As good as it gets? A meta-analysis and systematic review of methodological quality of heart rate variability studies in functional somatic disorders

Autonomic nervous system (ANS) dysfunction is a potential mechanism connecting psychosocial stress to functional somatic disorders (FSD), such as chronic fatigue syndrome, fibromyalgia and irritable bowel syndrome. We present the first meta-analysis and systematic review of methodological study quality on the association between cardiac ANS dysfunction, measured as parasympathetic nervous system (PNS) activity using heart rate variability (HRV), and FSD. Literature search revealed 23 available studies including data on 533 FSD patients. Meta-analysis on a subgroup of 14 studies with suitable outcome measures indicated lower PNS activity in FSD patients compared to controls (weighted standardized mean difference (SMD) = −0.32, 95% CI −0.63 to −0.01, p = 0.04). The reliability of this summary estimate was, however, significantly limited by unexplained heterogeneity in the effect sizes and potential publication bias (weighted SMD after correction for funnel plot asymmetry = 0.01, 95% CI −0.34 to 0.36, p = 0.95). The systematic review of overall methodological quality of HRV studies in FSD demonstrates that there is substantial room for improvement, especially in selection of healthy control subjects, blinding of researchers performing HRV measurements, report of adequate HRV outcomes, and assessment of and adjustment for potential confounders. Methodological study quality was, however, not a significant predictor of study findings. We conclude that current available evidence is not adequate to firmly reject or accept a role of ANS dysfunction in FSD. Quality criteria and recommendations to improve future research on HRV in FSD are provided.     

Heart rate variability and treatment outcome in major depression: A pilot study

Variations in heart rate variability (HRV) have been associated with major depressive disorder (MDD), but the relationship of baseline HRV to treatment outcome in MDD is unclear. We conducted a pilot study to examine associations between resting baseline HRV and MDD treatment outcome. We retrospectively tested several parameters of HRV in an MDD treatment study with escitalopram (ESC, N = 26) to generate a model of how baseline HRV related to treatment outcome, and cross-validated the model in a separate trial of MDD treatment with Iyengar yoga (IY, N = 16). Lower relative power of very low frequency (rVLF) HRV at baseline predicted improvement in depressive symptoms when adjusted for age and gender (R² > .43 and p < 0.05 for both trials). Although vagal parasympathetic measures were correlated with antidepressant treatment outcome, their predictive power was not significant after adjusting for age and gender. In conclusion, baseline resting rVLF was associated with depression treatment outcome in two independent MDD treatment studies. These results should be interpreted with caution due to limited sample size, but a strength of this study is its validation of the rVLF predictor in an independent sample. rVLF merits prospective confirmation as a candidate biomarker.     

Combined effect of depressive symptoms and hostility on autonomic nervous system function

Depression and hostility have been separately related to indicators of sympathetic hyperactivation and parasympathetic hypoactivation. We examined the associations of depressive symptoms, hostility, and their interaction with pre-ejection period (PEP) and high frequency heart rate variability (HRV), specific indices of sympathetic and parasympathetic cardiac control, respectively. Healthy, young adults (N = 120) completed questionnaires assessing depressive symptoms and hostility and underwent autonomic testing. Although main effects were not observed, a depressive symptoms × hostility interaction was detected for PEP (β = .25, p = .01). Simple slope analyses revealed that hostility was negatively related to PEP among individuals with low depressive symptoms but was not associated with PEP among those with mild-to-moderate depressive symptoms. No interaction effect was detected for high frequency HRV. Our findings suggest that depressive symptoms may moderate the link between hostility and sympathetic activation such that hostility is accompanied by sympathetic hyperactivation only when depressive symptoms are minimal.     

