Expiratory-gated Transcutaneous Auricular Vagus Nerve Stimulation (taVNS) does not Further Augment Heart Rate Variability During Slow Breathing at 0.1 Hz.

As cardiac vagal control is a hallmark of good health and self-regulatory capacity, researchers are seeking ways to increase vagally mediated heart rate variability (vmHRV) in an accessible and non-invasive way. Findings with transcutaneous auricular vagus nerve stimulation (taVNS) have been disappointing in this respect, as its effects on vmHRV are inconsistent at best. It has been speculated that combining taVNS with other established ways to increase vmHRV may produce synergistic effects. To test this idea, the present study combined taVNS with slow breathing in a cross-over design. A total of 22 participants took part in two sessions of breathing at 6 breaths/min: once combined with taVNS, and once combined with sham stimulation. Electrical stimulation (100 Hz, 400 µs) was applied during expiration, either to the tragus and cavum conchae (taVNS) or to the earlobe (sham). ECG was recorded during baseline, 20-minutes of stimulation, and the recovery period. Frequentist and Bayesian analyses showed no effect of taVNS (in comparison to sham stimulation) on the root mean square of successive differences between normal heartbeats, mean inter-beat interval, or spectral power of heart rate variability at a breathing frequency of 0.1 Hz. These findings suggest that expiratory-gated taVNS combined with the stimulation parameters examined here does not produce acute effects on vmHRV during slow breathing.

Investigating the stress-related fluctuations of level of personality functioning: A critical review and agenda for future research.

The Diagnostic and Statistical Manual of Mental Disorders (DSM-5) and the International Classification of Diseases (ICD-11) proposed a dimensional approach to the assessment of personality disorders (PDs). Both models dictate that the clinician first determines PD severity before assessing maladaptive traits, invoking the level of personality functioning (LPF) construct. We consider LPF a promising dimensional construct for translational research because of its clinical importance and conceptual overlap with the Research Domain Criteria (RDoC) Social Processes. We aim to identify biomarkers that co-vary with fluctuations in LPF in adulthood, ultimately to predict persistent decrease in LPF, associated with suicidality and morbidity. However, a theoretical framework to investigate stress-related oscillations in LPF is currently missing. In this article, we aim to fill this hiatus with a critical review about stress and LPF. First, we discuss acute stress and LPF. We briefly present the basics of the neurophysiological stress response and review the literature on momentary and daily fluctuations in LPF, both at a subjective and physiological level. Second, we review the effects of chronic stress on brain function and social behaviour and recapitulate the main findings from prospective cohort studies. This review underlies our suggestions for multimethod assessment of stress-related oscillations in LPF and our theoretical framework for future longitudinal studies, in particular studies using the experience sampling method (ESM).

Worries and concerns of inflammatory bowel disease (IBD) patients in Belgium - a validation of the Dutch rating form.

OBJECTIVES: Worry is the most common psychological complaint among patients with Inflammatory Bowel Disease (IBD). This study aimed to translate and test the psychometric properties the Rating Form of IBD Patient Concerns (RFIPC) among Dutch-speaking patients with IBD in Belgium. It also aimed to describe worries and concerns, and to examine possible differences in worry patterns between patients with different disease types and disease activities. METHODS: The RFIPC was translated into Dutch following the guidelines of the Rome Foundation and was completed by patients with Crohn's disease (CD, n = 336) and ulcerative colitis (UC, n = 160). To test concurrent validity, the Depression Anxiety Stress Scales (DASS-21) were used. Factor structure was examined with confirmatory factor analysis. RESULTS: The four-factor structure including subscales 'impact of the disease', 'sexual intimacy', 'complications of the disease' and 'body stigma' was confirmed in the Dutch sample. All factors had high internal consistency (>.70). Correlations with DASS-21 suggest good concurrent validity, all rs>.30, ps<.001. No differences in the RFIPC scores were observed between patients with CD and UC. Patients with active disease (53%) had higher scores than patients in remission (47%). Across all groups, the order of top concerns was consistent and included worries about energy level, side effects of medication, having an ostomy bag/surgery, and uncertain nature of the disease. CONCLUSIONS: The Dutch version of the RFIPC is a valid and reliable measure of IBD-specific worries and concerns which can be used in both research and clinical settings.

Relationship Between Different Experimental Measures of Distorted Symptom Perception in Functional Syndrome Patients.

