Heart rate and heart rate variability in patients with chronic inflammatory joint disease: the role of pain duration and the insular cortex.

BACKGROUND: Chronic inflammatory joint diseases (CIJD) have been linked to increased cardiovascular morbidity and mortality. A decisive reason could be a dysregulation of the autonomic nervous system, which is responsible for the control of cardiovascular function. So far, the cause of changes in autonomic nervous system functions remains elusive. In this study, we investigate the role of chronic pain and the insular cortex in autonomic control of cardiac functioning in patients with CIJD. METHODS: We studied the autonomic nervous system through the assessment of heart rate and heart rate variability (HRV) at rest and under cognitive stimulation. Furthermore, we investigated insular cortex volume by performing surface-based brain morphometry with FreeSurfer. For this study, 47 participants were recruited, 22 individual age- and sex-matched pairs for the magnetic resonance imaging analyses and 14 for the HRV analyses. All available patients' data were used for analysis. RESULTS: Pain duration was negatively correlated with the resting heart rate in patients with chronic inflammatory joint diseases (n = 20). In a multiple linear regression model including only CIJD patients with heart rate at rest as a dependent variable, we found a significant positive relationship between heart rate at rest and the volume of the left insular cortex and a significant negative relationship between heart rate at rest and the volume of the right insular cortex. However, we found no significant differences in HRV parameters or insular cortex volumes between both groups. CONCLUSIONS: In this study we provide evidence to suggest insular cortex involvement in the process of ANS changes due to chronic pain in CIJD patients. The study was preregistered with the German Clinical Trials Register ( https://www.drks.de ; DRKS00012791; date of registration: 28 July 2017).

Replicability, Repeatability, and Long-term Reproducibility of Cerebellar Morphometry.

To identify robust and reproducible methods of cerebellar morphometry that can be used in future large-scale structural MRI studies, we investigated the replicability, repeatability, and long-term reproducibility of three fully automated software tools: FreeSurfer, CEREbellum Segmentation (CERES), and automatic cerebellum anatomical parcellation using U-Net with locally constrained optimization (ACAPULCO). Replicability was defined as computational replicability, determined by comparing two analyses of the same high-resolution MRI data set performed with identical analysis software and computer hardware. Repeatability was determined by comparing the analyses of two MRI scans of the same participant taken during two independent MRI sessions on the same day for the Kirby-21 study. Long-term reproducibility was assessed by analyzing two MRI scans of the same participant in the longitudinal OASIS-2 study. We determined percent difference, the image intraclass correlation coefficient, the coefficient of variation, and the intraclass correlation coefficient between two analyses. Our results show that CERES and ACAPULCO use stochastic algorithms that result in surprisingly high differences between identical analyses for ACAPULCO and small differences for CERES. Changes between two consecutive scans from the Kirby-21 study were less than ± 5% in most cases for FreeSurfer and CERES (i.e., demonstrating high repeatability). As expected, long-term reproducibility was lower than repeatability for all software tools. In summary, CERES is an accurate, as demonstrated before, and reproducible tool for fully automated segmentation and parcellation of the cerebellum. We conclude with recommendations for the assessment of replicability, repeatability, and long-term reproducibility in future studies on cerebellar structure.

Hyperactivity/restlessness is associated with increased functional connectivity in adults with ADHD: a dimensional analysis of resting state fMRI.

