Short term cardiovascular symptoms improvement after deep brain stimulation in patients with Parkinson's disease: a systematic review.

BACKGROUND: Autonomic dysfunction is common and disabling in Parkinson's disease (PD). The effects of deep brain stimulation (DBS) on the cardiovascular system in PD remain poorly understood. We aimed to assess the effect of DBS on cardiovascular symptoms and objective measures in PD patients. METHODS: We conducted a systematic literature search in PubMed/MEDLINE. RESULTS: 36 out of 472 studies were included, mostly involving DBS of the subthalamic nucleus, and to a lesser extent the globus pallidus pars interna and pedunculopontine nucleus. Seventeen studies evaluated the effect of DBS on patient-reported or clinician-rated cardiovascular symptoms, showing an improvement in the first year after surgery but not with longer-term follow-up. DBS has no clear direct effects on blood pressure during an orthostatic challenge (n = 10 studies). DBS has inconsistent effects on heart rate variability (n = 10 studies). CONCLUSION: Current evidence on the impact of DBS on cardiovascular functions in PD is inconclusive. DBS may offer short-term improvement of cardiovascular symptoms in PD, particularly orthostatic hypotension, which may be attributed to dopaminergic medication reduction after surgery. There is insufficient evidence to draw conclusions on the direct effect of DBS on blood pressure and heart rate variability.

Compassionate mind training for people with Parkinson's disease: A pilot study and predictors of response.

INTRODUCTION: People with Parkinson's disease (PD) often present with disabling neuropsychiatric symptoms. Compassionate mind training (CMT) is a psychological approach effective in reducing stress and promoting psychological well-being. Heart rate variability (HRV), a measure reflecting sympathovagal balance, has been associated with psychological well-being and a compassionate attitude. AIM: To assess the feasibility and effectiveness of CMT in enhancing the quality of life and psychological well-being in PD patients. Additionally, we evaluated HRV as a physiomarker for assessing the CMT outcomes. METHODS: Twenty-four PD patients participated in the study. A 6-week online CMT intervention was delivered on a weekly basis. At baseline and post-intervention patients completed questionnaires assessing depression, anxiety and quality of life. In a subsample of 11 patients, HRV was measured at baseline and post-intervention in three conditions: at rest, during stress and after 3 min of deep breathing. RESULTS: The attendance rate was 94.3%. Quality of life and perceived stigma improved post-intervention as compared with baseline (p = 0.02 and p = 0.03 for PD Questionnaire-39 total score and Stigma subscore, respectively). After CMT, patients presented better physiological regulation to stress, as measured by higher HRV as compared with baseline (p = 0.005). Notably, patients who were more resilient to stress at baseline (less decrease in HRV during stress) experienced a more substantial reduction in anxiety and depression following CMT. CONCLUSIONS: CMT is feasible and can improve quality of life and stigma in PD patients. HRV emerges as a promising physiomarker for predicting and measuring the outcomes of psychological interventions in PD.

Mega-analysis methods in ENIGMA: The experience of the generalized anxiety disorder working group.

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.

Safe in my heart: resting heart rate variability longitudinally predicts emotion regulation, worry, and sense of safeness during COVID-19 lockdown.

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 degree of uncertainty and fear at a global level that characterizes the COVID-19 pandemic offers a unique opportunity to explore the utility of HRV measures as longitudinal predictors of stress resilience. This 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 predicted 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.

The association between pain-induced autonomic reactivity and descending pain control is mediated by the periaqueductal grey.

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. 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.

Regional cerebral blood flow as predictor of response to occipital nerve block in cluster headache.

