Central stress pathways in the development of cardiovascular disease.

PURPOSE: Mental stress is of essential consideration when assessing cardiovascular pathophysiology in all patient populations. Substantial evidence indicates associations among stress, cardiovascular disease and aberrant brain-body communication. However, our understanding of the flow of stress information in humans, is limited, despite the crucial insights this area may offer into future therapeutic targets for clinical intervention. METHODS: Key terms including mental stress, cardiovascular disease and central control, were searched in PubMed, ScienceDirect and Scopus databases. Articles indicative of heart rate and blood pressure regulation, or central control of cardiovascular disease through direct neural innervation of the cardiac, splanchnic and vascular regions were included. Focus on human neuroimaging research and the flow of stress information is described, before brain-body connectivity, via pre-motor brainstem intermediates is discussed. Lastly, we review current understandings of pathophysiological stress and cardiovascular disease aetiology. RESULTS: Structural and functional changes to corticolimbic circuitry encode stress information, integrated by the hypothalamus and amygdala. Pre-autonomic brain-body relays to brainstem and spinal cord nuclei establish dysautonomia and lead to alterations in baroreflex functioning, firing of the sympathetic fibres, cellular reuptake of norepinephrine and withdrawal of the parasympathetic reflex. The combined result is profoundly adrenergic and increases the likelihood of cardiac myopathy, arrhythmogenesis, coronary ischaemia, hypertension and the overall risk of future sudden stress-induced heart failure. CONCLUSIONS: There is undeniable support that mental stress contributes to the development of cardiovascular disease. The emerging accumulation of large-scale multimodal neuroimaging data analytics to assess this relationship promises exciting novel therapeutic targets for future cardiovascular disease detection and prevention.

Central mechanisms in sympathetic nervous dysregulation in obesity.

Cardiovascular and metabolic complications associated with excess adiposity are linked to chronic activation of the sympathetic nervous system, resulting in a high risk of mortality among obese individuals. Obesity-related positive energy balance underlies the progression of hypertension, end-organ damage, and insulin resistance, driven by increased sympathetic tone throughout the body. It is, therefore, important to understand the central network that drives and maintains sustained activation of the sympathetic nervous system in the obese state. Experimental and clinical studies have identified structural changes and altered dynamics in both grey and white matter regions in obesity. Aberrant activation in certain brain regions has been associated with altered reward circuitry and metabolic pathways including leptin and insulin signaling along with adiposity-driven systemic and central inflammation. The impact of these pathways on the brain via overactivity of the sympathetic nervous system has gained interest in the past decade. Primarily, the brainstem, hypothalamus, amygdala, hippocampus, and cortical structures including the insular, orbitofrontal, temporal, cingulate, and prefrontal cortices have been identified in this context. Although the central network involving these structures is much more intricate, this review highlights recent evidence identifying these regions in sympathetic overactivity in obesity.

Functional Connectivity Analysis of Transcutaneous Vagus Nerve Stimulation (tVNS) Using Magnetoencephalography (MEG).

Altered brain functional connectivity has been observed in conditions such as schizophrenia, dementia and depression and may represent a target for treatment. Transcutaneous vagus nerve stimulation (tVNS) is a form of non-invasive brain stimulation that is increasingly used in the treatment of a variety of health conditions. We previously combined tVNS with magnetoencephalography (MEG) and observed that various stimulation frequencies affected different brain areas in healthy individuals. We further investigated whether tVNS had an effect on functional connectivity with a focus on brain regions associated with mood. We compared functional connectivity (whole-head and region of interest) in response to four stimulation frequencies of tVNS using data collected from concurrent MEG and tVNS in 17 healthy participants using Weighted Phase Lag Index (WPLI) to calculate correlation between brain areas. Different frequencies of stimulation lead to changes in functional connectivity across multiple regions, notably areas linked to the default mode network (DMN), salience network (SN) and the central executive network (CEN). It was observed that tVNS delivered at a frequency of 24 Hz was the most effective in increasing functional connectivity between these areas and sub-networks in healthy participants. Our results indicate that tVNS can alter functional connectivity in regions that have been associated with mood and memory disorders. Varying the stimulation frequency led to alterations in different brain areas, which may suggest that personalized stimulation protocols can be developed for the targeted treatment of different medical conditions using tVNS.

Effect of Stimulation Current in Transcutaneous Vagus Nerve Stimulation (tVNS): A Study Using Concurrent Magnetoencephalography (MEG).