BACKGROUND: Adult attention-deficit/hyperactivity disorder (ADHD) is a serious and frequent psychiatric disorder of multifactorial pathogenesis. Several lines of evidence support the idea that ADHD is, in its core, a disorder of dysfunctional brain connectivity within and between several neurofunctional networks. The primary aim of this study was to investigate associations between the functional connectivity within resting state brain networks and the individual severity of core ADHD symptoms (inattention, hyperactivity, and impulsivity). METHODS: Resting state functional magnetic resonance imaging (rs-fMRI) data of 38 methylphenidate-naïve adults with childhood-onset ADHD (20 women, mean age 40.5 years) were analyzed using independent component analysis (FSL's MELODIC) and FSL's dual regression technique. For motion correction, standard volume-realignment followed by independent component analysis-based automatic removal of motion artifacts (FSL's ICA-AROMA) were employed. To identify well-established brain networks, the independent components found in the ADHD group were correlated with brain networks previously found in healthy participants (Smith et al. PNAS 2009;106:13040-5). To investigate associations between functional connectivity and individual symptom severity, sex, and age, linear regressions were performed. RESULTS: Decomposition of resting state brain activity of adults with ADHD resulted in similar resting state networks as previously described for healthy adults. No significant differences in functional connectivity were seen between women and men. Advanced age was associated with decreased functional connectivity in parts of the bilateral cingulate and paracingulate cortex within the executive control network. More severe hyperactivity was associated with increased functional connectivity in the left putamen, right caudate nucleus, right central operculum and a portion of the right postcentral gyrus within the auditory/sensorimotor network. CONCLUSIONS: The present study supports and extends our knowledge on the involvement of the striatum in the pathophysiology of ADHD, in particular, in the pathogenesis of hyperactivity. Our results emphasize the usefulness of dimensional analyses in the study of ADHD, a highly heterogeneous disorder. TRIAL REGISTRATION: ISRCTN12722296 ( https://doi.org/10.1186/ISRCTN12722296 ).

Motor recovery beginning 23 years after ischemic stroke.

It is widely believed that most stroke recovery occurs within 6 mo, with little benefit of physiotherapy or other modalities beyond 1 yr. We report a remarkable case of stroke recovery beginning 23 yr after a severe stroke due to embolization from the innominate artery and subclavian artery, resulting from compression of the right subclavian artery by a cervical rib. The patient had a large right frontoparietal infarction with severe left hemiparesis and a totally nonfunctional spastic left hand. He experienced some recovery of hand function that began 23 yr after the stroke, 1 yr after he took up regular swimming. As a result, intensive physiotherapy was initiated, with repetitive large muscle movement and a spring-loaded mechanical orthosis that provides resistance to finger flexors and supports finger extensors. Within 2 yr, he could pick up coins with the previously useless left hand. Functional MRI studies document widespread distribution of the recovery in both hemispheres. This case provides impetus not only to more intensive and prolonged physiotherapy, but also to treatment with emerging modalities such as stem cell therapy and exosome and microRNA therapies.NEW & NOTEWORTHY Widespread bilateral activation of both sides of the cerebrum and cerebellum are demonstrated on functional MRI after motor recovery of a completely nonfunctional left hand that began 23 yr after a severe stroke. This suggests that the generally accepted window of recovery beyond which further therapy is not indicated should be entirely reconsidered. Physiotherapy and new modalities in development might be indicated long after a stroke.

Human cerebral circuitry related to cardiac control: A neuroimaging meta-analysis.

Serious arrhythmias often follow stroke, highlighting the important role that the cerebral cortex has in neural regulation of the heart. Neuroimaging studies reveal patterns of activation associated with autonomic cardiovascular responses. Using the activation likelihood estimation, a meta-analysis was performed to identify cortical activation patterns related to heart rate and heart rate variability across studies that used differing stimuli of cardiovascular arousal. Consistent associations with heart rate and heart rate variability were observed in the anterior cingulate, amygdala, insula, and prefrontal cortex, among others. Also, evidence is provided of insular lateralization associated with autonomic cardiac responses. Ann Neurol 2016;79:709-716.

Synthetic Cannabinoid Use in a Psychiatric Patient Population: A Pilot Study.