BACKGROUND: Cluster headache is an excruciating disorder with no cure. Greater occipital nerve blockades can transiently suppress attacks in approximately 50% of patients, however, its mechanism of action remains uncertain, and there are no reliable predictors of treatment response. To address this, we investigated the effect of occipital nerve blockade on regional cerebral blood flow (rCBF), an index of brain activity, and differences between treatment responders and non-responders. Finally, we compared baseline perfusion maps from patients to a matched group of healthy controls. METHODS: 21 male, treatment-naive patients were recruited while in a cluster headache bout. During a pain-free phase between headaches, patients underwent pseudo-continuous arterial spin labelled MRI assessments to provide quantitative indices of rCBF. MRIs were performed prior to and 7-to-21 days following treatment. Patients also recorded the frequency of their headache attacks in a daily paper diary. Neuropsychological assessment including anxiety, depression and quality of life measures was performed in a first, scanning free session for each patient. RESULTS: Following treatment, patients demonstrated relative rCBF reductions in posterior temporal gyrus, cerebellum and caudate, and rCBF increases in occipital cortex. Responders demonstrated relative rCBF increases, compared to non-responders, in medial prefrontal cortex and lateral occipital cortex at baseline, but relative reductions in cingulate and middle temporal cortices. rCBF was increased in patients compared to healthy controls in cerebellum and hippocampus, but reduced in orbitofrontal cortex, insula and middle temporal gyrus. CONCLUSIONS: We provide new mechanistic insights regarding the aetiology of cluster headache, the mechanisms of action of occipital nerve blockades and potential predictors of treatment response. Future investigation should determine whether observed effects are reproducible and extend to other headache disorders.

Revealing the mechanisms behind novel auditory stimuli discrimination: An evaluation of silent functional MRI using looping star.

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.

Cortical thickness and resting-state cardiac function across the lifespan: A cross-sectional pooled mega-analysis.

Understanding the association between autonomic nervous system [ANS] function and brain morphology across the lifespan provides important insights into neurovisceral mechanisms underlying health and disease. Resting-state ANS activity, indexed by measures of heart rate [HR] and its variability [HRV] has been associated with brain morphology, particularly cortical thickness [CT]. While findings have been mixed regarding the anatomical distribution and direction of the associations, these inconsistencies may be due to sex and age differences in HR/HRV and CT. Previous studies have been limited by small sample sizes, which impede the assessment of sex differences and aging effects on the association between ANS function and CT. To overcome these limitations, 20 groups worldwide contributed data collected under similar protocols of CT assessment and HR/HRV recording to be pooled in a mega-analysis (N = 1,218 (50.5% female), mean age 36.7 years (range: 12-87)). Findings suggest a decline in HRV as well as CT with increasing age. CT, particularly in the orbitofrontal cortex, explained additional variance in HRV, beyond the effects of aging. This pattern of results may suggest that the decline in HRV with increasing age is related to a decline in orbitofrontal CT. These effects were independent of sex and specific to HRV; with no significant association between CT and HR. Greater CT across the adult lifespan may be vital for the maintenance of healthy cardiac regulation via the ANS-or greater cardiac vagal activity as indirectly reflected in HRV may slow brain atrophy. Findings reveal an important association between CT and cardiac parasympathetic activity with implications for healthy aging and longevity that should be studied further in longitudinal research.

Linking Pain Sensation to the Autonomic Nervous System: The Role of the Anterior Cingulate and Periaqueductal Gray Resting-State Networks.

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.

Blood pressure-related hypoalgesia: a systematic review and meta-analysis.

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.

Noxious pressure stimulation demonstrates robust, reliable estimates of brain activity and self-reported pain.

Functional neuroimaging techniques have provided great insight in the field of pain. Utilising these techniques, we have characterised pain-induced responses in the brain and improved our understanding of key pain-related phenomena. Despite the utility of these methods, there remains a need to assess the test retest reliability of pain modulated blood-oxygen-level-dependant (BOLD) MR signal across repeated sessions. This is especially the case for more novel yet increasingly implemented stimulation modalities, such as noxious pressure, and it is acutely important for multi-session studies considering treatment efficacy. In the present investigation, BOLD signal responses were estimated for noxious-pressure stimulation in a group of healthy participants, across two separate sessions. Test retest reliability of functional magnetic resonance imaging (fMRI) data and self-reported visual analogue scale measures were determined by the intra-class correlation coefficient. High levels of reliability were observed in several key brain regions known to underpin the pain experience, including in the thalamus, insula, somatosensory cortices, and inferior frontal regions, alongside "excellent" reliability of self-reported pain measures. These data demonstrate that BOLD-fMRI derived signals are a valuable tool for quantifying noxious responses pertaining to pressure stimulation. We further recommend the implementation of pressure as a stimulation modality in experimental applications.