OBJECTIVE: Patients with functional somatic syndromes show reduced correspondence between induced physiological changes and self-reported symptoms in a rebreathing paradigm, as well as elevated symptoms unrelated to physiological changes after induction of negative affective states in an affective picture-viewing paradigm. Detailed results of both paradigms separately were published elsewhere. The main goal of the current report is to describe the relationship between the responses to these two paradigms measuring distortions in symptom perception in a well-described sample of patients with fibromyalgia and/or chronic fatigue syndrome. METHODS: Patients (N = 81) with fibromyalgia and/or chronic fatigue syndrome participated in a test session comprising four well-validated paradigms, including the picture-viewing and rebreathing paradigm. Using mixed model analyses, we tested whether the amount of affective modulation of symptom reporting was related to distorted perception of induced dyspnea. In an exploratory way, we assessed the role of several individual difference variables as moderators. RESULTS: There was no relationship between patients' amount of affective modulation of symptom reporting, as assessed with the picture paradigm, and level of distortion in dyspnea perception, as assessed with the rebreathing paradigm (effect of affective modulation in the subjective recovery from induced dyspnea: F1,70 = 0.16, p = .70; time by affective modulation interaction effect: F4,70 = 0.14, p = .97). CONCLUSIONS: Biased symptom reporting in one paradigm is unrelated to biased symptom reporting in the other paradigm, indicating that distortions in symptom perception in patients with functional somatic syndromes are not a trait-like, cross-situationally stable condition, but a versatile dysfunction that is context dependent.

Observing dyspnoea in others elicits dyspnoea, negative affect and brain responses.

Dyspnoea is usually caused by diagnosable cardiorespiratory mechanisms. However, frequently dyspnoea relates only weakly or not at all to cardiorespiratory functioning, suggesting that additional neuropsychosocial processes contribute to its experience. We tested whether the mere observation of dyspnoea in others constitutes such a process and would elicit dyspnoea, negative affect and increased brain responses in the observer.In three studies, series of pictures and videos were presented, which either depicted persons suffering from dyspnoea or nondyspnoeic control stimuli. Self-reports of dyspnoea and affective state were obtained in all studies. Additionally, respiratory variables and brain responses during picture viewing (late positive potentials in electroencephalograms) were measured in one study.In all studies, dyspnoea-related pictures and videos elicited mild-to-moderate dyspnoea and increased negative affect compared to control stimuli. This was paralleled by increased late positive potentials for dyspnoea-related pictures while respiratory variables did not change. Moreover, increased dyspnoea correlated modestly with higher levels of empathy in observers.The present results demonstrate that observing dyspnoea in others elicits mild-to-moderate dyspnoea, negative affect, and increased brain responses in the absence of respiratory changes. This vicarious dyspnoea has clinical relevance, as it might increase suffering in the family and medical caregivers of dyspnoeic patients.

The Influence of Pain-Related Expectations on Intensity Perception of Nonpainful Somatosensory Stimuli.

OBJECTIVE: The extent to which pain-related expectations, known to affect pain perception, also affect perception of nonpainful sensations remains unclear, as well as the potential role of unpredictability in this context. METHODS: In a proprioceptive fear conditioning paradigm, various arm extension movements were associated with predictable and unpredictable electrocutaneous pain or its absence. During a subsequent test phase, nonpainful electrocutaneous stimuli with a high or low intensity were presented during movement execution. We used hierarchical drift diffusion modeling to examine the influence of expecting pain on the perceptual decision-making process underlying intensity perception of nonpainful sensations. In the first experiment (n = 36), the pain stimulus was never presented during the test phase after conditioning. In the second experiment (n = 39), partial reinforcement was adopted to prevent extinction of pain expectations. RESULTS: In both experiments, movements that were associated with (un)predictable pain led to higher pain expectancy, self-reported fear, unpleasantness, and arousal as compared with movements that were never paired with pain (effect sizes η2 ranging from 0.119 to 0.557; all p values < .05). Only in the second experiment-when the threat of pain remained present-we found that the expectation of pain affected decision making. Compared with the no pain condition, an a priori decision-making bias toward the high-intensity decision threshold was found with the strongest bias during unpredictable pain (effect sizes η2 ranging from 0.469 to 0.504; all p-values < .001). CONCLUSIONS: Thus, the expectation of pain affects inferential processes not only for subsequent painful but also for nonpainful bodily stimuli, with unpredictability moderating these effects, and only when the threat of pain remains present due to partial reinforcement.