BACKGROUND: Consumption of natural cannabis (NC) and synthetic cannabinoids (SCs) has been associated with psychotic disorders. We compared the prevalence of use, consumer profiles, and psychosis-inducing potential of NC and SCs in a specific high-risk population. METHODS: This prospective pilot study included 332 patients (18-64 years, mean 36.83, SD 13.33). Patients' sociodemographics and medical histories as well as illicit substance use and psychiatric symptom histories were collected using a drug consumption survey that assessed the use of new psychoactive substances and the Psychotic Symptoms Interview. RESULTS: In total, 7.2% of all patients, 10.6% of psychotic patients, and 4.5% of nonpsychotic patients reported SC consumption. Compared with SCs, NC was consumed much more frequently by its users (mean 222.73, SD 498.27). NC and SC use induced persistent psychosis. Psychotic symptoms were first experienced by patients with a history of NC or SC use during intoxication and persisted after cessation (>1 year) of drug use. Positive and negative symptoms tended to be more severe in SC and NC users, respectively. CONCLUSIONS: NC and SCs may cause different symptom clusters. These relationships should be further evaluated.

Longitudinal observations of the effects of ischemic stroke on binaural perception.

Acute ischemic stroke, characterized by a localized reduction in blood flow to specific areas of the brain, has been shown to affect binaural auditory perception. In a previous study conducted during the acute phase of ischemic stroke, two tasks of binaural hearing were performed: binaural tone-in-noise detection, and lateralization of stimuli with interaural time- or level differences. Various lesion-specific, as well as individual, differences in binaural performance between patients in the acute phase of stroke and a control group were demonstrated. For the current study, we re-invited the same group of patients, whereupon a subgroup repeated the experiments during the subacute and chronic phases of stroke. Similar to the initial study, this subgroup consisted of patients with lesions in different locations, including cortical and subcortical areas. At the group level, the results from the tone-in-noise detection experiment remained consistent across the three measurement phases, as did the number of deviations from normal performance in the lateralization task. However, the performance in the lateralization task exhibited variations over time among individual patients. Some patients demonstrated improvements in their lateralization abilities, indicating recovery, whereas others' lateralization performance deteriorated during the later stages of stroke. Notably, our analyses did not reveal consistent patterns for patients with similar lesion locations. These findings suggest that recovery processes are more individual than the acute effects of stroke on binaural perception. Individual impairments in binaural hearing abilities after the acute phase of ischemic stroke have been demonstrated and should therefore also be targeted in rehabilitation programs.

The impact of aging on morphometric changes in the cerebellum: A voxel-based morphometry study.

Introduction: Aging influences the morphology of the central nervous system. While several previous studies focused on morphometric changes of the supratentorial parts, investigations on age-related cerebellar changes are rare. The literature concerning the morphological changes in the cerebellum is heterogenous depending (i) on the methods used (cerebellar analysis in the context of a whole brain analysis or specific methods for a cerebellar analysis), (ii) the life span that was investigated, and (iii) the analytic approach (i.e., using linear or non-linear methods). Methods: We fill this research gap by investigating age-dependent cerebellar changes in the aging process occurring before the age of 70 in healthy participants, using non-linear methods and the spatially unbiased infratentorial template (SUIT) toolbox which is specifically developed to examine the cerebellum. Furthermore, to derive an overview of the possible behavioral correlates, we relate our findings to functional maps of the cerebellum. Twenty-four older participants (mean age 64.42 years, SD ± 4.8) and 25 younger participants (mean age 24.6 years, SD ± 2.14) were scanned using a 3 T-MRI, and the resulting data were processed using a SUIT. Results: Gray matter (GM) volume loss was found in older participants in three clusters in the right cerebellar region, namely crus I/II and lobule VI related to the frontoparietal network, with crus I being functionally related to the default-mode network and lobule VI extending into vermis VIIa related to the ventral-attention-network. Discussion: Our results underline an age-related decline in GM volume in the right cerebellar regions that are functionally predominantly related to non-motor networks and cognitive tasks regions of the cerebellum before the age of 70.

Corrigendum: Effects of acute ischemic stroke on binaural perception.

[This corrects the article DOI: 10.3389/fnins.2022.1022354.].

Brain, heart, and sudden death.