Sustained perturbation in functional connectivity induced by cold pain.

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.

Can't get it off my brain: Meta-analysis of neuroimaging studies on perseverative cognition.

Perseverative cognition (i.e. rumination and worry) describes intrusive, uncontrollable, repetitive thoughts. These negative affective experiences are accompanied by physiological arousal, as if the individual were facing an external stressor. Perseverative cognition is a transdiagnostic symptom, yet studies of neural mechanisms are largely restricted to specific clinical populations (e.g. patients with major depression). The present study applied activation likelihood estimation (ALE) meta-analyses to 43 functional neuroimaging studies of perseverative cognition to elucidate the neurobiological substrates across individuals with and without psychopathological conditions. Task-related and resting state functional connectivity studies were examined in separate meta-analyses. Across task-based studies, perseverative cognition engaged medial frontal gyrus, cingulate gyrus, insula, and posterior cingulate cortex. Resting state functional connectivity studies similarly implicated posterior cingulate cortex together with thalamus and anterior cingulate cortex (ACC), yet the involvement of ACC distinguished between perseverative cognition in healthy controls (HC) and clinical groups. Perseverative cognition is accompanied by the engagement of prefrontal, insula and cingulate regions, whose interaction may support the characteristic conjunction of self-referential and affective processing with (aberrant) cognitive control and embodied (autonomic) arousal. Within this context, ACC engagement appears critical for the pathological expression of rumination and worry.

Response time as a proxy of ongoing mental state: A combined fMRI and pupillometry study in Generalized Anxiety Disorder.

In Generalized Anxiety Disorder (GAD), fluctuations in ongoing thoughts (i.e., mind-wandering) often take the form of rigid and intrusive perseverative cognition, such as worry. Here, we sought to characterise the neural correlates of mind-wandering and perseverative cognition, alongside autonomic nervous system indices of central arousal, notably pupil dilation. We implemented a protocol incorporating the dynamic delivery of thought-probes within a functional neuroimaging task. Sixteen individuals with GAD and sixteen matched healthy controls (HC) underwent functional magnetic resonance imaging with concomitant pupillometry. Participants performed a series of low-demand tracking tasks, responding to occasional changes in a target stimulus. Such a task is typically accompanied by self-generated, off-task thinking. Thought-probes were triggered based on an individual's response time (RT) when responding to the change in the target. Subjective reports showed that long RT predicted off-task thinking/mind-wandering. Moreover, long RT and mind-wandering were also associated with larger pupil diameter. This effect was exaggerated in GAD patients during perseverative cognition. Within brain, during both pre-target periods and target events, there were distinct neural correlates for mind-wandering (e.g., anterior cingulate and paracingulate activation at target onset) and perseverative cognition (e.g., opposite patterns of activation in posterior cingulate and cerebellum at target onset in HC and GAD). Results suggest that not only attention systems but also sensory-motor cortices are important during off-task states. Interestingly, changes across the 'default mode network' also tracked fluctuations in pupillary size. Autonomic expression in pupillary changes mirrors brain activation patterns that occur during different forms of repetitive thinking.

Cortical morphometric predictors of autonomic dysfunction in generalized anxiety disorder.

