Elena Makovac

Resting heart rate variability (HRV), a surrogate index of cardiac vagal modulation, is considered a putative biomarker of stress resilience as it reflects the ability to effectively regulate emotions in a changing environment. However, most studies are cross-sectional, precluding longitudinal inferences. The high levels of uncertainty and fear at a global level that characterize the COVID-19 pandemic offer a unique opportunity to explore the utility of HRV measures as longitudinal predictors of stress resilience. The present study examined whether resting measures of HRV prior to the COVID-19 outbreak (i.e., nearly 2 years before; Time 0) could predict emotion regulation strategies and daily affect in healthy adults during the May 2020 lockdown (Time 1). Moreover, we evaluated the association between HRV measures, emotion regulation strategies, subjective perception of COVID-19 risk, and self-reported depressive symptoms at Time 1. Higher resting HRV at Time 0 resulted a significant predictor of a stronger engagement in more functional emotion regulation strategies, as well as of higher daily feelings of safeness and reduced daily worry at Time 1. Moreover, depressive symptoms negatively correlated with HRV and positively correlated with the subjective perception of COVID-19 risk at Time 1. Current data support the view that HRV might not only be a marker but also a precursor of resilience under stressful times.

There is a strict interaction between the autonomic nervous system (ANS) and pain, which might involve descending pain modulatory mechanisms. The periaqueductal grey (PAG) is involved both in descending pain modulation and ANS, but its role in mediating this relationship has not yet been explored. Here, we sought to determine brain regions mediating ANS and descending pain control associations. Thirty participants underwent conditioned pain modulation (CPM) assessments, in which they rated painful pressure stimuli applied to their thumbnail, either alone or with a painful cold contralateral stimulation. Differences in pain ratings between ‘pressure‐only’ and ‘pressure + cold’ stimuli provided a measure of descending pain control. In 18 of the 30 participants, structural scans and two functional MRI assessments, one pain‐free and one during cold‐pain were acquired. Heart rate variability (HRV) was simultaneously recorded. Normalised low‐frequency HRV (LF‐HRVnu) and the CPM score were negatively correlated; individuals with higher LF‐HRVnu during pain reported reductions in pain during CPM. PAG‐ventro‐medial prefrontal cortex (vmPFC) and PAG‐rostral ventromedial medulla (RVM) functional connectivity correlated negatively with the CPM. Importantly, PAG‐vmPFC functional connectivity mediated the strength of the LF‐HRVnu‐CPM association. CPM response magnitude was also negatively correlated with vmPFC GM volume. Our multi‐modal approach, using behavioural, physiological and MRI measures, provides important new evidence of interactions between ANS and descending pain mechanisms. ANS dysregulation and dysfunctional descending pain modulation are characteristics of chronic pain. We suggest that further investigation of body‐brain interactions in chronic pain patients may catalyse the development of new treatments. image Key points: Heart rate variability (HRV) is associated with descending pain modulation as measured by the conditioned pain modulation protocol (CPM). There is an association between CPM scores and the functional connectivity between the periaqueductal grey (PAG) and ventro‐medial prefrontal cortex (vmPFC). CPM scores are also associated with vmPFC grey matter volume. The strength of functional connectivity between the PAG and vmPFC mediates the association between HRV and CPM. Our data provide new evidence of interactions between the autonomic nervous system and descending pain mechanisms.

Looping Star is a near‐silent, multi‐echo, 3D functional magnetic resonance imaging (fMRI) technique. It reduces acoustic noise by at least 25dBA, with respect to gradient‐recalled echo echo‐planar imaging (GRE‐EPI)‐based fMRI. Looping Star has successfully demonstrated sensitivity to the cerebral blood‐oxygen‐level‐dependent (BOLD) response during block design paradigms but has not been applied to event‐related auditory perception tasks. Demonstrating Looping Star's sensitivity to such tasks could (a) provide new insights into auditory processing studies, (b) minimise the need for invasive ear protection, and (c) facilitate the translation of numerous fMRI studies to investigations in sound‐averse patients. We aimed to demonstrate, for the first time, that multi‐echo Looping Star has sufficient sensitivity to the BOLD response, compared to that of GRE‐EPI, during a well‐established event‐related auditory discrimination paradigm: the “oddball” task. We also present the first quantitative evaluation of Looping Star's test–retest reliability using the intra‐class correlation coefficient. Twelve participants were scanned using single‐echo GRE‐EPI and multi‐echo Looping Star fMRI in two sessions. Random‐effects analyses were performed, evaluating the overall response to tones and differential tone recognition, and intermodality analyses were computed. We found that multi‐echo Looping Star exhibited consistent sensitivity to auditory stimulation relative to GRE‐EPI. However, Looping Star demonstrated lower test–retest reliability in comparison with GRE‐EPI. This could reflect differences in functional sensitivity between the techniques, though further study is necessary with additional cognitive paradigms as varying cognitive strategies between sessions may arise from elimination of acoustic scanner noise.