During the past 30 years, rate of coronary artery disease (CAD), as the main cause of sudden death (SD), has decreased more than rate of SD. Likewise, cause of SD remains elusive in not a trivial portion of its victims. One possible reason is attention to only one organ, the heart, as the cause of SD. In fact, SD literature focuses more on the heart, less on the brain, and seldom on both. A change is required. In this paper, we first review the pathological findings seen in heart autopsies of SD victims after psychological stressors such as physical assault victims without internal injuries. Then, we summarize new studies investigating brain areas, like the insula, whose malfunctions and injuries are related to SD. Next, we review prototypes of neurological diseases and psychological stressors associated with SD and look at heart failure (HF)-related SD providing evidence for the brain-heart connection. Finally, we propose a new look at SD risk factors considering both brain and heart in their association with SD, and review strategies for prevention of SD from this perspective.

Effects of acute ischemic stroke on binaural perception.

Stroke-induced lesions at different locations in the brain can affect various aspects of binaural hearing, including spatial perception. Previous studies found impairments in binaural hearing, especially in patients with temporal lobe tumors or lesions, but also resulting from lesions all along the auditory pathway from brainstem nuclei up to the auditory cortex. Currently, structural magnetic resonance imaging (MRI) is used in the clinical treatment routine of stroke patients. In combination with structural imaging, an analysis of binaural hearing enables a better understanding of hearing-related signaling pathways and of clinical disorders of binaural processing after a stroke. However, little data are currently available on binaural hearing in stroke patients, particularly for the acute phase of stroke. Here, we sought to address this gap in an exploratory study of patients in the acute phase of ischemic stroke. We conducted psychoacoustic measurements using two tasks of binaural hearing: binaural tone-in-noise detection, and lateralization of stimuli with interaural time- or level differences. The location of the stroke lesion was established by previously acquired MRI data. An additional general assessment included three-frequency audiometry, cognitive assessments, and depression screening. Fifty-five patients participated in the experiments, on average 5 days after their stroke onset. Patients whose lesions were in different locations were tested, including lesions in brainstem areas, basal ganglia, thalamus, temporal lobe, and other cortical and subcortical areas. Lateralization impairments were found in most patients with lesions within the auditory pathway. Lesioned areas at brainstem levels led to distortions of lateralization in both hemifields, thalamus lesions were correlated with a shift of the whole auditory space, whereas some cortical lesions predominantly affected the lateralization of stimuli contralateral to the lesion and resulted in more variable responses. Lateralization performance was also found to be affected by lesions of the right, but not the left, basal ganglia, as well as by lesions in non-auditory cortical areas. In general, altered lateralization was common in the stroke group. In contrast, deficits in tone-in-noise detection were relatively scarce in our sample of lesion patients, although a significant number of patients with multiple lesion sites were not able to complete the task.

Increased prefrontal cortex connectivity associated with depression vulnerability and relapse.

BACKGROUND: Major depressive disorder (MDD) is a highly prevalent mood disorder, characterized by depressed mood, reduced capabilities to concentrate, impaired cognition, as well as a high risk of relapse. Unaffected siblings who have high risks for MDD development and yet without clinical symptoms may be helpful for understanding the neural mechanisms of MDD traits. METHODS: We investigated both regional fluctuation and inter-regional synchronization in 31 fully remitted MDD patients, 29 unaffected siblings and 43 age, gender, and educational level matched helathy controls (HCs) using resting-state functional magnetic resonance imaging (rs-fMRI). The 17-item HAMD and neurocognitive scales were performed. Fractional amplitude of low-frequency fluctuation (fALFF) and functional connectivity (FC) strength were investigated. RESULTS: Compared with healthy control group, patients with remitted MDD and unaffected siblings showed increased fALFF in the left dorsomedial prefrontal cortex (dmPFC) and increased FC between the left dmPFC and the right ventromedial prefrontal cortex (vmPFC). In addition, a negative correlation was observed between the fALFF value in the left dmPFC and the speed of Trail Making Test in the remitted MDD patients. Higher vmPFC-dmPFC FC was positively correlated with Wisconsin Card Sorting Test (WCST) total correct, and negatively correlated with WCST random errors. CONCLUSIONS: In the absence of clinical symptoms, individuals with remitted MDD and unaffected siblings showed increased fALFF in left dmPFC as well as the vmPFC-dmPFC connectivity. These results suggest a specific trait abnormality in the default mode network associated with vulnerability to MDD, which may have implications for developing effective therapies using this network as a target.