Transcranial direct current stimulation influences the cardiac autonomic nervous control

To investigate whether the manipulation of brain excitability by transcranial direct current stimulation (tDCS) modulates the heart rate variability (HRV), the effect of tDCS applied at rest on the left temporal lobe in athletes (AG) and non-athletes (NAG) was evaluated. The HRV parameters (natural logarithms of LF, HF, and LF/HF) was assessed in 20 healthy men before, and immediately after tDCS and sham stimulation. After anodal tDCS in AG the parasympathetic activity (HF_log) increased (P < 0.01) and the sympathetic activity (LF_log) and sympatho-vagal balance (LF/HF_log) decreased (P < 0.01), whereas no significant effects were detected in NAG (P > 0.05). No significant changes in HRV indexes were provoked by sham stimulation in both AG and NAG (P > 0.05). In conclusion, tDCS applied on the left temporal lobe significantly increased the overall HRV in AG, enhancing the parasympathetic and decreasing the sympathetic modulation of heart rate. Consequently the sympatho-vagal balance decreased at rest in AG but not in NAG. Releasing a weak electric current to stimulate selected brain areas may induce favorable effects on the autonomic control to the heart in highly fit subjects.     

Autonomic nervous system reactivity to positive and negative mood induction: the role of acute psychological responses and frontal electrocortical activity

The differential effects of positive versus negative emotions on autonomic nervous system activity are insufficiently understood. This study examined the role of acute mood responses and central nervous system activity on heart rate variability (HRV) using 5-min event recall tasks (happiness and anger recall) and a 5-min Stroop Color Word Test (SCWT) in 20 healthy individuals (mean age 25 ± 4 years, 55% female). HRV was measured in high frequency (HF) and low frequency (LF) domains, and frontal brain activity using electroencephalography (EEG) in the alpha frequency band in F3 and F4. Happiness Recall resulted in increased LF-HRV (p = 0.005) but not HF-HRV (p = 0.71). Anger Recall did not change HRV (p-values > 0.10). The SCWT produced decreases in HF-HRV (p = 0.001) as well as LF-HRV (p = 0.001). The magnitude of feeling “happy” during Happiness Recall was positively correlated with ΔHF-HRV (p = 0.050), whereas an incongruent mood state (“frustrated”) was associated with smaller ΔHF-HRV (p = 0.070). Associations between frontal EEG activation and HRV responses were mostly non-significant, except for increased right frontal activation during Happiness Recall which was associated with a decrease in LF/HF ratio (p = 0.009). It is concluded that positive and negative mood induction result in differential HRV responses, which is related to both task valence and the intensity of task-induced emotions.     

Hormonal responses to physical and cognitive stress in a school setting

Little is known about the influence of physical and cognitive stress on the concentration of steroid hormones (SHs) in a school setting. Forty high school students from the 9th grade were randomly assigned to two intervention groups: physical and cognitive stress. Saliva collection took place before (pre-test) and after (post-test) 12 min of high intensity exercise in a defined heart rate (HR) interval (70–85% HR _max; n = 19) and cognitive testing (Letter Digit Span and d2-test, n = 21), respectively. Saliva was analyzed for testosterone (T) and cortisol (C). Results indicated a significant increase of T and C due to a physical but not cognitive stressor. Thus, only the physical stressor was capable of activating the hypothalamic–pituitary–adrenal (HPA) and the hypothalamic–pituitary–gonadal (HPG) axis.     

Cortisol responses to emotional stress in men: association with a functional polymorphism in the 5HTR2C gene

The serotonin 5HTR2C receptor has been shown to mediate HPA axis activation during stress. We hypothesized that a functional polymorphism (rs6318) of the 5HTR2C gene would be associated with HPA axis response to a laboratory stress protocol. The present sample consisted of 41 men (22 African Americans, 19 Caucasians). We found that at rest men with the more active rs6318 Ser23 C allele had similar cortisol values compared to those with the less active Cys23 G allele. During laboratory stress, however, men with the Ser23 C allele exhibited the predicted significantly higher cortisol levels (p < 0.001), as well as larger increases in anger (p = 0.08) and depressive mood (p = 0.006) ratings, compared to the Cys23 G carriers. The increase in cortisol was significantly related to the increases in ratings of anger and depression assessed before and after the emotion induction, and these correlations became nonsignificant when rs6318 genotype was covaried. We conclude that genetic variation in 5HTR2C may be associated with HPA axis activation and stimulated by emotional stress, and also with both psychological and physiological endophenotypes that increase the risk of cardiovascular disease and type-2 diabetes.     