Generalized anxiety disorder (GAD) is associated with both autonomic dysfunction, notably decreased vagally-mediated heart rate variability (vmHRV), and neurostructural abnormalities. Regional differences in brain morphometry correlate with vmHRV in healthy individuals. Here, we tested the hypothesis that specific focal abnormalities in cortical structure in GAD underpin decreased vmHRV. Adult female patients with GAD (n = 17) and matched controls (n = 18) underwent structural magnetic resonance imaging after characterization of symptoms and quantification of resting vmHRV derived from continuous pulse oximetry. Cortical reconstruction was performed using the FreeSurfer image analysis suite. A priori analysis was conducted only within brain regions involved in vagal control of heart rate. Compared to controls, patients with GAD showed cortical thinning of the (i) left rostral anterior cingulate cortex, (ii) left medial orbitofrontal cortex, and (iii) right isthmus cingulate gyrus. Significant negative relationships were identified between the severity of anxiety symptoms and cortical thickness of the left medial orbitofrontal cortex and right isthmus cingulate gyrus. Compared to controls, patients with GAD showed decreased vmHRV at rest. In controls only, cortical thickness of the left caudal anterior cingulate cortex correlated positively with resting vmHRV. These results extend evidence in GAD for structural abnormalities within cortical areas implicated in emotion regulation and cognition. In addition, these findings may implicate abnormal integrity of anterior cingulate cortex in the psychophysiological expression of GAD and suggest that interventional targeting of this region may normalize autonomic function in GAD.

Network abnormalities in generalized anxiety pervade beyond the amygdala-pre-frontal cortex circuit: Insights from graph theory.

Generalized anxiety disorder (GAD) has excessive anxiety and uncontrollable worry as core symptoms. Abnormal cerebral functioning underpins the expression and perhaps pathogenesis of GAD:. Studies implicate impaired communication between the amygdala and the pre-frontal cortex (PFC). Our aim was to longitudinally investigate whether such network abnormalities are spatially restricted to this circuit or if the integrity of functional brain networks is globally disrupted in GAD. We acquired resting-state functional magnetic resonance imaging data from 16 GAD patients and 16 matched controls at baseline and after 1 year. Using network modeling and graph-theory, whole-brain connectivity was characterized from local and global perspectives. Overall lower global efficiency, indicating sub-optimal brain-wide organization and integration, was present in patients with GAD compared to controls. The amygdala and midline cortices showed higher betweenness centrality, reflecting functional dominance of these brain structures. Third, lower betweenness centrality and lower degree emerged for PFC, suggesting weakened inhibitory control. Overall, network organization showed impairments consistent with neurobiological models of GAD (involving amygdala, PFC, and cingulate cortex) and further pointed to an involvement of temporal regions. Such impairments tended to progress over time and predict anxiety symptoms. A graph-analytic approach represents a powerful approach to deepen our understanding of GAD.

Quantitative Magnetization Transfer of White Matter Tracts Correlates with Diffusion Tensor Imaging Indices in Predicting the Conversion from Mild Cognitive Impairment to Alzheimer's Disease.

Patients with amnestic mild cognitive impairment (aMCI) have higher probability to develop Alzheimer's disease (AD) than elderly controls. The detection of subtle changes in brain structure associated with disease progression and the development of tools to identify patients at high risk for dementia in a short time is crucial. Here, we used probabilistic white matter (WM) tractography to explore microstructural alterations within the main association, limbic, and commissural pathways in aMCI patients who converted to AD after 1 year follow-up (MCIconverters) and those who remained stable (MCIstable). Both diffusion tensor imaging (DTI) and quantitative magnetization transfer (qMT) parameters have been considered for a comprehensive pathophysiological characterization of the WM damage. Overall, tract-specific parameters derived from qMT and DTI at baseline were able to differentiate aMCI patients who converted to AD from those who remained stable in time. In particular, the qMT exchange rate, RMB0, of the right uncinate fasciculus was significantly decreased in MCIconverters, whereas fractional anisotropy was significantly decreased in the bilateral superior cingulum in MCIconverters compared to MCIstable. These results confirm the involvement of WM and particularly of association fibers in the progression of AD, highlighting disconnection as a potential mechanism.

The verbal nature of worry in generalized anxiety: Insights from the brain.