Endogenous Pain Modulation: Association with Resting Heart Rate Variability and Negative Affectivity.

Objectives: Several chronic pain syndromes are characterized by deficient endogenous pain modulation as well as elevated negative affectivity and reduced resting heart rate variability. In order to elucidate the relationships between these characteristics, we investigated whether negative affectivity and heart rate variability are associated with endogenous pain modulation in a healthy population. Design, Subjects, and Methods: An offset analgesia paradigm with noxious thermal stimulation calibrated to the individual's pain threshold was used to measure endogenous pain modulation magnitude in 63 healthy individuals. Pain ratings during constant noxious heat stimulation to the arm (15 seconds) were compared with ratings during noxious stimulation comprising a 1 °C rise and return of temperature to the initial level (offset trials, 15 seconds). Offset analgesia was defined as the reduction in pain following the 1 °C decrease relative to pain at the same time point during continuous heat stimulation. Results: Evidence for an offset analgesia effect could only be found when noxious stimulation intensity (and, hence, the individual's pain threshold) was intermediate (46 °C or 47 °C). Offset analgesia magnitude was also moderated by resting heart rate variability: a small but significant offset effect was found in participants with high but not low heart rate variability. Negative affectivity was not related to offset analgesia magnitude. Conclusions: These results indicate that resting heart rate variability (HRV) is related to endogenous pain modulation (EPM) in a healthy population. Future research should focus on clarifying the causal relationship between HRV and EPM and chronic pain by using longitudinal study designs.

A mind cleared by walnut oil: The effects of polyunsaturated and saturated fat on extinction learning.

The treatment of anxiety-based psychopathology often hinges upon extinction learning. Research in nutritional neuroscience has observed that the regular consumption of perilla oil (50% alpha-linolenic acid (ALA)) facilitates extinction learning in rats (Yamamoto et al., 1988). However, acute facilitation of extinction learning by oils rich in ALA has not been reported for rats or humans, though the acute consumption of rapeseed oil (10% ALA) has been observed to improve cognitive processing speed in humans (Jones, Sünram-Lea, & Wesnes, 2012). For this reason, the present laboratory work examined the effects of adding walnut oil (12% ALA) to a chocolate milkshake on the acquisition, generalization, and extinction of a fear-based prediction in young adults. It compared performance between subjects. The other participants consumed a similar milkshake with either an equicaloric amount of cream (saturated fat), or with no added fat (control). Acquisition and generalization of the fear-based prediction were similar for all groups. However, those who consumed walnut oil extinguished most rapidly and profoundly. Implications for extinction learning are discussed.

The Specificity of Health-Related Autobiographical Memories in Patients With Somatic Symptom Disorder.

OBJECTIVE: Patients with somatic symptom disorder (SSD) have persistent distressing somatic symptoms that are associated with excessive thoughts, feelings, and behaviors. Reduced autobiographical memory specificity (rAMS) is related to a range of emotional disorders and is considered a vulnerability factor for an unfavorable course of pathology. The present study investigated whether the specificity of health-related autobiographical memories is reduced in patients with SSD with medically unexplained dyspnea complaints, compared with healthy controls. METHODS: Female patients with SSD (n = 30) and matched healthy controls (n = 24) completed a health-related Autobiographical Memory Test, the Beck Depression Inventory, the Ruminative Response Scale, and rumination scales concerning bodily reactions. Depressive symptoms and rumination were assessed because both variables previously showed associations with rAMS. RESULTS: Patients with SSD recalled fewer specific (F(1,52) = 13.63, p = .001) and more categoric (F(1,52) = 7.62, p = .008) autobiographical memories to health-related cue words than healthy controls. Patients also reported higher levels of depressive symptoms and rumination (all t > 3.00, p < .01). Importantly, the differences in memory specificity were independent of depressive symptoms and trait rumination. CONCLUSIONS: The present study extends findings on rAMS to a previously unstudied sample of patients with SSD. Importantly, the presence of rAMS could not be explained by increased levels of depressive symptoms and rumination. We submit that rAMS in this group reflects how health-related episodes and associated symptoms are encoded in memory.