Personality and physiological reactions to acute psychological stress

Stable personality traits have long been presumed to have biological substrates, although the evidence relating personality to biological stress reactivity is inconclusive. The present study examined, in a large middle aged cohort (N = 352), the relationship between key personality traits and both cortisol and cardiovascular reactions to acute psychological stress. Salivary cortisol and cardiovascular activity were measured at rest and in response to a psychological stress protocol comprising 5 min each of a Stroop task, mirror tracing, and a speech task. Participants subsequently completed the Big Five Inventory to assess neuroticism, agreeableness, openness to experience, extraversion, and conscientiousness. Those with higher neuroticism scores exhibited smaller cortisol and cardiovascular stress reactions, whereas participants who were less agreeable and less open had smaller cortisol and cardiac reactions to stress. These associations remained statistically significant following adjustment for a range of potential confounding variables. Thus, a negative personality disposition would appear to be linked to diminished stress reactivity. These findings further support a growing body of evidence which suggests that blunted stress reactivity may be maladaptive.     

Histories of major depression and premenstrual dysphoric disorder: Evidence for phenotypic differences

This study examined unique versus shared stress and pain-related phenotypes associated with premenstrual dysphoric disorder (PMDD) and prior major depressive disorder (MDD). Sympathetic nervous system (SNS) and hypothalamic-pituitary-adrenal (HPA)-axis measures were assessed at rest and during mental stress, as well as sensitivity to cold pressor and tourniquet ischemic pain tasks in four groups of women: (1) non-PMDD with no prior MDD (N = 18); (2) non-PMDD with prior MDD (N = 9); (3) PMDD with no prior MDD (N = 17); (4) PMDD with prior MDD (N = 10). PMDD women showed blunted SNS responses to stress compared to non-PMDD women, irrespective of prior MDD; while women with prior MDD showed exaggerated diastolic blood pressure responses to stress versus never depressed women, irrespective of PMDD. However, only in women with histories of MDD did PMDD women have lower cortisol concentrations than non-PMDD women, and only in non-PMDD women was MDD associated with reduced cold pressor pain sensitivity. These results suggest both unique phenotypic differences between women with PMDD and those with a history of MDD, but also indicate that histories of MDD may have special relevance for PMDD.     

Hormonal contraception use alters stress responses and emotional memory

Emotionally arousing material is typically better remembered than neutral material. Since norepinephrine and cortisol interact to modulate emotional memory, sex-related influences on stress responses may be related to sex differences in emotional memory. Two groups of healthy women – one naturally cycling (NC women, n = 42) and one using hormonal contraceptives (HC women, n = 36) – viewed emotionally arousing and neutral images. Immediately after, they were assigned to Cold Pressor Stress (CPS) or a control procedure. One week later, participants received a surprise free recall test. Saliva samples were collected and later assayed for salivary alpha-amylase (biomarker for norepinephrine) and cortisol. Compared to NC women, HC women exhibited significantly blunted stress hormone responses to the images and CPS. Recall of emotional images differed between HC and NC women depending on noradrenergic and cortisol responses. These findings may have important implications for understanding the neurobiology of emotional memory disorders, especially those that disproportionately affect women.     

Sustained acceleration of colonic transit following chronic homotypic stress in oxytocin knockout mice

Acute restraint stress delays gastric emptying and accelerates colonic transit via central corticotropin releasing factor (CRF) in rats. In contrast, central oxytocin has anxiolytic effects and attenuates the hypothalamus–pituitary–adrenal (HPA) axis in response to stress. Our recent study showed that up regulated oxytocin expression attenuates hypothalamic CRF expression and restores impaired gastric motility following chronic homotypic stress in mice. We studied the effects of acute and chronic homotypic stress on colonic transit and hypothalamic CRF mRNA expression in wild type (WT) and oxytocin knockout (OXT-KO) mice. Colonic transit was measured following acute restraint stress or chronic homotypic stress (repeated restraint stress for 5 consecutive days). ⁵¹Cr was injected via a catheter into the proximal colon. Ninety minutes after restraint stress loading, the entire colon was removed. The geometric center (GC) was calculated to evaluate colonic transit. Expression of CRF mRNA in the supraoptic nucleus (SON) was measured by real time RT-PCR. Colonic transit was significantly accelerated following acute stress in WT (GC = 8.1 ± 0.8; n = 7) and OXT KO mice (GC =9.4 ± 0.3; n = 7). The accelerated colonic transit was significantly attenuated in WT mice (GC = 6.6 ± 0.5; n = 9) following chronic homotypic stress while it was still accelerated in OXT KO mice (GC = 9.3 ± 0.5; n = 8). The increase in CRF mRNA expression at the SON was much greater in OXT-KO mice, compared to WT mice following chronic homotypic stress. It is suggested that oxytocin plays a pivotal role in mediating the adaptation mechanism following chronic homotypic stress in mice.     

