Physical exercise augmented cognitive behaviour therapy for older adults with generalised anxiety disorder (PEXACOG): a feasibility study for a randomized controlled trial.

BACKGROUND: Generalised anxiety disorder (GAD) is a frequent and severe disorder among older adults. For older adults with GAD the effect of the recommended treatment, cognitive behaviour therapy (CBT), is reduced. Physical exercise (PE) may enhance the effect of CBT by improving cognitive function and increasing levels of brain-derived neurotrophic factor (BDNF), a predictor of the effect of CBT in patients with anxiety. The aim of the study was to assess the feasibility of a randomized controlled trial (RCT) investigating treatment effect of the combination of CBT and PE for GAD in a sample of older adults, including procedures for assessment and treatment. METHODS: Four participants aged 62-70 years (M = 65.5, SD = 3.2) with a primary diagnosis of GAD were included. Participants received 15 weeks of PE in combination with 10 weeks of CBT. Participants completed self-report measures, and clinical, biological, physiological and neuropsychological tests at pre-, interim- and post-treatment. RESULTS: Procedures, protocols, and results are presented. One participant dropped out during treatment. For the three participants completing, the total adherence to PE and CBT was 80% and 100%, respectively. An independent assessor concluded that the completers no longer fulfilled the criteria for GAD after treatment. Changes in self-report measures suggest symptom reduction related to anxiety and worry. The sample is considered representative for the target population. CONCLUSIONS: The results indicate that combining CBT and PE for older adults with GAD is feasible, and that the procedures and tests are suitable and manageable for the current sample. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02690441. Registered on 24 February 2016, https://clinicaltrials.gov/ct2/show/NCT02690441 .

Fear-induced bradycardia in mental disorders: Foundations, current advances, future perspectives.

Fear-induced bradycardia, a transient heart rate deceleration related to a threatening event, is a powerful technique used to assess fear conditioning in humans. During the last century, studies highlighted its usefulness, even when applied to patients with various psychiatric disorders. Here, we provide an insight into these first steps in the field as well as modern works, which helped in refining the methodology. As data is still limited, future endeavors will continue to deepen the knowledge on fear-induced bradycardia and ensure its use as a biomarker to expedite and improve psychiatric interventions, thus lowering the socio-economic burden associated with these disorders.

Transcutaneous vagus nerve stimulation reduces spontaneous but not induced negative thought intrusions in high worriers.

Worrying is a central component of anxiety disorders. We tested whether non-invasive vagus nerve stimulation reduces negative thought intrusions in high worriers. Worry was assessed with a Breathing Focus Task, which consists of a pre-worry period, a worry induction, and a post-worry period. Ninety-seven high worriers were randomly allocated to receive transcutaneous electrical stimulation of the auricular branch of the vagus nerve at the concha (tVNS), or of the earlobe (sham stimulation) throughout the lab session. Participants who received tVNS reported significantly fewer negative thought intrusions during the pre-worry period, but the effects of tVNS after the worry induction were mixed. An exploratory analysis indicated that participants in the tVNS condition were more likely to report negative thought intrusions shortly after the worry induction, but became less likely to do so as the post-worry period went on. No effects of tVNS on RMSSD were observed. These findings provide preliminary indications that tVNS may decrease the occurrence of worrisome thoughts.

Effects of Body Mass Index on Parasympathetic Nervous System Reactivity and Recovery Following Orthostatic Stress.

Vagally mediated heart rate variability (vmHRV), defined as the beat-to-beat fluctuations in a heart series mediated by the vagus nerve, serves as a non-invasive index of parasympathetic nervous system (PNS) activity. Lower resting state vmHRV is associated with greater body mass index (BMI), providing a psychophysiological pathway linking obesity with health and disease. However little research has been conducted to examine how BMI may influence PNS reactivity to orthostatic stress. The present study sought to explore this in a sample of 59 individuals (44 females, mean age = 24.37 years, age range 19-65 years). VmHRV was measured throughout the 5-minute baseline (sitting), orthostatic (standing), and recovery (sitting) conditions. Individuals were stratified into low (BMI < 20), moderate (BMI 20-25), and high (BMI > 25) BMI groups. Results indicate that the high BMI group had a greater decrease in vmHRV from baseline to standing in comparison to the moderate BMI group. Furthermore, the low BMI group showed lower vmHRV during recovery compared to baseline, suggesting that these individuals did not fully recover from the standing position. Taken together, these results extend previous literature showing that those with low and high BMI can show different yet maladaptive patterns of vmHRV in response to orthostatic stress.