Inducing Somatic Symptoms in Functional Syndrome Patients: Effects of Manipulating State Negative Affect.

OBJECTIVE: Induction of negative affective states can enhance bodily symptoms in high habitual symptom reporters among healthy persons and in patients with irritable bowel syndrome. The aims of this study were to replicate this effect in patients with fibromyalgia and chronic fatigue syndrome and to investigate the role of moderators, focusing on alexithymia, negative affectivity, and absorption. METHODS: Patients with fibromyalgia and/or chronic fatigue syndrome (n = 81) and HCs (n = 41) viewed series of neutral, positive, and negative affective pictures. After every picture series, participants filled out a somatic symptom checklist and rated emotions experienced during the picture series on valence, arousal, and perceived control. RESULTS: Patients reported more somatic symptoms after viewing negative pictures (least square mean [LSM] = 19.40, standard error (SE) = 0.50) compared with neutral (LSM = 17.59, SE = 0.42, p < .001) or positive (LSM = 17.04, SE = 0.41, p < .001) pictures, whereas somatic symptom ratings of HCs after viewing negative picture series (LSM = 12.07, SE = 0.71) did not differ from ratings after viewing neutral (LSM = 11.07, SE = 0.59, p = .065) or positive (LSM = 11.10, SE = 0.58, p = .93) pictures. Negative affectivity did not moderate the symptom-enhancing effect of negative affective pictures, whereas the alexithymia factor "difficulty identifying feelings" and absorption did (p = .016 and p = .006, respectively). CONCLUSION: Negative affective states elicit elevated somatic symptom reports in patients experiencing fibromyalgia and/or chronic fatigue syndrome. This symptom-enhancing effect is greater in patients having higher difficulty to identify feelings and higher absorption scores. The results are discussed in a predictive coding framework of symptom perception.

Hemodynamic Profiles of Functional and Dysfunctional Forms of Repetitive Thinking.

BACKGROUND: The ability of the human brain to escape the here and now (mind wandering) can take functional (problem solving) and dysfunctional (perseverative cognition) routes. Although it has been proposed that only the latter may act as a mediator of the relationship between stress and cardiovascular disease, both functional and dysfunctional forms of repetitive thinking have been associated with blood pressure (BP) reactivity of the same magnitude. However, a similar BP reactivity may be caused by different physiological determinants, which may differ in their risk for cardiovascular pathology. PURPOSE: To examine the way (hemodynamic profile) and the extent (compensation deficit) to which total peripheral resistance and cardiac output compensate for each other in determining BP reactivity during functional and dysfunctional types of repetitive thinking. METHODS: Fifty-six healthy participants randomly underwent a perseverative cognition, a mind wandering, and a problem solving induction, each followed by a 5-min recovery period while their cardiovascular parameters were continuously monitored. RESULTS: Perseverative cognition and problem solving (but not mind wandering) elicited BP increases of similar magnitude. However, perseverative cognition was characterized by a more vascular (versus myocardial) profile compared to mind wandering and problem solving. As a consequence, BP recovery was impaired after perseverative cognition compared to the other two conditions. CONCLUSIONS: Given that high vascular resistance and delayed recovery are the hallmarks of hypertension the results suggest a potential mechanism through which perseverative cognition may act as a mediator in the relationship between stress and risk for developing precursors to cardiovascular disease.

Learned Fear of Gastrointestinal Sensations in Healthy Adults.

BACKGROUND & AIMS: Gastrointestinal symptom-specific fear and anxiety are important determinants of gastrointestinal symptom perception. We studied learning of fear toward innocuous gastrointestinal sensations as a putative mechanism in the development of gastrointestinal symptom-specific fear and anxiety. METHODS: Fifty-two healthy subjects (26 women) received 2 types of esophageal balloon distention at a perceptible but nonpainful intensity (conditioned stimulus [CS], the innocuous sensation) and at a painful intensity (unconditioned stimulus [US]). Subjects were assigned randomly to 1 of 2 groups. During the learning phase, the innocuous CS preceded the painful US in the experimental group (n = 26). In the control group (n = 26), on the contrary, the US never followed the CS directly. During a subsequent extinction phase, both groups received only CS distention-the painful US was no longer administered. Indexes of fear learning toward the innocuous CS distention included the skin conductance response, fear-potentiated startle (measured by the eye-blink electromyogram), and self-reported expectancy of the US. RESULTS: During the learning phase, only the experimental group learned to fear the innocuous gastrointestinal CS, based on the increase in US expectancy (compared with the control group, P = .04), increased skin conductance response (compared with the control group, P = .03), and potentiated startle reflex (compared with the control group, P = .001) in response to the CS. The differences between the experimental and control groups in US expectancy and skin conductance, but not fear-potentiated startle, disappeared during the extinction phase. CONCLUSIONS: Fear toward innocuous gastrointestinal sensations can be established through associative learning in healthy human beings. This may be an important mechanism in the development of fear of gastrointestinal symptoms, implicated in the pathophysiology of functional gastrointestinal disorders.