Delayed reactive cries demonstrate emotional and physiological dysregulation in newborns of depressed mothers

The purpose of the present study was to examine newborns’ behavioral and physiological reactions to the cry of another infant (labeled a reactive cry). 101 newborns of depressed (N = 40) and non-depressed (N = 61) mothers were assessed on the Brazelton Neonatal Behavioral Assessment Scale (NBAS, Brazelton and Nugent, 1995) and 89 of those infants also participated in an auditory task. Cardiovascular activity (heart period, parasympathetic tone, and recovery to basal activity) was obtained from a sub-sample of these infants (n = 37). Vocal distress and regulatory behaviors were examined when newborns listened to another infant's cry and to a simulated sound (the control condition). ANOVAs indicated that newborns of depressed mothers showed lower basal parasympathetic tone. In addition, newborns of depressed mothers responded with less vocal distress to the cry sounds of another infant, and were delayed in physiological regulation following this sound. These findings suggest that newborns of depressed mothers show altered, possibly dysregulated, behavioral and physiological patterns during socio-emotional situations in comparison to newborns of non-depressed mothers.     

An increase in salivary interleukin-6 level following acute psychosocial stress and its biological correlates in healthy young adults

Although interleukin-6 (IL-6) has been investigated frequently in stress research, knowledge regarding the biological processes of IL-6 in association with psychosocial stress remains incomplete. This study focused on salivary IL-6 and reports its temporal variation and biological correlates following acute psychosocial stress. Fifty healthy young adults (39 male and 11 female students) were subjected to the psychosocial stress test ‘Trier Social Stress Test’ (TSST), wherein the participants were asked to deliver a speech and perform a mental arithmetic task in front of 2 audiences. Collection of saliva samples, measurement of heart rate, and assessment of negative moods by visual analogue scales were conducted before, during, and after TSST. Salivary IL-6 levels increased by approximately 50% in response to the TSST and remained elevated for 20 min after the stress tasks were completed. Cluster analyses revealed that individuals with sustained elevation of IL-6 levels following the TSST exhibited a lower cortisol response compared to individuals with lower IL-6 levels. In the correlation analyses, a greater IL-6 response was associated with a higher heart rate during the mental arithmetic task (r = .351, p < .05) and with a lower cortisol response (r = −.302, p < .05). This study demonstrates that salivary IL-6 levels are elevated for a relatively long period following acute psychosocial stress, and suggests that sympathetic activity and cortisol secretion are involved in elevation of salivary IL-6 levels.     

Sleep misperception,EEG characteristics and Autonomic Nervous System activity in primary insomnia: A retrospective study on polysomnographic data

Misperception of Sleep Onset Latency, often found in Primary Insomnia, has been cited to be influenced by hyperarousal, reflected in EEG- and ECG-related indices. The aim of this retrospective study was to examine the association between Central Nervous System (i.e. EEG) and Autonomic Nervous System activity in the Sleep Onset Period and the first NREM sleep cycle in Primary Insomnia (n = 17) and healthy controls (n = 11). Furthermore, the study examined the influence of elevated EEG and Autonomic Nervous System activity on Stage2 sleep-protective mechanisms (K-complexes and sleep spindles). Confirming previous findings, the Primary Insomnia-group overestimated Sleep Onset Latency and this overestimation was correlated with elevated EEG activity. A higher amount of beta EEG activity during the Sleep Onset Period was correlated with the appearance of K-complexes immediately followed by a sleep spindle in the Primary Insomnia-group. This can be interpreted as an extra attempt to protect sleep continuity or as a failure of the sleep-protective role of the K-complex by fast EEG frequencies following within one second. The strong association found between K-alpha (K-complex within one second followed by 8–12 Hz EEG activity) in Stage2 sleep and a lower parasympathetic Autonomic Nervous System dominance (less high frequency HR) in Slow-wave sleep, further assumes a state of hyperarousal continuing through sleep in Primary Insomnia.     

