Tag: brainstem

Subcortical and Default Mode Network connectivity is impaired in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex chronic condition with core symptoms of fatigue, and cognitive dysfunction suggesting a key role for the central nervous system, in the pathophysiology of this disease. Several studies have reported altered functional connectivity (FC) related to motor and cognitive deficits in ME/CFS patients. In this study, we compared functional connectivity differences between 31 ME/CFS and 15 healthy controls (HC) using 7 Tesla MRI. Functional scans were acquired during a cognitive Stroop color-word task and blood oxygen level-dependent (BOLD) time-series were computed for 27 regions of interest (ROIs) in the cerebellum, brainstem, and salience and default mode networks.

Region-based comparison detected reduced FC between the pontine nucleus and cerebellum vermis IX (p=0.027) for ME/CFS patients compared to HC. Our ROI-to-voxel analysis found significant impairment of FC within ponto-cerebellar regions in ME/CFS. Correlation analyses of connectivity with clinical scores in ME/CFS patients detected associations of FC with ‘duration of illness’ and ‘memory scores’ in salience network hubs and cerebellum vermis, and with ‘respiratory rate’ within medulla and the default mode network FC.

This novel investigation is the first to report extensive involvement of aberrant ponto-cerebellar connections consistent with ME/CFS symptomatology. This highlights the involvement of the brainstem and the cerebellum in the pathomechanism of ME/CFS.

Source: Maira INDERYAS, Kiran Thapaliya, Sonya Marshall-Gradisnik, Markus Barth, Leighton Barnden. Subcortical and Default Mode Network connectivity is impaired in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Front. Neurosci. Sec. Brain Imaging Methods. Volume 17 – 2023 | doi: 10.3389/fnins.2023.1318094 https://www.frontiersin.org/articles/10.3389/fnins.2023.1318094/full (Full text)

Altered brain connectivity in Long Covid during cognitive exertion: a pilot study

Abstract:

Introduction: Debilitating Long-Covid symptoms occur frequently after SARS-COVID-19 infection.

Methods: Functional MRI was acquired in 10 Long Covid (LCov) and 13 healthy controls (HC) with a 7 Tesla scanner during a cognitive (Stroop color-word) task. BOLD time series were computed for 7 salience and 4 default-mode network hubs, 2 hippocampus and 7 brainstem regions (ROIs). Connectivity was characterized by the correlation coefficient between each pair of ROI BOLD time series. We tested for HC versus LCov differences in connectivity between each pair of the 20 regions (ROI-to-ROI) and between each ROI and the rest of the brain (ROI-to-voxel). For LCov, we also performed regressions of ROI-to-ROI connectivity with clinical scores.

Results: Two ROI-to-ROI connectivities differed between HC and LCov. Both involved the brainstem rostral medulla, one connection to the midbrain, another to a DM network hub. Both were stronger in LCov than HC. ROI-to-voxel analysis detected multiple other regions where LCov connectivity differed from HC located in all major lobes. Most, but not all connections, were weaker in LCov than HC. LCov, but not HC connectivity, was correlated with clinical scores for disability and autonomic function and involved brainstem ROI.

Discussion: Multiple connectivity differences and clinical correlations involved brainstem ROIs. Stronger connectivity in LCov between the medulla and midbrain may reflect a compensatory response. This brainstem circuit regulates cortical arousal, autonomic function and the sleep-wake cycle. In contrast, this circuit exhibited weaker connectivity in ME/CFS. LCov connectivity regressions with disability and autonomic scores were consistent with altered brainstem connectivity in LCov.

Source: Barnden L, Thapaliya K, Eaton-Fitch N, Barth M, Marshall-Gradisnik S. Altered brain connectivity in Long Covid during cognitive exertion: a pilot study. Front Neurosci. 2023 Jun 22;17:1182607. doi: 10.3389/fnins.2023.1182607. PMID: 37425014; PMCID: PMC10323677. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10323677/ (Full text)

Achieving symptom relief in patients with Myalgic encephalomyelitis by targeting the neuro-immune interface and optimizing disease tolerance

Abstract:

Myalgic encephalomyelitis, ME, previously also known as chronic fatigue syndrome (CFS) is a heterogeneous, debilitating syndrome of unknown etiology responsible for long-lasting disability in millions of patients worldwide. The most well-known symptom of ME is post-exertional malaise, but many patients also experience autonomic dysregulation, cranial nerve dysfunction and signs of immune system activation. Many patients also report a sudden onset of disease following an infection.