Influence of Interoceptive Fear Learning on Visceral Perception.

OBJECTIVES: Interoceptive fear learning and generalization have been hypothesized to play a key role in unexplained abdominal and esophageal pain in patients with functional gastrointestinal disorders. However, there is no experimental evidence demonstrating that fear learning and generalization to visceral sensations can be established in humans and alter visceral perception. METHODS: In a novel fear learning-generalization paradigm, an innocuous esophageal balloon distension served as conditioned stimulus (CS), and distensions at three different pressure levels around the pain detection threshold were used as generalization stimuli. During fear learning, the CS was paired with a painful electrical stimulus (unconditioned stimulus) in the conditioning group (n = 30), whereas in the control group (n = 30), the unconditioned stimulus was delivered alone. Before and after fear learning, visceral perception thresholds for first sensation, discomfort, and pain and visceral discrimination sensitivity were assessed. RESULTS: Fear learning was established in the conditioning group only (potentiated eye-blink startle to the CS (t(464.06) = 3.17, p = .002), and fear generalization to other stimulus intensities was observed (t(469.12) = 2.97, p = .003; t(464.29) = 4.17, p < .001). The thresholds for first sensation habituated in the control group, whereas it remained constant in the conditioning group (F(1,43) = 9.77, p = .003). CONCLUSIONS: These data show that fear learning using visceral stimuli induces fear generalization and influences visceral perception. These findings support the idea that in functional gastrointestinal disorder, fear learning and generalization can foster gastrointestinal-specific anxiety and contribute to visceral hypersensitivity.

The effects of transcutaneous vagus nerve stimulation on conditioned fear extinction in humans.

A critical component of the treatment for anxiety disorders is the extinction of fear via repeated exposure to the feared stimulus. This process is strongly dependent on successful memory formation and consolidation. Stimulation of the vagus nerve enhances memory formation in both animals and humans. The objective of this study was to assess whether transcutaneous stimulation of the vagus nerve (tVNS) can accelerate extinction memory formation and retention in fear conditioned humans. To assess fear conditioning and subsequent fear extinction, we assessed US expectancy ratings, fear potentiated startle responses and phasic heart rate responses. We conducted a randomized controlled trial in thirty-one healthy participants. After fear conditioning participants were randomly assigned to receive tVNS or sham stimulation during the extinction phase. Retention of extinction memory was tested 24h later. tVNS accelerated explicit fear extinction learning (US expectancy ratings), but did not lead to better retention of extinction memory 24h later. We did not find a differential physiological conditioning response during the acquisition of fear and thus were unable to assess potential effects of tVNS on the extinction of physiological indices of fear. These findings complement recent studies that suggest vagus nerve stimulation could be a promising tool to improve memory consolidation and fear extinction.

Healing Words: Using Affect Labeling to Reduce the Effects of Unpleasant Cues on Symptom Reporting in IBS Patients.

PURPOSE: The present study aimed to induce elevated symptom reports through the presentation of unpleasant cues in patients with irritable bowel syndrome (IBS) and examine whether applying an emotion regulation technique (affect labeling) can reduce symptom reporting in patients. METHODS: Patients diagnosed with IBS (N = 29) and healthy controls (N = 26) were presented with six picture series (three pleasant, three unpleasant) under three within-subject conditions: merely viewing, emotional labeling, or content (non-emotional) labeling. Each picture viewing trial was followed by affect ratings and a symptom checklist, consisting of general arousal and IBS-specific symptoms. RESULTS: Viewing unpleasant pictures led to overall increased symptom reports, both for arousal and gastrointestinal symptoms, in both groups. Labeling the pictures did not reduce these effects significantly, although a trend toward less arousal symptoms after unpleasant cues emerged in the patient group only, especially during emotional labeling. CONCLUSIONS: Current findings indicate that the mere presentation of unpleasant cues can induce elevated symptom reports in IBS patients. The results of the labeling manipulation provide modest support for the effectiveness of emotion regulation strategies in reversing these effects of unpleasant cues in patients suffering from functional syndromes. Methodological issues that may have confounded present results are discussed.

