Disrupted connectivity within visual, attentional and salience networks in the visual snow syndrome.

Here we investigate brain functional connectivity in patients with visual snow syndrome (VSS). Our main objective was to understand more about the underlying pathophysiology of this neurological syndrome. Twenty-four patients with VSS and an equal number of gender and age-matched healthy volunteers attended MRI sessions in which whole-brain maps of functional connectivity were acquired under two conditions: at rest while watching a blank screen and during a visual paradigm consisting of a visual-snow like stimulus. Eight unilateral seed regions were selected a priori based on previous observations and hypotheses; four seeds were placed in key anatomical areas of the visual pathways and the remaining were derived from a pre-existing functional analysis. The between-group analysis showed that patients with VSS had hyper and hypoconnectivity between key visual areas and the rest of the brain, both in the resting state and during a visual stimulation, compared with controls. We found altered connectivity internally within the visual network; between the thalamus/basal ganglia and the lingual gyrus; between the visual motion network and both the default mode and attentional networks. Further, patients with VSS presented decreased connectivity during external sensory input within the salience network, and between V5 and precuneus. Our results suggest that VSS is characterised by a widespread disturbance in the functional connectivity of several brain systems. This dysfunction involves the pre-cortical and cortical visual pathways, the visual motion network, the attentional networks and finally the salience network; further, it represents evidence of ongoing alterations both at rest and during visual stimulus processing

Perceptual Inference in Chronic Pain:An Investigation into the Economy of Action Hypothesis

Objective: The experience of chronic pain critically alters one's ability to interact with their environment. One fundamental issue that has received little attention, however, is whether chronic pain disrupts how one perceives their environment in the first place. The Economy of Action hypothesis purports that the environment is spatially scaled according to the ability of the observer. Under this hypothesis it has been proposed that the perception of the world is different between those with and without chronic pain. Such a possibility has profound implications for the investigation and treatment of pain. The present investigation tested the application of this hypothesis to a heterogenous chronic pain population. Methods: Individuals with chronic pain (36; 27F) and matched pain-free controls were recruited. Each participant was required to judge the distance to a series of target cones, to which they were to subsequently walk. In addition, at each distance, participants used Numerical Rating Scales to indicate their perceived effort and perceived pain associated with the distance presented. Results: Our findings do not support the Economy of Action hypothesis: there were no significant differences in distance estimates between the chronic pain and pain-free groups (F 1,60 =0.927; P=0.340). In addition, we found no predictive relationship in the chronic pain group between anticipated pain and estimated distance (F 1,154 =0.122, P=0.727), nor anticipated effort (1.171, P=0.281) and estimated distance (F 1,154 =1.171, P=0.281). Discussion: The application of the Economy of Action hypothesis and the notion of spatial perceptual scaling as a means to assess and treat the experience of chronic pain are not supported by the results of this study

Insular and occipital changes in visual snow syndrome: a BOLD fMRI and MRS study.

OBJECTIVE To investigate the pathophysiology of visual snow (VS), through a combined functional neuroimaging and magnetic resonance spectroscopy (1 H-MRS) approach. METHODS We applied a functional MRI block-design protocol studying the responses to a visual stimulation mimicking VS, in combination with 1 H-MRS over the right lingual gyrus, in 24 patients with VS compared to an equal number of age- and gender-matched healthy controls. RESULTS We found reduced BOLD responses to the visual stimulus with respect to baseline in VS patients compared to controls, in the left (k = 291; P = 0.025; peak MNI coordinate [-34 12 -6]) and right (k = 100; P = 0.003; peak MNI coordinate [44 14 -2]) anterior insula. Our spectroscopy analysis revealed a significant increase in lactate concentrations in patients with respect to controls (0.66 ± 0.9 mmol/L vs. 0.07 ± 0.2 mmol/L; P < 0.001) in the right lingual gyrus. In this area, there was a significant negative correlation between lactate concentrations and BOLD responses to visual stimulation (P = 0.004; r = -0.42), which was dependent on belonging to the patient group. INTERPRETATION As shown by our BOLD analysis, VS is characterized by a difference in bilateral insular responses to a visual stimulus mimicking VS itself, which could be due to disruptions within the salience network. Our results also suggest that patients with VS have a localized disturbance in extrastriate anaerobic metabolism, which may in turn cause a decreased metabolic reserve for the regular processing of visual stimuli