The brainstem is a suspected focal point in ME pathogenesis and patients with structural impairment to the brainstem often show ME-like symptoms. The brainstem is also where the vagus nerve originates, a critical neuro-immune interface and mediator of the inflammatory reflex which regulate systemic inflammation.

Here we report the results of a randomized, placebo-controlled trial using intranasal mechanical stimulation (INMEST) targeting nerve endings in the nasal cavity, likely from the trigeminal nerve, possibly activating additional centers in the brainstem of ME-patients and correlating with a ∼30% reduction in overall symptom scores after eight weeks of treatment.

By performing longitudinal, systems-level monitoring of the blood immune system in these patients, we uncover signs of chronic immune activation in ME, as well as immunological correlates of improvement that center around gut-homing immune cells and reduced inflammation.

The mechanisms of symptom relief remains to be determined, but transcriptional analyses suggest an upregulation of disease tolerance mechanisms. We believe that these results are suggestive of ME as a condition explained by a maladaptive disease tolerance response following infection.

Source: Lucie Rodriguez, Christian Pou, Tadepally Lakshmikanth, Jingdian Zhang, Constantin Habimana Mugabo, Jun Wang, Jaromir Mikes, Axel Olin, Yang Chen, Joanna Rorbach, Jan-Erik Juto, Tie Qiang Li, Per Julin, Petter Brodin, Achieving symptom relief in patients with Myalgic encephalomyelitis by targeting the neuro-immune interface and optimizing disease tolerance, Oxford Open Immunology, 2023;, iqad003, https://doi.org/10.1093/oxfimm/iqad003 (Full text available as PDF file)

Long COVID: Cognitive and FDG PET evolutions in six patients

Abstract:

Long COVID is often characterized by cognitive complaints and deficits occurring immediately or several weeks after the infectious disease. Neuropsychological tests can revealed attention and executive function anomalies and FDG PET can display hypometabolic areas affecting various regions including frontal and cingulate cortices as well as precuneus and brainstem. We report here the cognitive and FDG PET evolutions over one year in 6 patients suffering from long COVID. Our study shows cognitive and FDG PET improvements in most of the cases and highlight the importance of a careful neurological follow-up in these patients.

Source: Jacques Hugon, Karim Farid, Mathieu Queneau et al. Long COVID: Cognitive and FDG PET evolutions in six patients, 03 April 2023, PREPRINT (Version 1) available at Research Square. https://doi.org/10.21203/rs.3.rs-2703691/v1 https://www.researchsquare.com/article/rs-2703691/v1 (Full text)

Brainstem volume changes in myalgic encephalomyelitis/chronic fatigue syndrome and long COVID patients

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and long COVID patients have overlapping neurological, autonomic, pain, and post-exertional symptoms. We compared volumes of brainstem regions for 10 ME/CFS (CCC or ICC criteria), 8 long COVID (WHO Delphi consensus), and 10 healthy control (HC) subjects on 3D, T1-weighted MRI images acquired using sub-millimeter isotropic resolution using an ultra-high field strength of 7 Tesla.

Group comparisons with HC detected significantly larger volumes in ME/CFS for pons (p = 0.004) and whole brainstem (p = 0.01), and in long COVID for pons (p = 0.003), superior cerebellar peduncle (p = 0.009), and whole brainstem (p = 0.005). No significant differences were found between ME/CFS and long COVID volumes. In ME/CFS, we detected positive correlations between the pons and whole brainstem volumes with “pain” and negative correlations between the midbrain and whole brainstem volumes with “breathing difficulty.”

In long COVID patients a strong negative relationship was detected between midbrain volume and “breathing difficulty.” Our study demonstrated an abnormal brainstem volume in both ME/CFS and long COVID consistent with the overlapping symptoms.