There is a strict interaction between the autonomic nervous system (ANS) and pain, which might involve descending pain modulatory mechanisms. The periaqueductal grey (PAG) is involved both in descending pain modulation and ANS, but its role in mediating this relationship has not yet been explored. Here, we sought to determine brain regions mediating ANS and descending pain control associations. 30 participants underwent Conditioned Pain Modulation (CPM) assessments, in which they rated painful pressure stimuli applied to their thumbnail, either alone or with a painful cold contralateral stimulation. Differences in pain ratings between ‘pressure-only’ and ‘pressure+cold’ stimuli provided a measure of descending pain control. In 18 of the 30 participants, structural scans and two functional MRI assessments, one pain-free and one during cold-pain, were acquired. Heart Rate Variability (HRV) was simultaneously recorded. Low frequency HRV (LF-HRV) and the CPM score were negatively correlated; individuals with higher LF-HRV during pain reported reductions in pain during CPM. PAG-frontal medial cortex (FMC) and PAG-rostral ventro-medial medulla (RVM) functional connectivity correlated negatively with the CPM. Importantly, PAG-FMC functional connectivity mediated the strength of HRV-CPM association. CPM response magnitude was also negatively associated with PAG and positively associated with FMC grey matter volumes. Our multi-modal approach, using behavioral, physiological and MRI measures, provides important new evidence of interactions between ANS and descending pain mechanisms. ANS dysregulation and dysfunctional descending pain modulation are characteristics of chronic pain. We suggest that further investigation of body-brain interactions in chronic pain patients may catalyse the development of new treatments.

Background: Functional connectivity (FC) perturbations have been reported in multiple chronic pain phenotypes, but the nature of reported changes varies between cohorts and may relate to the consequences of living with chronic‐pain related comorbidities, such as anxiety and depression. Healthy volunteer studies provide opportunities to study the effects of tonic noxious stimulation independently of these sequelae. Connectivity changes in task negative and positive networks, for example, the default mode and salience networks (DMN/SN), respectively, have been described, but how these and other connectivity networks, for example, those governing descending pain control are affected by the presence of tonic, noxious stimulation in healthy, pain‐free individuals, remains unknown.Method: In 20 healthy volunteers, we assessed FC prior to, during, and following tonic cold painful stimulation in the ventromedial prefrontal cortex (vmPFC), rostral anterior insula (rAI), subgenual anterior cingulate cortex (ACC) and periaqueductal grey (PAG). We also recorded subjectively reported pain using a computerised visual analogue scale.Results: We saw DMN FC changes during painful stimulation and that inter‐network connectivity between the rAI with the vmPFC increased during pain, whereas PAG‐precuneus FC decreased. Pain‐induced FC alterations persisted following noxious stimulation. FC changes related to the magnitude of individuals' subjectively reported pain.Conclusions: We demonstrate FC changes during and following tonic cold‐pain in healthy participants. Similarities between our findings and reports of patients with chronic pain suggest that some FC changes observed in these patients may relate to the presence of an ongoing afferent nociceptive drive.Significance: How pain‐related resting state networks are affected by tonic cold‐pain remains unknown. We investigated functional connectivity alterations during and following tonic cold pain in healthy volunteers. Cold pain perturbed the functional connectivity of the ventro‐medial prefrontal cortex, anterior insula, and the periacquaductal grey area. These connectivity changes were associated with the magnitude of individuals’ reported pain. We suggest that some connectivity changes described in chronic pain patients may be due to an ongoing afferent peripheral drive.

The ENIGMA group on Generalized Anxiety Disorder (ENIGMA‐Anxiety/GAD) is part of a broader effort to investigate anxiety disorders using imaging and genetic data across multiple sites worldwide. The group is actively conducting a mega‐analysis of a large number of brain structural scans. In this process, the group was confronted with many methodological challenges related to study planning and implementation, between‐country transfer of subject‐level data, quality control of a considerable amount of imaging data, and choices related to statistical methods and efficient use of resources. This report summarizes the background information and rationale for the various methodological decisions, as well as the approach taken to implement them. The goal is to document the approach and help guide other research groups working with large brain imaging data sets as they develop their own analytic pipelines for mega‐analyses.