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

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.This work was funded by a Medical Research Council Experimental Medicine Challenge Grant (MR/N026969/1). MAH, SM, OO and SW are also supported by the NIHR Biomedical Research Centre for Mental Health at the South London and Maudsley NHS Trust. JOM is supported by a Sir Henry Dale Fellowship jointly funded by the Welcome Trust and the Royal Society (grant number 206675/Z/17/Z) and a Medical Research Council (MRC) Centre grant (MR/N026063/1)

Erythritol and xylitol differentially impact brain networks involved in appetite regulation in healthy volunteers

Background: There is a growing consensus that sugar consumption should be reduced and the naturally occurring, low-calorie sweeteners xylitol and erythritol are gaining popularity as substitutes, but their effect on brain circuitry regulating appetite is unknown. Aim: The study’s objective was to examine the effects of the two sweeteners on cerebral blood flow (rCBF) and resting functional connectivity in brain networks involved in appetite regulation, and test whether these effects are related to gut hormone release. Methods: The study was performed as a randomized, double-blind, placebo-controlled, cross-over trial. Twenty volunteers received intragastric (ig) loads of 50g xylitol, 75g erythritol, 75g glucose dissolved in 300mL tap water or 300mL tap water. Resting perfusion and blood oxygenation level-dependent data were acquired to assess rCBF and functional connectivity. Blood samples were collected for determination of CCK, PYY, insulin and glucose. Results: We found: (i) xylitol, but not erythritol, increased rCBF in the hypothalamus, whereas glucose had the opposite effect; (ii) graph analysis of resting functional connectivity revealed a complex pattern of similarities and differences in brain network properties following xylitol, erythritol, and glucose; (iii) erythritol and xylitol induced a rise in CCK and PYY, (iv) erythritol had no and xylitol only minimal effects on glucose and insulin. Conclusion: Xylitol and erythritol have a unique combination of properties: no calories, virtually no effect on glucose and insulin while promoting the release of gut hormones, and impacting appetite-regulating neurocircuitry consisting of both similarities and differences with glucose

A randomised controlled feasibility trial of intermittent theta burst stimulation with an open longer-term follow-up for young people with persistent anorexia nervosa (RaISE):Study protocol

OBJECTIVE: We present the protocol of a feasibility randomised controlled trial (RCT) of intermittent theta burst stimulation (iTBS) for young people with anorexia nervosa (AN). Effective first-line psychological therapies exist for young people with AN, but little is known about how to treat those who do not respond. Non-invasive neuromodulation, such as iTBS, could address unmet treatment needs by targeting neurocircuitry associated with the development and/or maintenance of AN.DESIGN: Sixty-six young people (aged 13-30 years) with persistent AN will be randomly allocated to receive 20 sessions of real or sham iTBS over the left dorsolateral prefrontal cortex in addition to their usual treatment. Outcomes will be measured at baseline, post-treatment (1-month post-randomisation) and 4-months post-randomisation (when unblinding will occur). Additional open follow-ups will be conducted at 12- and 24-months post-randomisation. The primary feasibility outcome is the proportion of participants retained in the study at 4-months. Secondary outcomes include AN symptomatology, other psychopathology, quality of life, service utilisation, neurocognitive processes, and neuroimaging measures.DISCUSSION: Findings will inform the development of a future large-scale RCT. They will also provide exploratory data on treatment efficacy, and neural and neurocognitive predictors and correlates of treatment response to iTBS in AN.</p