A meta-analysis on pain sensitivity in self-injury.

Individuals engaging in self-injurious behavior (SIB) frequently report absence of pain during acts of SIB. While altered pain sensitivity is discussed as a risk factor for the engagement in SIB, results have been mixed with considerable variance across reported effect sizes, in particular with respect to the effect of co-morbid psychopathology. The present meta-analysis aimed to summarize the current evidence on pain sensitivity in individuals engaging in SIB and to identify covariates of altered pain processing. Three databases were searched without restrictions. Additionally a hand search was performed and reference lists of included studies were checked for potential studies eligible for inclusion. Thirty-two studies were identified after screening 720 abstracts by two independent reviewers. Studies were included if they reported (i) an empirical investigation, in (ii) humans, including a sample of individuals engaging in (iii) SIB and a group of (iv) healthy controls, (v) receiving painful stimulation. Random-effects meta-analysis was performed on three pain-related outcomes (pain threshold, pain tolerance, pain intensity) and several population- and study-level covariates (i.e. age, sex, clinical etiology) were subjected to meta-regression. Meta-analysis revealed significant main effects associated with medium to large effect sizes for all included outcomes. Individuals engaging in SIB show greater pain threshold and tolerance and report less pain intensity compared to healthy controls. Clinical etiology and age are significant covariates of pain sensitivity in individuals engaging in SIB, such that pain threshold is further increased in borderline personality disorder compared to non-suicidal self-injury. Mechanisms underlying altered pain sensitivity are discussed.

Association Strength of Three Adiposity Measures with Autonomic Nervous System Function in Apparently Healthy Employees.

OBJECTIVES: To investigate the association of different measures of central (abdominal) and overall adiposity with autonomic nervous system (ANS) function, indexed by heart rate variability (HRV), in apparently healthy human adults. DESIGN AND MEASUREMENTS: Cross-sectional data of 8,538 participants (20% female, age: 41 ± 11 years, body mass index (BMI): 24 ± 4 kg/m2, waist circumference (WC): 91 ± 12 cm, waist-to-height ratio (WHtR): 0.45 ± 0.08) were available for analysis. RESULTS: All measures of adiposity were inversely correlated with vagally-mediated HRV indexed by RMSSD (all p<0.001). Strongest associations were found with WC and RMSSD (r = -0.29). Associations were stronger in males (WC r = -0.32) than in females (WC r = -0.23). Partial correlations revealed the same pattern for RMSSD (WC all pcc = -0.12 p<0.001; WC male pcc = -0.14 p<0.001; WC female pcc = -0.06 p<0.05). Correlation strength of BMI and WHtR with RMSSD were similar and significantly weaker compared to WC (p < .001) in unadjusted analysis. Overall, nonparametric Kendall's τb led to the same conclusions. CONCLUSION: The present data supports previous findings, that HRV is related to measures of adiposity in healthy individuals. In line with previous research, we found that WC is more strongly related to measures of HRV, indicating that WC best captures adiposity related risk.

Lower heart rate variability predicts increased level of C-reactive protein 4 years later in healthy, nonsmoking adults.

BACKGROUND: Inflammation and vagally mediated heart rate variability (vmHRV) have been implicated in a number of conditions including diabetes and cardiovascular disease. Consistent with the inflammatory reflex termed the 'cholinergic anti-inflammatory pathway', numerous cross-sectional studies have demonstrated negative associations between vmHRV and inflammatory markers such as C-reactive protein (CRP). The only prospective study, however, showed the opposite: higher CRP at baseline predicted higher high-frequency heart rate variability (HF-HRV) at follow-up. Thus, additional studies are needed to examine the prospective association between vmHRV and CRP. METHODS: Healthy employees participated in a voluntary on-site health assessment. Blood samples and ambulatory heart rate recordings were obtained, and night-time HF-HRV was calculated. Useable heart rate data were available in 2007 for 106 nonsmoking employees (9% women; age 44.4 ± 8 years), all of whom returned for an identical follow-up health assessment in 2011. Bootstrapped (500 replications) bivariate (r) and partial Pearson's correlations (ppc) adjusting for sex, age and body mass index at baseline (2007) were calculated. RESULTS: Zero-order correlations indicated that higher HF-HRV was associated with lower levels of CRP at both time-points (2007: r = -0.19, P < 0.05; 2011: r = -0.34, P < 0.001). After adjustment, HF-HRV remained a significant predictor of CRP (ppc = -0.20, P < 0.05). CONCLUSION: In this study, we have provided in vivo support for the cholinergic anti-inflammatory pathway in humans. Cardiac vagal modulation at baseline predicts level of CRP 4 years later. Our findings have important implications for the role of vmHRV as a risk factor for cardiovascular disease morbidity and mortality. Interventions targeted at vmHRV might be useful in the prevention of diseases associated with elevated systemic inflammation.