Resting parietal EEG asymmetry and cardiac vagal tone predict attentional control

The present study explores both resting cortical EEG asymmetry and vagally-mediated heart rate variability (HRV), as an index for vagal tone, as physiological correlates of self-reported attentional control in a sample of 53 healthy young adults. Regression analyses indicate that higher vagally-mediated HRV and lower right-sided parietal activity in the β2 frequency range (20–30 Hz) are significant predictors of larger attentional control. Results are in line with some of the basic features of the neurovisceral integration model and stress the role of parietal areas in attentional control capabilities, thus aiming to consider attentional control as a trait-like disposition.     

Self- or parent report of (co-occurring) internalizing and externalizing problems,and basal or reactivity measures of HPA-axis functioning: A systematic evaluation of the internalizing-hyperresponsivity versus externalizing-hyporesponsivity HPA-axis hypothesis

Background

Previous research findings on the link between adolescents’ psychopathology and hypothalamic–pituitary–adrenal (HPA) axis activity have been heterogeneous.

Method

Adolescents (n = 211) with a preadolescent DSM-IV diagnosis participated in a lab-based social stress task. Saliva cortisol was assessed at awakening and during social stress. It was investigated if continuous measures of internalizing and externalizing problems and their interaction, using both self- and parent report, were associated with basal or reactivity measures of HPA-axis functioning

Results

During social stress, an enhanced total release of cortisol was associated with self-reported internalizing problems and a blunted total release of cortisol with self-reported externalizing problems. Post hoc analyses revealed that the association between enhanced cortisol output and internalizing problems held for boys but not for girls. Associations with morning cortisol measures were overall weak

Conclusions

Only in the context of stress, and particularly when based on self-report, blunted cortisol output was associated with externalizing and enhanced cortisol output with internalizing problems. Our broad approach demonstrates the importance of who reports on psychopathology, the use of dimensional measures of psychopathology, simultaneous analysis of internalizing and externalizing problems, and the use of awakening and social stress related measures of cortisol.     

Salivary alpha-amylase response to acute psychosocial stress: the impact of age

The impact of stress on health varies across the different stages of human life. Aging is associated with psychobiological changes that could limit our ability to cope with stressors. Therefore, it is crucial to clarify the physiological mechanisms that underlie the stress response and the changes that occur in them as we age. Our aim was to investigate age differences in the salivary alpha amylase (sAA) response to stress, and its relationship with other typical stress biomarkers such as cortisol and heart rate (HR). Sixty-two participants divided into two age groups (younger group: N = 31, age range: 18-35 years; older group: N = 31, age range: 54-71 years) were exposed to the Trier Social Stress Test and a control condition in a crossover design. No age differences were found in the sAA or HR responses to stress. However, the sAA global output was higher in older than younger adults. Additionally, in the stress condition, the total amount of cortisol released was positively related to the total sAA released, while the HR increase was positively related to the sAA increase. Our results do not support the existence of an attenuated autonomic nervous system response to stress in older adults, but rather a heightened sympathetic tone. Furthermore, we found further evidence of the coordination between the hypothalamus-pituitary-adrenal system and the autonomic nervous system in their response to acute psychosocial stress.     

