic strategy for neuroprotection, modulating inflammation in the central nervous system.

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Fibromyalgia (FM) is characterized by chronic non-inflammatory widespread pain (CWP) and changes in sympathetic function. In attempt to elucidate the pathophysiological mechanisms of FM we used a well-established CWP animal model. We aimed to evaluate changes in cardiac autonomic balance and baroreflex function in response to CWP induction in rats. CWP was induced by two injections of acidic saline (pH 4.0, n=8) five days apart into the left gastrocnemius muscle. Control animals were injected twice with normal saline (pH 7.2, n=6). One day after the second injection of acidic saline or normal saline, the animals had pulse interval (PI) and systolic arterial pressure (SAP) variability, and spontaneous baroreflex sensitivity (BRS) evaluated. After induction of CWP, there was an increase of power in the low frequency (LF) band of PI spectrum (12.75 ± 1.04 nu), a decrease in the high frequency (HF) band (87.25 ± 1.04 nu) and an increase of LF/HF ratio (0.16 ± 0.01), when compared to control animals (7.83 ± 1.13 nu LF; 92.16 ± 1.13 nu HF; 0.08 ± 0.01 LF/HF). In addition, there was an increase of power in the LF band of SAP spectrum (7.93 ± 1.39 mmHg2) when compared to control animals (2.97 ± 0.61 mmHg2). BRS was lower in acidic saline injected rats (0.59 ± 0.06 ms/mmHg) when compared to control animals (0.71 ± 0.03 ms/mmHg). Our results showed that induction of CWP in rats shifts cardiac sympathovagal balance towards sympathetic predominance and decreases BRS. These data corroborate findings in humans with FM.