Body mass index is related to autonomic nervous system activity as measured by heart rate variability--a replication using short term measurements.

OBJECTIVES: The present analysis is a replication of previous findings presenting first evidence of an association between body mass index (BMI) and autonomic nervous system (ANS) activity as measured by heart rate variability (HRV), in healthy non-obese adults. DESIGN: A total of fifty-nine apparently healthy male (M) and female (F) individuals (M/F = 15/44) were included in the trial. HRV data for analysis was derived from 5 minutes of baseline recordings, while the subject was sitting on a comfortable chair. Subjects' body measures (weight and height) were taken and BMI was obtained according to common calculation (kg/m²). RESULTS: BMI was inversely related to pNN50 and RMSSD components of HRV. Statistically significant differences between stratified groups (BMI<20, BMI 20-25, BMI >25) only occurred for analysis of pNN50 components. The pNN50 components and RMSSD are strongly associated with cardiac vagal influence, and thus represents parasympathetic activity. CONCLUSIONS: The present data supports previous findings, that sympatho-vagal balance is related to BMI in non-obese, healthy individuals, providing evidence for a prominent role of the vagus nerve in the modulation of the energy expenditure of the human organism. Furthermore, this relation can be observed in short term recordings of HRV of 5 minutes in length.

Heart rate variability and experimentally induced pain in healthy adults: a systematic review.

BACKGROUND: Reactivity of the autonomic nervous system to experimental pain stimuli has been extensively studied using measures of heart rate and blood pressure. Heart rate variability (HRV) attempts to tease out the relative contributions of sympathetic and parasympathetic activity in the autonomic control of the heart and may therefore be more appropriate to investigate autonomic response to short-term nociceptive stimulation in detail. The current evidence on HRV and experimentally induced pain has not yet been synthesized within a systematic review. METHOD: English articles indexed in PubMed, EMBASE, Psyndex, PsycINFO, CINAHL and the Cochrane Library were reviewed for eligibility under pre-specified inclusion criteria. Studies were included when they reported empirical work on autonomic response (specifically, HRV) to experimentally induced pain in healthy adults. The method of pain induction, the methodological features of HRV analysis (time domain and frequency domain measures), as well as pain and HRV-related findings were derived from the studies. RESULTS: The search revealed a total of 20 publications eligible for inclusion. Key results demonstrate an increase in sympathetic-baroreflex activity and a decrease in vagal-parasympathetic activity as reflected by changes in frequency domain measures of HRV. CONCLUSION: HRV has several advantages compared to other measures of autonomic reactivity in studies investigating physiological response to nociceptive stimulation. Future studies should focus on comparisons between different methods of pain induction, interindividual variability in pain sensitivity by baseline autonomic activity, and the implications of both on the use of HRV within routine clinical evaluations.

Neuroticism, extraversion, stressful life events and asthma: a cohort study of middle-aged adults.