Transcutaneous vagus nerve stimulation (tVNS) is a non-invasive method of brain stimulation that has been investigated for its use in the clinical treatment of a number of different conditions. There has been little investigation into the stimulation current that is delivered and the effect on individual variability in response to tVNS.Seventeen participants underwent tVNS, and stimulation current was determined based on individual pain threshold. To investigate individual variability, brain dynamics were measured concurrently using magnetoencephalography (MEG) in response to two different stimulation protocols of tVNS. The first protocol consisted of a sequence of equally spaced short (1ms) stimulation pulses applied 24 times per second (24 Hz), and the second consisted of a sequence of 24 pulses per second spaced according to a 6 Hz pulse frequency modulation (PFM). Both stimulation sequences were delivered to the cymba concha in the left ear.The difference in brain responses to the two sequences was initially calculated using a one-sample t-test at the group level, based on z-scoring of the data at the individual level, and no statistically significant differences were observed. Further investigation of individual variability suggested that participants fell into two groups; one that responded more strongly to 24 Hz and one that responded more strongly to the irregular spacing of pulses in the PFM protocol.We tested whether the stimulation current that the participant received could predict how they would respond to the stimulation, but we did not observe any correlation. This supports the literature that suggests that selecting stimulation current based on individual pain threshold is a suitable procedure for tVNS, and higher stimulation intensities does not correspond to stronger brain response. Further investigation into individual variability in response to different frequencies and pulse spacing of tVNS should also be investigated further and may lead to the development of personalised stimulation protocols.Clinical relevance- The stimulation current at which tVNS is delivered does not appear to influence brain response to stimulation, and the value of stimulation current should be selected based on individual participant comfort.

Measuring brain response to transcutaneous vagus nerve stimulation (tVNS) using simultaneous magnetoencephalography (MEG).

Objective.Transcutaneous vagus nerve stimulation (tVNS) is a form of non-invasive brain stimulation that delivers a sequence of electrical pulses to the auricular branch of the vagus nerve and is used increasingly in the treatment of a number of health conditions such as epilepsy and depression. Recent research has focused on the efficacy of tVNS to treat different medical conditions, but there is little conclusive evidence concerning the optimal stimulation parameters. There are relatively few studies that have combined tVNS with a neuroimaging modality, and none that have attempted simultaneous magnetoencephalography (MEG) and tVNS due to the presence of large stimulation artifacts produced by the electrical stimulation which are many orders of magnitude larger than underlying brain activity.Approach.The aim of this study is to investigate the utility of MEG to gain insight into the regions of the brain most strongly influenced by tVNS and how variation of the stimulation parameters can affect this response in healthy participants.Main results.We have successfully demonstrated that MEG can be used to measure brain response to tVNS. We have also shown that varying the stimulation frequency can lead to a difference in brain response, with the brain also responding in different anatomical regions depending on the frequency.Significance.The main contribution of this paper is to demonstrate the feasibility of simultaneous pulsed tVNS and MEG recording, allowing direct investigation of the changes in brain activity that result from different stimulation parameters. This may lead to the development of customised therapeutic approaches for the targeted treatment of different conditions.

Critical Review of Transcutaneous Vagus Nerve Stimulation: Challenges for Translation to Clinical Practice.

Several studies have illustrated that transcutaneous vagus nerve stimulation (tVNS) can elicit therapeutic effects that are similar to those produced by its invasive counterpart, vagus nerve stimulation (VNS). VNS is an FDA-approved therapy for the treatment of both depression and epilepsy, but it is limited to the management of more severe, intervention-resistant cases as a second or third-line treatment option due to perioperative risks involved with device implantation. In contrast, tVNS is a non-invasive technique that involves the application of electrical currents through surface electrodes at select locations, most commonly targeting the auricular branch of the vagus nerve (ABVN) and the cervical branch of the vagus nerve in the neck. Although it has been shown that tVNS elicits hypo- and hyperactivation in various regions of the brain associated with anxiety and mood regulation, the mechanism of action and influence of stimulation parameters on clinical outcomes remains predominantly hypothetical. Suppositions are largely based on correlations between the neurobiology of the vagus nerve and its effects on neural activity. However, tVNS has also been investigated for several other disorders, including tinnitus, migraine and pain, by targeting the vagus nerve at sites in both the ear and the neck. As most of the described methods differ in the parameters and protocols applied, there is currently no firm evidence on the optimal location for tVNS or the stimulation parameters that provide the greatest therapeutic effects for a specific condition. This review presents the current status of tVNS with a focus on stimulation parameters, stimulation sites, and available devices. For tVNS to reach its full potential as a non-invasive and clinically relevant therapy, it is imperative that systematic studies be undertaken to reveal the mechanism of action and optimal stimulation modalities.