Source: Thapaliya K, Marshall-Gradisnik S, Barth M, Eaton-Fitch N, Barnden L. Brainstem volume changes in myalgic encephalomyelitis/chronic fatigue syndrome and long COVID patients. Frontiers in Neuroscience, 2023 March 2; 17:1125208. https://www.frontiersin.org/articles/10.3389/fnins.2023.1125208/full (Full text)

A Prospect to Ameliorate Affective Symptoms and to Enhance Cognition in Long COVID Using Auricular Transcutaneous Vagus Nerve Stimulation

Abstract:

Long COVID, the postviral disorder caused by COVID-19, is expected to become one of the leading causes of disability in Europe. The cognitive consequences of long COVID have been described as “brain fog” and characterized by anxiety and depression, and by cognitive deficits. Long COVID is assumed to be a complex condition arising from multiple causes, including persistent brainstem dysfunction and disrupted vagal signaling.

We recommend the potential application of auricular transcutaneous vagus nerve stimulation (atVNS) as an ADD-ON instrument to compensate for the cognitive decline and to ameliorate affective symptoms caused by long COVID. This technique enhances vagal signaling by directly activating the nuclei in the brainstem, which are hypoactive in long COVID to enhance mood and to promote attention, memory, and cognitive control-factors affected by long COVID.

Considering that atVNS is a non-pharmacological intervention, its ADD-ON to standard pharmaceutical agents will be useful for non-responders, making of this method a suitable tool. Given that atVNS can be employed as an ecological momentary intervention (EMI), we outline the translational advantages of atVNS in the context of accelerating the cognitive and affective recovery from long COVID.

Source: Colzato LS, Elmers J, Beste C, Hommel B. A Prospect to Ameliorate Affective Symptoms and to Enhance Cognition in Long COVID Using Auricular Transcutaneous Vagus Nerve Stimulation. J Clin Med. 2023 Feb 2;12(3):1198. doi: 10.3390/jcm12031198. PMID: 36769845. https://www.mdpi.com/2077-0383/12/3/1198 (Full text)

Altered Pain in the Brainstem and Spinal Cord of Fibromyalgia Patients During the Anticipation and Experience of Experimental Pain

Abstract:

Chronic pain associated with fibromyalgia (FM) affects a large portion of the population but the underlying mechanisms leading to this altered pain are still poorly understood. Evidence suggests that FM involves altered neural processes in the central nervous system and neuroimaging methods such as functional magnetic resonance imaging (fMRI) are used to reveal these underlying alterations. While many fMRI studies of FM have been conducted in the brain, recent evidence shows that the changes in pain processing in FM may be linked to autonomic and homeostatic dysregulation, thus requiring further investigation in the brainstem and spinal cord.

Functional magnetic resonance imaging data from 15 women with FM and 15 healthy controls were obtained in the cervical spinal cord and brainstem at 3 tesla using previously established methods. In order to investigate differences in pain processing in these groups, participants underwent trials in which they anticipated and received a predictable painful stimulus, randomly interleaved with trials with no stimulus. Differences in functional connectivity between the groups were investigated by means of structural equation modeling.

The results demonstrate significant differences in brainstem/spinal cord network connectivity between the FM and control groups which also correlated with individual differences in pain responses. The regions involved in these differences in connectivity included the LC, hypothalamus, PAG, and PBN, which are known to be associated with autonomic homeostatic regulation, including fight or flight responses. This study extends our understanding of altered neural processes associated with FM and the important link between sensory and autonomic regulation systems in this disorder.

Source: Ioachim G, Warren HJM, Powers JM, Staud R, Pukall CF, Stroman PW. Altered Pain in the Brainstem and Spinal Cord of Fibromyalgia Patients During the Anticipation and Experience of Experimental Pain. Front Neurol. 2022 May 6;13:862976. doi: 10.3389/fneur.2022.862976. PMID: 35599729; PMCID: PMC9120571. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9120571/ (Full text)

Review of the Midbrain Ascending Arousal Network Nuclei and Implications for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), Gulf War Illness (GWI) and Postexertional Malaise (PEM)