BACKGROUND: Stressful life events can trigger asthma exacerbations, but could also contribute to the development of incident asthma. However, only few studies have investigated the association between stressful life events and adult asthma prospectively. Likewise, stress-related personality traits (e.g. neuroticism and extraversion) may increase asthma risk, but this has been examined in only one prospective study. We therefore aimed to investigate the association between neuroticism, extraversion, stressful life events and incident asthma. METHODS: A population-based sample of 5114 middle-aged adults completed questionnaires between 1992 and 1995. Among those alive in 2002/2003, 4010 (83%) were followed-up by questionnaires. Exposures of interest included neuroticism, extraversion and three stressful life events (unemployment, having broken off a life partnership and death of a close person). Associations with incident asthma were estimated by multivariable risk ratios (RR) and 95% confidence intervals (95% CI) using Poisson regression. RESULTS: High vs low neuroticism predisposed to developing asthma (RR = 3.07, 95% CI = 1.71-5.48), but high extraversion did not (RR = 1.30, 95% CI = 0.79-2.15). Having broken off a life partnership significantly increased asthma risk (RR = 2.24, 95% CI = 1.20-4.21) in contrast to death of a close person (RR = 1.06, 95% CI = 0.64-1.75) or unemployment (RR = 1.65, 95% CI = 0.72-3.78). CONCLUSIONS: High levels of neuroticism may increase the risk of asthma in middle-aged adults. Having broken off a life partnership was the only stressful event, which was associated with incident asthma. Synthesized with evidence from earlier studies, this could reflect that interpersonal conflicts may increase asthma risk, possibly along an immunological pathway.

Heart rate variability, overnight urinary norepinephrine and C-reactive protein: evidence for the cholinergic anti-inflammatory pathway in healthy human adults.

OBJECTIVES: C-reactive protein (CRP) has been identified as an independent predictor of cardiovascular mortality and morbidity in population-based studies. Recent advances have suggested a prominent role for the autonomic nervous system (ANS) in the regulation of inflammation. However, no in vivo human studies have examined indices of sympathetic and parasympathetic nervous system activity simultaneously in relationship to inflammatory markers in apparently healthy adults. Therefore, the objective of this study was to assess the immunomodulatory effects of the ANS. METHODS AND RESULTS: The study population comprised 611 apparently healthy employees of an airplane manufacturing plant in southern Germany. Urinary NE was positively associated with white blood cell count (WBC) in the total sample. We found an inverse association between indices of vagally mediated heart rate variability and plasma levels of (CRP), which was significantly larger in females than in males after controlling for relevant covariates including NE. Similar results were found using the percentage of interbeat interval differences >50 ms and WBC. CONCLUSIONS: We report here for the first time, in a large sample of healthy human adults, evidence supporting the hypothesis of a clinically relevant cholinergic anti-inflammatory pathway after controlling for sympathetic nervous system activity. This suggests an important role for the vagal control of systemic inflammatory activity in cardiovascular disease.

Salt-sensitive men show reduced heart rate variability, lower norepinephrine and enhanced cortisol during mental stress.

Salt sensitivity (SS) represents a risk factor for essential hypertension, which has been related to enhanced cardiovascular stress reactivity possibly mediated by increased noradrenergic susceptibility. We investigated biophysiological responses to mental stress in salt-sensitive (ss) and salt-resistant (sr) subjects, hypothesizing lower heart rate variability (HRV) and higher cortisol in the ss. A total of 48 healthy normotensive Caucasian men (age 25.6+/-2.6, body mass index 22.9+/-2.3) were phenotyped for SS (defined as significant drop in mean arterial pressure>3 mm Hg under the low-salt diet) by a 2-week high- versus low-salt diet. Subjects underwent a standardized mental stress task with continuous cardiovascular monitoring before, during and after the test (Finapres; Ohmeda, Louisville, CO, USA). Blood samples were drawn to examine cortisol and catecholamines before, after and 20 min after stress. The task elicited significant increases of systolic blood pressure (SBP), diastolic BP (DBP) and heart rate (HR) and a significant decrease of HRV (all time effects P<0.0001). The ss subjects showed lower norepinephrine (NE) and higher cortisol, indicated by significant group effects (P=0.009 and 0.025, respectively). HR increased and HRV decreased more in the ss under the stress, shown by significant time by group interactions (P=0.045 and 0.003, respectively). The observation of a more pronounced HR rise coupled with a greater decrease of HRV in healthy ss men under the influence of brief mental stress confirms their enhanced physiological stress reactivity. The lower peripheral NE may represent an effort to compensate for increased noradrenergic receptor sensitivity. The enhanced cortisol levels are backed by recent genetic findings on HSD11B2 polymorphisms and may promote hypertension.

The quest for the EEG reference revisited: a glance from brain asymmetry research.