Inhalation/Exhalation ratio modulates the effect of slow breathing on heart rate variability and relaxation.

Slow breathing is widely applied to improve symptoms of hyperarousal, but it is unknown whether its beneficial effects relate to the reduction in respiration rate per se, or, to a lower inhalation/exhalation (i/e) ratio. The present study examined the effects of four ventilatory patterns on heart rate variability and self-reported dimensions of relaxation. Thirty participants were instructed to breathe at 6 or 12 breaths/min, and with an i/e ratio of 0.42 or 2.33. Participants reported increased relaxation, stress reduction, mindfulness and positive energy when breathing with the low compared to the high i/e ratio. A lower compared to a higher respiration rate was associated only with an increased score on positive energy. A low i/e ratio was also associated with more power in the high frequency component of heart rate variability, but only for the slow breathing pattern. Our results show that i/e ratio is an important modulator for the autonomic and subjective effects of instructed ventilatory patterns.

Disease acceptance, but not perceived control, is uniquely associated with inflammatory bowel disease-related disability.

BACKGROUND AND AIMS: Disability, an important aspect of disease burden in patients with inflammatory bowel disease (IBD), has been suggested as a valuable clinical endpoint. We aimed to investigate how disease acceptance and perceived control, two psychological predictors of subjective health, are associated with IBD-related disability. METHODS: In this cross-sectional study, adult IBD patients from the University Hospitals Leuven received a survey with questions about clinical and demographic characteristics, disease acceptance and perceived control (Subjective Health Experience model questionnaire), and IBD-related disability (IBD Disk). Multiple linear regressions assessed predictors of IBD-related disability in the total sample and in the subgroups of patients in clinical remission or with active disease. RESULTS: In the total sample (N = 1250, 54.2% female, median [IQR] age 51 [39-61] years, 61.3% Crohn's disease, 34.9% active disease), adding the psychological predictors to the model resulted in an increased explained variance in IBD-related disability of 19% compared to a model with only demographic and clinical characteristics (R2adj 38% vs. 19%, p<.001). The increase in explained variance was higher for patients in clinical remission (ΔR2adj 20%, p<.001) compared to patients with active disease (ΔR2adj 10%, p<.001). Of these predictors, disease acceptance was most strongly associated with disability in the total sample (ß=-0.44, p<.001), as well as in both subgroups (ß=-0.47, p<.001 and ß=-0.31, p<.001 respectively). Perceived control was not significantly associated with disability when accounting for all other predictors. CONCLUSIONS: Disease acceptance is strongly associated with IBD-related disability, supporting further research into disease acceptance as a treatment target.

Effects of transcutaneous auricular vagus nerve stimulation on P300 magnitudes and salivary alpha-amylase during an auditory oddball task.

Transcutaneous auricular vagus nerve stimulation (taVNS) is a non-invasive neurostimulation technique that is thought to modulate noradrenergic activity. Previous studies have demonstrated inconsistent effects of taVNS on noradrenergic activity, which is possibly due to insufficient statistical power, suboptimal stimulation parameter settings, and data collection procedures. In this preregistered within-subject experiment, 44 healthy participants received taVNS and sham (earlobe) stimulation during two separate experimental sessions. Stimulation intensity was individually calibrated to the maximum level below pain. During each session, participants received the stimulation continuously ten minutes before an auditory novelty oddball task till the end of the experimental session. The P3b component of the event-related potential served as a marker of phasic noradrenergic activity, whereas P3a magnitude was explored as an index of dopaminergic activity. Salivary alpha-amylase (sAA) was measured as an index of tonic noradrenergic activity before and at the end of the stimulation. The taVNS and sham conditions did not differ in P3a or P3b magnitudes, nor sAA secretion. These findings call into question whether taVNS, administered continuously at high, nonpainful stimulation intensities, reliably augments noradrenergic activity via the vagus nerve.