Effect and neural mechanisms of the transcutaneous vagus nerve stimulation for relapse prevention in patients with remitted major depressive disorder: protocol for a longitudinal study.

INTRODUCTION: After the first episode, patients with remitted major depressive disorder (MDD) have a 60% chance of experiencing a second episode. There are currently no accepted, effective methods to prevent the recurrence of MDD in remission. Transcutaneous vagus nerve stimulation (taVNS) is a non-invasive, safe and economical approach based on the efficacy of VNS in improving clinical depression symptoms. This clinical trial will study the efficacy of taVNS in preventing MDD relapse and investigate the underlying mechanisms of this. METHODS AND ANALYSIS: We will conduct a multicentre, randomised, patient-blinded and evaluators double-blinded trial. We will randomise 90 eligible participants with recurrent MDD in remission in a 1:1 ratio into a real or sham taVNS group. All participants will be given six biopsychosocial assessments: proinflammatory cytokines, serum monoamine neurotransmitters, cognition, affective neuropsychology, multimodal neuroimaging and endocrinology. After the baseline measurements, all participants will be given corresponding interference for 6 months and then complete a 1-year follow-up. The assessments will be performed three times: at baseline, post-treatment and at the end of 1-year follow-up (except for multimodal MRI scanning, which will be conducted at the first two assessments only). Change in 17-item Hamilton Depression Rating Scale scores for MDD is the primary outcome parameter. ETHICS AND DISSEMINATION: The study protocol was approved by the Medical Ethical Committee of Beijing Hospital of Traditional Chinese Medicine on 18 January 2019 (2018BL-076). The trial results will be published in peer-reviewed journals and at conferences. TRIAL REGISTRATION NUMBER: ChiCTR1900022618.

The C4EB study-Transvamix (10% THC / 5% CBD) to treat chronic pain in epidermolysis bullosa: A protocol for an explorative randomized, placebo controlled, and double blind intervention crossover study.

Patients with the genetic blistering skin condition epidermolysis bullosa (EB) report severe pain as a consequence of skin and mucous membrane lesions including blisters, wounds, and scars. Adequate symptom alleviation is not often achieved using conventional pharmacologic interventions. Finding novel approaches to pain care in EB is imperative to improve the quality of life of patients living with EB. There are several anecdotal reports on the use of cannabinoid-based medicines (CBMs) by EB patients to reduce the burden of symptoms. However, controlled clinical investigations assessing these reported effects are lacking. As the pain quality "unpleasantness" delineates EB pain, we hypothesize the modulation of affective pain processing in the brain by way of intervention with CBMs comprising the cannabinoids Δ-9-tetrahydrocannabinol and cannabidiol-objectified by functional magnetic resonance imaging (fMRI). The C4EB study is an investigator-initiated, single-centre, randomized, double-blind, placebo-controlled and crossover trial. Adult patients with the diagnosis epidermolysis bullosa, reporting chronic pain will be eligible to participate. Following baseline measurements, participants will be randomized to receive the sublingually administered interventions placebo and Transvamix® in forward or reversed orders, each for two weeks and separated by a washout. The primary outcome is the difference in numeric rating scale pain scores between grouped interventions, using affective descriptors within the Short-form McGill Pain Questionnaire-2. Secondary outcomes include pain self-efficacy, concomitant analgesic medication-use and adverse events. Additionally, fMRI will be employed to assess brain connectivity related to neuroanatomic pain circuits at baseline, placebo and Transvamix® interventions. The study was approved by the ethical committee at the University Medical Center of Groningen in the Netherlands. Results will be submitted for publication in a peer-reviewed journal. Trial registration number: Netherlands Trial Register: NL9347 (Acronym: C4EB).