Recent findings suggested that the choice of the EEG reference might be a critical issue for the study of anterior asymmetry in the alpha band. The present paper investigates the validity of different reference schemes for the measurement of alpha asymmetry. A 32-channel resting EEG was recorded with a common vertex reference (Cz), and transformed into computer-averaged ears (A1 + A2), average reference (AR), and current source density derivations. A correlation analysis of an alpha asymmetry measure between all derivation schemes indicated a poor convergent validity for anterior sites but an excellent convergent validity for posterior sites. Further analyses suggested the presence of substantial alpha activity at the various reference sites (Cz, A1 + A2, AR), which might be similar in magnitude to anterior but smaller than posterior alpha. These findings suggest that the validity of a reference scheme is a function of the signal-to-noise ratio of the electrical activities at target and reference sites. The limitations of each reference scheme for the measurement of anterior alpha asymmetry are discussed.

Heart rate and heart rate variability changes in the intracarotid sodium amobarbital test.

PURPOSE: Changes in heart rate and heart rate variability have been found in prior studies performed during the intracarotid sodium amobarbital (ISA) test. However, these results are not entirely consistent with current models of differential cerebral involvement in the modulation of the heart. This study was designed to re-investigate this topic with a larger N than has heretofore been used. METHODS: The electrocardiogram was recorded during left and right ISAs in 73 subjects. Raw heart rate and heart rate variability were calculated. RESULTS: Raw heart rate increased during inactivation of either hemisphere, but more so for the right hemisphere. Heart rate variability changes consistent with decreasing parasympathetic tone also were found to occur during either ISA, but to a significant degree, only during right ISA. CONCLUSIONS: The right hemisphere appears to have a greater role in cerebral regulation of cardiac function, perhaps by virtue of the modification of parasympathetic effects.

Neurological bases for balance-anxiety links.

This review paper examines neurologic bases of links between balance control and anxiety based upon neural circuits that are shared by pathways that mediate autonomic control, vestibulo-autonomic interactions, and anxiety. The core of this circuitry is a parabrachial nucleus network, consisting of the parabrachial nucleus and its reciprocal relationships with the extended central amygdaloid nucleus, infralimbic cortex, and hypothalamus. Specifically, the parabrachial nucleus is a site of convergence of vestibular information processing and somatic and visceral sensory information processing in pathways that appear to be involved in avoidance conditioning, anxiety, and conditioned fear. Monoaminergic influences on these pathways are potential modulators of both effects of vigilance and anxiety on balance control and the development of anxiety and panic. This neurologic schema provides a unifying framework for investigating the neurologic bases for comorbidity of balance disorders and anxiety.

Derivation of chronotropic indices of autonomic nervous system activity using impedance cardiography.

The impedance cardiograph has been widely used to examine cardiac sympathetic inotropic activity. Recently evidence was presented indicating that left ventricular ejection time (LVET) may be a useful index of sympathetic chronotropic influences derivable from the impedance cardiograph. The goal of the present research was to derive an index of parasympathetic chronotropic influences. In addition, further support for LVET as a sympathetic chronotropic index was sought. Eight healthy college-age subjects participated in a within-subjects design experiment. Tasks were chosen to elicit a wide range of cardiovascular responses resulting from differing combinations of sympathetic and parasympathetic activity. Results indicated that heart rate corrected for LVET (HR-LVET) correlated highly with respiratory sinus arrhythmia (RSA), an index of vagal cardiac chronotropic activity. In addition, principal components analysis indicated that heart rate, RSA, LVET, HR-LVET, and HR corrected for RSA (HR-RSA) all loaded on a single factor distinct from inotropic or vascular indices. These results provide support for the use of impedance cardiography to derive indices of sympathetic (LVET) and parasympathetic (HR-LVET) chronotropic influences.

A dynamical systems interpretation of a dimensional model of emotion.

The dimensional structure of emotion was investigated using self reports of induced mood and idiographic and nomothetic analyses. Subjects attended four experimental sessions during which an array of affective states was induced via auditory, visual, and imaginal channels. For each of 118 stimulus events, subjects self-rated their response. Factor analysis yielded the predicted bipolar factors of valence and arousal: these were obtained in group-aggregated analysis and subsequently confirmed as change dimensions at the intraindividual level. Controversy over the fundamental dimensions of affective space was considered with respect to methodological issues such as factor rotation and sampling of data space. Valence and arousal are discussed as motivational, driving parameters of affective experience and a dynamical systems conceptualization of emotion is proposed.