Background: The Cognitive Avoidance Theory of Worry argues that worry is a cognitive strategy adopted to control the physiological arousal associated with anxiety. According to this theory, pathological worry, as in Generalized Anxiety Disorder (GAD), is verbal in nature, negative and abstract, rather than concrete. Neuroimaging studies link the expression of worry to characteristic modes of brain functional connectivity, especially in relation to the amygdala. However, the distinctive features of worry (verbal, abstract, negative), and their relationship to physiological arousal, have not so far been mapped to brain function. Methods: We addressed this omission by undertaking a resting-state functional magnetic resonance neuroimaging study of 19 patients with GAD and 21 controls, before and after induction of perseverative cognitions, while measuring emotional bodily arousal from heart rate (HR). Seed-based analyses quantified brain changes in whole brain functional connectivity from the amygdala. Results: In GAD, the induction increased negative thoughts and their verbal content. In line with predictions, the verbal expression of worry in GAD was associated with higher HR at baseline and attenuated HR increases after induction of perseverative cognitions. Within brain, the increased use of words during worry, and the associated dampening of HR after induction were mediated by the strength of functional connectivity between the amygdala and default mode network 'hubs' and the opercular cortex. The negative content of worry was further related to functional communication between amygdala and cingulo-opercular and temporal cortices. Conclusions: Findings provide a neurobiological basis for the impact of verbal worry on HR in GAD.

Fear processing is differentially affected by lateralized stimulation of carotid baroreceptors.

Information processing, particularly of salient emotional stimuli, is influenced by cardiovascular afferent signals. Carotid baroreceptors signal the state of cardiovascular arousal to the brain, controlling blood pressure and heart rate via the baroreflex. Animal studies suggest a lateralization of this effect: Experimental stimulation of the right carotid sinus has a greater impact on heart rate when compared to left-sided stimulation. We tested, in humans, whether the processing of emotional information from faces was differentially affected by right versus left carotid afferents. To achieve so, we used an automated neck suction device to stimulate the carotid mechanoreceptors in the carotid sinus (parasympathetic pathway) synchronously with functional magnetic resonance imaging (fMRI) acquisition whilst participants were engaged in an emotional rating task of fearful and neutral faces. We showed that both right and left carotid stimulation (CS) influenced brain activity within opercular regions, although a stronger activation was observed within left insula during right stimulation compared to left stimulation. As regards the processing of fearful faces, right, but not left carotid stimulation attenuated the perceived intensity of fear, and (albeit to a lesser extent) enhanced intensity ratings of neutral faces. Mirroring the behavioural effects, there was a significant expression-by-stimulation interaction for right carotid stimulation only, when bilateral amygdala responses were attenuated to fear faces and amplified to neutral faces. Individual differences in basal heart rate variability (HRV) predicted the extent to which right carotid stimulation attenuated amygdala responses during fear processing. Our study provides unique evidence for lateralized viscerosensory effects on brain systems supporting emotional processing.

A meta-analysis of non-invasive brain stimulation and autonomic functioning: Implications for brain-heart pathways to cardiovascular disease.

Given the intrinsic connection between the brain and the heart, a recent body of research emerged with the aim to influence cardiovascular system functioning by non-invasive brain stimulation (NIBS) methods such as repetitive transcranial magnetic stimulation and transcranial direct current stimulation. Despite the implications of cardiovascular activity modulation for therapeutic purposes, such effects of NIBS have not yet been quantified. The aim of this study was to meta-analyze studies on NIBS effects on blood pressure (BP), heart rate (HR) and its variability (HRV). PubMed and Scopus databases were searched for English language studies conducted in humans. Twenty-nine studies were eligible for the analyses. Pooled effect sizes (Hedges' g) were compared. Random effect models were used. NIBS was effective in reducing HR (g=0.17) and enhancing HRV (g=0.30). A marginal effect emerged for BP (g=0.21). Significant moderators were the stimulation technique and the site of stimulation. Results show that NIBS affects cardiovascular and autonomic nervous system activity, confirming a potential pathogenic brain-heart pathway to cardiovascular disease.