Objective: Spontaneous or experimentally induced high blood pressure (BP) is associated with reduced pain perception, known as BP-related hypoalgesia. Despite its clinical implications, such as the interference with early detection of myocardial infarction in ‘at risk’ groups, the size of the association between high BP and pain has not yet been quantified. Moreover, the distinct association between high BP and physiological or psychological components of pain has not yet been considered so far. The aim of this study was to overcome this gap by performing separate meta-analyses on nociceptive response versus quantifiable perceptual measures of pain in relation to high BP. Methods: PubMed and Web of Knowledge databases were searched for English language studies conducted in humans. Fifty-nine studies were eligible for the analyses. Pooled effect sizes (Hedges’ g) were compared. Random effect models were used. Results show that higher BP is significantly associated with lower nociceptive response (g = 0.38; k = 6) and reduced pain perception, assessed by quantifiable measures (g = 0.48; k = 59). Results: The association between BP and pain perception, derived from highly heterogeneous studies, was characterized by significant publication bias. BP assessment, pain assessment, site of pain stimulation, percentage of female participants in the sample, and control for potential confounders were significant moderators. Conclusion: Current meta-analytic results confirm the presence of BP-related hypoalgesia and point towards the need for a better understanding of its underlying mechanisms.

There are bi-directional interactions between the autonomic nervous system (ANS) and pain. This is likely underpinned by a substantial overlap between brain areas of the central autonomic network and areas involved in pain processing and modulation. To date, however, relatively little is known about the neuronal substrates of the ANS-pain association. Here, we acquired resting state fMRI scans in 21 healthy subjects at rest and during tonic noxious cold stimulation. As indicators of autonomic function, we examined how heart rate variability (HRV) frequency measures were influenced by tonic noxious stimulation and how these variables related to participants’ pain perception and to brain functional connectivity in regions known to play a role in both ANS regulation and pain perception, namely the right dorsal anterior cingulate cortex (dACC) and periaqueductal gray (PAG). Our findings support a role of the cardiac ANS in brain connectivity during pain, linking functional connections of the dACC and PAG with measurements of low frequency (LF)-HRV. In particular, we identified a three-way relationship between the ANS, cortical brain networks known to underpin pain processing, and participants’ subjectively reported pain experiences. LF-HRV both at rest and during pain correlated with functional connectivity between the seed regions and other cortical areas including the right dorsolateral prefrontal cortex (dlPFC), left anterior insula (AI), and the precuneus. Our findings link cardiovascular autonomic parameters to brain activity changes involved in the elaboration of nociceptive information, thus beginning to elucidate underlying brain mechanisms associated with the reciprocal relationship between autonomic and pain-related systems.

Functional connectivity (FC) perturbations have been reported in multiple chronic pain phenotypes, but the nature of reported changes is varied and inconsistent between cohorts. Increases and decreases in connectivity strength in task negative and positive networks, for example, the default mode and salience networks (DMN/SN), respectively, have been described, but how other networks are effected, for example, descending pain control networks, remains unknown. Whether connectivity changes relate to peripherally-mediated nociceptive afferent input, represent coping strategies or are sequelae of chronic pain, e.g. anxiety/depression, is also unknown. Here, we examined FC changes in response to experimentally-administered tonic cold pain in healthy volunteers as a means of disambiguating the nature of connectivity changes. We assessed FC prior to, during, and following tonic cold painful stimulation in four seed regions: ventromedial prefrontal cortex (vmPFC), rostral anterior insula (rAI), subgenual anterior cingulate cortex (ACC) and periaqueductal grey (PAG) and recorded subjectively reported pain using a computerised visual analogue scale. We saw DMN FC changes during painful stimulation and that inter-network communication between the rAI and sgACC seeds with the vmPFC became less anti-correlated during pain, whereas PAG-precuneus FC decreased. Pain-induced FC alterations largely persisted during a 6-minute recovery period following cessation of the painful stimulus. Observed FC changes related to the magnitude of individuals’ subjectively reported pain. We provide new insights into FC changes during and following tonic cold-pain and suggest that some FC changes observed in chronic pain patients may relate to the presence of an ongoing afferent peripheral drive.