Stuttered swallowing: electric stimulation of the right insula interferes with water swallowing. A case report.

BACKGROUND: Various functional resonance imaging, magnetoencephalographic and lesion studies suggest the involvement of the insular cortex in the control of swallowing. However, the exact location of insular activation during swallowing and its functional significance remain unclear. CASE PRESENTATION: Invasive electroencephalographic monitoring was performed in a 24-year-old man with medically intractable stereotyped nocturnal hypermotor seizures due to a ganglioglioma. During stimulation of the right inferior posterior insular cortex with depth electrodes the patient spontaneously reported a perception of a "stutter in swallowing". Stimulation of the inferior posterior insular cortex at highest intensity (4 mA) was also associated with irregular and delayed swallows. Swallowing was not impaired during stimulation of the superior posterior insular cortex, regardless of stimulation intensity. CONCLUSIONS: These results indicate that the right inferior posterior insular cortex is involved in the neural circuitry underlying the control of swallowing.

On pain - Virginia Woolf and the language of poets and patients.

Influenced by Virginia Woolf pain is traditionally believed to be a private object that defies language. However, our analysis of classical and contemporary works of British and American poets, in addition to our own clinical experiences, leads us to challenge this notion. In accordance with Wittgenstein we instead view pain as a concept and objective experience that should encourage interaction. Reasons why patients and healthcare providers often assume language to be insufficient to grasp the complexity of pain are manifold. Based on neuro-cognitive mechanisms we propose an important contributor might be that patients in pain speak a different language than their pain-free peers and doctors.

Functional MRI of Native and Non-native Speech Sound Production in Sequential German-English Bilinguals.

Bilingualism and multilingualism are highly prevalent. Non-invasive brain imaging has been used to study the neural correlates of native and non-native speech and language production, mainly on the lexical and syntactic level. Here, we acquired continuous fast event-related FMRI during visually cued overt production of exclusively German and English vowels and syllables. We analyzed data from 13 university students, native speakers of German and sequential English bilinguals. The production of non-native English sounds was associated with increased activity of the left primary sensorimotor cortex, bilateral cerebellar hemispheres (lobule VI), left inferior frontal gyrus, and left anterior insula compared to native German sounds. The contrast German > English sounds was not statistically significant. Our results emphasize that the production of non-native speech requires additional neural resources already on a basic phonological level in sequential bilinguals.

Use of Transcutaneous Auricular Vagus Nerve Stimulation as an Adjuvant Therapy for the Depressive Symptoms of COVID-19: A Literature Review.

The coronavirus disease 2019 (COVID-19) comprises more than just severe acute respiratory syndrome. It also interacts with the cardiovascular, nervous, renal, and immune systems at multiple levels, increasing morbidity in patients with underlying cardiometabolic conditions and inducing myocardial injury or dysfunction. Transcutaneous auricular vagus nerve stimulation (taVNS), which is derived from auricular acupuncture, has become a popular therapy that is increasingly accessible to the general public in modern China. Here, we begin by outlining the historical background of taVNS, and then describe important links between dysfunction in proinflammatory cytokine release and related multiorgan damage in COVID-19. Furthermore, we emphasize the important relationships between proinflammatory cytokines and depressive symptoms. Finally, we discuss how taVNS improves immune function via the cholinergic anti-inflammatory pathway and modulates brain circuits via the hypothalamic-pituitary-adrenal axis, making taVNS an important treatment for depressive symptoms on post-COVID-19 sequelae. Our review suggests that the link between anti-inflammatory processes and brain circuits could be a potential target for treating COVID-19-related multiorgan damage, as well as depressive symptoms using taVNS.