Vagal nerve activity moderates brain-immune relationships and is measured by heart rate variability

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 Brain-immune interactions control inflammation and the response to stress. An exciting study with tremendous practical significance was just published in the Journal of Neuroimmunology that shows how vagal nerve activity, which can be measured in the clinic by heart rate variability analysis (HRV), is a key moderator of the brain-immune web and determines the immune and physiological responses to acute stress. Highlights include:

  • Vagal tone indexed by heart rate variability reflects biological regulatory capacity.
  • Vagal tone is linked with flexible immune and physiological stress responses.
  • Frontal-striatal network mediates effects of vagal tone on stress responses.

Journal of NeuroimmunologyThe authors note:

“The bidirectional communication between the immune and nervous systems is considered to involve neural pathways that link these systems and expression of receptors for ligands such as cytokines and neurotransmitters. The brain produces immune-regulatory effects, and immunity has sensory functions (Haddad, 2008). Specifically, descending neural influences on immunity include neural innervation of lymphatic organs (Madden et al., 1995), expression of receptors for neurotransmitters on immune cells (Levite, 2008; Tracey, 2009) and differential left versus right hemisphere influences on immunity (Davidson et al., 1999; Sumner et al., 2011). Ascending immune-to-brain pathways include immune signals entering brain regions that lack a blood-brain barrier (BBB), prostaglandins on both sides of the BBB that mediate inflammatory signals, and an immune-to-brain conversion of inflammatory information by the vagus nerve (Ek et al., 1998; Dantzer et al., 2000; Davidson et al., 2001; Tracey, 2009).”

Fortunately there is increasing interest in understanding the brain-immune web and how the brain modulates the immune system during acute stress. Earlier studies have shown that the brain regions involved in executive functions and stress coping also modulate adaptive immune activities, and are responsible for making the physiological response to stress flexible and appropriate. The authors observe:

“Such associations between the neural and immune systems may depend on and be affected by a third variable, relevant to both systems, specifically tonic activity of the vagus nerve (Thayer and Sternberg, 2010). The vagus nerve expresses receptors for interleukin-1, enabling it to convert immune to nerve information via ascending acetylcholine signals to the brain stem (Ek et al., 1998). In return, the descending vagus modulates the activity of peripheral leukocytes and inflammation via the HPA axis and neural routes that inhibit cytokine production by macrophages (Tracey, 2009). Importantly, brain regions regulating activity of the vagus nerve partly overlap with brain regions involved in immune regulation, including the medial prefrontal cortex (MPFC) and DLPFC (Lane et al., 2009; Ohira et al., 2009). Given the strategic location of the vagus nerve mediating between the periphery and the brain and given its neuroimmunomodulatory roles, we hypothesized that tonic activity of the vagus nerve, indexed by heart rate variability (HRV) in a resting state, moderates transient brain–immune relationships accompanying acute stress.”


“…it was previously reported that individuals with a higher resting HRV showed faster recovery in their acute stress responses of immune, neuroendocrine, and cardiovascular parameters (Weber et al., 2010). These data suggest that higher resting HRV is associated with context-appropriate responses including adaptive recovery after termination of stress, and that the autonomic and endocrine systems mediate the associations between brain and immunity.”

Correlations between regional cerebral blood flow with proportion of natural killer cells and concentration of adrenocorticotropic hormone in high heart rate variability group.

Correlations between regional cerebral blood flow with proportion of natural killer cells and concentration of adrenocorticotropic hormone in high heart rate variability group.

So they set out to investigate whether vagus nerve activity as measured by HRV modulates brain-immune associations including the autonomic nervous system and endocrine (HPA) responses to acute stress. They subjected their study subjects to a learning task that has been proven to psychological and physiological stress and serve as a valid acute stressor for study purposes. The participants underwent PET scans of the brain, had blood sampled after each stress for the ratio of NK cells (natural killer cells) and helper T cells, and amounts of norepinephrine as an index of sympathetic activity and ACTH as an index of endocrine (HPA) activity. Their findings are fascinating:

“There were two main findings of the present study. First, low tonic vagal activity (low resting HRV) was associated with blunted responses in NK cells, norepinephrine, and ACTH to an acute stressor, whereas high tonic vagal activity (high resting HRV) was associated with more sensitive responses in those physiological parameters. Second, low and high tonic vagal activity was related to a qualitatively different neural matrix associated with immune, sympathetic, and endocrine changes. While low HRV participants showed only a correlation between ACTH and activity in the VLPFC, high HRV participants showed stronger associations between their brain activities and NK cells and ACTH. Specifically, in the high HRV participants, NK cell proportions were correlated with activity in the rostral ACC which is a portion of the MPFC and the dorsal striatum (nucleus caudate). The ACTH levels of the high HRV participants correlated with activation in the insula, OFC, cerebellum, and dorsal ACC. To the best of our knowledge, this is the first study to demonstrate that tonic vagal activity moderates brain–immune and brain–neuroendocrine associations accompanying acute stress.”

They discuss some of the important implications of their findings:

“Importantly, we observed that high HRV participants showed…associations between NK cell proportions and activity in [several brain regions]…By contrast, in low HRV participants, NK cell proportions showed no correlation with brain activity. These findings suggest that in individuals with high tonic vagal activity, immune responses to stress are associated with a higher and more complex regulatory neural network that…may enable regulation of NK-cell responses.”


“The observation that individuals with high HRV initially showed a reduced NK cell response to an ongoing stressor during the initial learning task suggests that high HRV reflects the ability to habituate to stress. This is consistent with a previous finding by Weber et al. (2010) indicating that individuals with high HRV recovered cardiovascular, endocrine, and immune responses more rapidly after termination of an acute stressor than individuals with low HRV…By contrast, low HRV individuals demonstrated blunted immune, sympathetic, and endocrine reactivity to the stressor. These data suggest a greater physiological adaptability of in high HRV individuals and a potential moderating role of the vagus nerve in neuroimmuno-endocrine responses to stress.”

It was a similar story for the excitatory neurotransmitter norepinephrine:

Changes of norepinephrine due to stress showed a similar pattern to that in NK cells, with an initial decrease followed by increase after reversal of contingency between options and outcomes in the high HRV group, compared to a more blunted reactivity in the low HRV group.”

And for ACTH (adrenocorticotrophic hormone produced in the pituitary that stimulates adrenal production of cortisol):

Values of ACTH showed a continuous decrease in the high HRV group, reflecting a habituation process, but not in the low HRV group.”

For clinicians reading this who wisely do HRV assessments in their practice:

“…rating of subjective stress at baseline (before measurement of baseline HRV) did not differ between the low and high HRV groups. This suggest that baseline HRV, which was measured before the experimental procedure, might reflect the basic characteristics of an individuals’ vagal tone, rather than individual differences in phasic reactivity of HRV affected by anticipatory anxiety.”

In other words, this implies that heart rate variability assessments really does give us objective data about the patient’s vagal and parasympathetic resources. Other insights that emerge include:

low HRV participants had some impairment in the connections between the brain and peripheral physiology, with consequent differential patterns in physiological responses to the stressor…The high HRV group manifested greater sensitivity in their immune and physiological responses and greater association and possibly regullation by the brain over these responses. Although whether this is an adaptive response is an open question, it is possible that a high tonic vagal activity is a prerequisite for top-down rapid regulation of immune, autonomic, and endocrine responses to acute stress. By contrast, lower vagal activity may result in slower recovery (Weber et al., 2010) or lack of changes of immune responses to environmental challenges, possibly because of impairment in neuro-immune circuits.”

And regarding the premiere factor of inflammation:

An impaired regulation of immune responses can result in inflammation, which is etiologic to various chronic diseases, such as coronary-artery disease, cancer, and dementia, in which the vagus nerve was recently postulated to play a protective role via regulation of multiple basic processes (De Couck et al., 2012).”

Summing up their findings regarding vagal actvity as measured by HRV and the brain-immune response to stress:

“…our study revealed that tonic vagal nerve activity may be an important determinant of neuro- immune and neurophysiological associations and the regulation of the multisystem responses under acute stress.”

Since we can easily measure vagal (parasympathetic) tone in the clinic with HRV and we have sustainable interventions to increase vagal activity (BioCranial Therapy and many others), it’s hard to overemphasize the practical significance of this research.

Readers may also enjoy earlier posts on HRV including Nervous system regulation of inflammation, cytokines, and heart rate variability showing how vagal tone correlates with inflammatory cytokines in the bloodstream.

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