Polymorphisms of interleukin 6 and interleukin 10 in Egyptian people with Behcet's disease

Cytokines play critical roles in the pathogenesis of Behçet's disease (BD). They mediated many of the effectors and regulatory functions of immune and inflammatory responses. Many studies have linked Interleukin-6 (IL-6) and Interleukin-10 (IL-10) pathologically to BD. Thus, this study aimed to investigate the associations between IL-6 and IL-10 promoter single-nucleotide polymorphisms (SNPs) and the susceptibility to BD and their implication on plasma levels. We genotyped IL-6 −174 G/C (rs1800795) using Mutagenically Separated Polymerase Chain Reaction PCR (MS-PCR) and IL-10 −1082 G/A (rs1800896) and −819 C/T (rs1800871) using Sequence Specific Primer PCR (SSP-PCR) in 87 Egyptian patients and 97 controls. The plasma levels of IL-6 and IL-10 were measured using Enzyme-linked Immunosorbent Assay (ELISA). Significant increase in the frequency of −1082 GG genotype (P < 0.05, OR = 2.25, 95%CI = 1.03–4.91) and significant decrease in the frequency of −1082 GA genotype (P < 0.05, OR = 0.53, 95%CI = 0.29–0.96) was demonstrated in BD patients compare to controls. Patients with genital ulcer had significantly lower frequency of −1082 GG (P < 0.05, OR 0.2, 95% CI = 0.04–0.99) and G allele (P < 0.05, OR = 0.28, 95%CI = 0.08–0.93), while patients with ocular manifestations had significantly higher frequency of −1082 G allele (P < 0.01, OR = 2.28, 95%CI = 1.19–4.36). BD patients had significantly higher level of IL-6 (P < 0.001) and significantly lower level of IL-10 (P < 0.001) compared to controls. The changes in the level of cytokines were independent of any genotype of IL-6 or any genotype/haplotype of IL-10. Patients with active disease state had significantly higher level of IL-6 compared to patients in remission (P < 0.05). In conclusion, our preliminary study indicates that the polymorphism at IL-10 −1082 G/A may play a role in BD susceptibility. The significant increase in IL-6 level and the significant decrease in IL-10 level in BD patients were independent of any particular genotype in IL-6 or any particular genotype/haplotype in IL-10.     

Children's internalizing symptoms: the role of interactions between cortisol and respiratory sinus arrhythmia

We examined interactions between children's physiological activity across two systems, the hypothalamic-pituitary-adrenal (HPA)-axis and the parasympathetic nervous system (PNS), as predictors of child-reported internalizing symptoms (depression, anxiety). HPA activity was indexed by baseline salivary cortisol, and PNS activity was indexed by baseline respiratory sinus arrhythmia (RSA). Study 1 consisted of 57 children (54% girls; M age = 8.81 years ±.34), and Study 2 included 219 children (51% girls; M age = 9.31 years ±.79). Cortisol interacted with RSA to explain unique variance in children's internalizing symptoms. Across the two studies, children with higher cortisol levels in conjunction with higher RSA levels tended to exhibit the lowest levels of depression and anxiety symptoms. Findings demonstrate that contemporaneous consideration of physiological activity across multiple systems can advance understanding of internalizing symptoms in children.     

The incidence of stress symptoms and heart rate variability during sleep and orthostatic test

This study examined the relation of self-reported stress to cardiac autonomic modulation in real-life conditions. The participants for the study were healthy male (N = 59) and female (N = 40) employees (age 40 ± 10 years). A single-item question and a 14-item questionnaire on perceived stress were administered to the participants before the experimental night. RR-intervals (RRI) were recorded during night sleep and an orthostatic test after awakening at home. The RRI data were analyzed for heart rate (HR) and heart rate variability (HRV) in time and frequency domains. Nocturnal urinary stress hormone (cortisol, adrenal and noradrenal) secretion was also analyzed. Based on the self-reported stress, the participants were divided into either low or high stress group. The results showed that higher incidence of stress symptoms was significantly associated with lower HRV in the orthostatic test regardless of age and gender. Differences between the stress groups in HRV indices were approximately 20–50 and 30–75% in supine and standing positions, respectively. No difference was found in nocturnal HR, HRV, or stress hormone secretion between the stress groups. Higher incidence of stress symptoms was significantly associated with greater decrease of HRV from night sleep to the orthostatic test, as a response to awakening. In conclusion, the present findings support the view that autonomic modulation measured in the orthostatic test, but not during night sleep, is related to self-reported stress.