Abstract:
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS and Gulf War Illness (GWI) share features of post-exertional malaise (PEM), exertional exhaustion, or postexertional symptom exacerbation. In a two-day model of PEM, submaximal exercise induced significant changes in activation of the dorsal midbrain during a high cognitive load working memory task (Washington 2020) (Baraniuk this issue). Controls had no net change. However, ME/CFS had increased activity after exercise, while GWI had significantly reduced activity indicating differential responses to exercise and pathological mechanisms.
These data plus findings of the midbrain and brainstem atrophy in GWI inspired a review of the anatomy and physiology of the dorsal midbrain and isthmus nuclei in order to infer dysfunctional mechanisms that may contribute to disease pathogenesis and postexertional malaise. The nuclei of the ascending arousal network were addressed. Midbrain and isthmus nuclei participate in threat assessment, awareness, attention, mood, cognition, pain, tenderness, sleep, thermoregulation, light and sound sensitivity, orthostatic symptoms, and autonomic dysfunction and are likely to contribute to the symptoms of postexertional malaise in ME/CFS and GWI.
Source: James N. Baraniuk. Review of the Midbrain Ascending Arousal Network Nuclei and Implications for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), Gulf War Illness (GWI) and Postexertional Malaise (PEM) Brain Sci. 2022, 12(2), 132; https://doi.org/10.3390/brainsci12020132 (registering DOI) https://www.mdpi.com/2076-3425/12/2/132/htm (Full text)

Brainstem Abnormalities in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Scoping Review and Evaluation of Magnetic Resonance Imaging Findings

Abstract:

Background: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a multisystem medical condition with heterogeneous symptom expression. Currently, there is no effective cure or treatment for the standard care of patients. A variety of ME/CFS symptoms can be linked to the vital life functions of the brainstem, the lower extension of the brain best known as the hub relaying information back and forth between the cerebral cortex and various parts of the body.

Objective/Methods: Over the past decade, Magnetic Resonance Imaging (MRI) studies have emerged to understand ME/CFS with interesting findings, but there has lacked a synthesized evaluation of what has been found thus far regarding the involvement of the brainstem. We conducted this study to review and evaluate the recent MRI findings via a literature search of the MEDLINE database, from which 11 studies met the eligibility criteria.

Findings: Data showed that MRI studies frequently reported structural changes in the white and gray matter. Abnormalities of the functional connectivity within the brainstem and with other brain regions have also been found. The studies have suggested possible mechanisms including astrocyte dysfunction, cerebral perfusion impairment, impaired nerve conduction, and neuroinflammation involving the brainstem, which may at least partially explain a substantial portion of the ME/CFS symptoms and their heterogeneous presentations in individual patients.

Conclusions: This review draws research attention to the role of the brainstem in ME/CFS, helping enlighten future work to uncover the pathologies and mechanisms of this complex medical condition, for improved management and patient care.

Source: Nelson T, Zhang LX, Guo H, Nacul L, Song X. Brainstem Abnormalities in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Scoping Review and Evaluation of Magnetic Resonance Imaging Findings. Front Neurol. 2021 Dec 17;12:769511. doi: 10.3389/fneur.2021.769511. PMID: 34975729; PMCID: PMC8718708. https://www.frontiersin.org/articles/10.3389/fneur.2021.769511/full (Full text)

Persistent Brainstem Dysfunction in Long-COVID: A Hypothesis

Abstract:

Long-COVID is a postviral illness that can affect survivors of COVID-19, regardless of initial disease severity or age. Symptoms of long-COVID include fatigue, dyspnea, gastrointestinal and cardiac problems, cognitive impairments, myalgia, and others. While the possible causes of long-COVID include long-term tissue damage, viral persistence, and chronic inflammation, the review proposes, perhaps for the first time, that persistent brainstem dysfunction may also be involved.

This hypothesis can be split into two parts. The first is the brainstem tropism and damage in COVID-19. As the brainstem has a relatively high expression of ACE2 receptor compared with other brain regions, SARS-CoV-2 may exhibit tropism therein. Evidence also exists that neuropilin-1, a co-receptor of SARS-CoV-2, may be expressed in the brainstem. Indeed, autopsy studies have found SARS-CoV-2 RNA and proteins in the brainstem. The brainstem is also highly prone to damage from pathological immune or vascular activation, which has also been observed in autopsy of COVID-19 cases.

The second part concerns functions of the brainstem that overlap with symptoms of long-COVID. The brainstem contains numerous distinct nuclei and subparts that regulate the respiratory, cardiovascular, gastrointestinal, and neurological processes, which can be linked to long-COVID. As neurons do not readily regenerate, brainstem dysfunction may be long-lasting and, thus, is long-COVID. Indeed, brainstem dysfunction has been implicated in other similar disorders, such as chronic pain and migraine and myalgic encephalomyelitis or chronic fatigue syndrome.

Source: Yong SJ. Persistent Brainstem Dysfunction in Long-COVID: A Hypothesis. ACS Chem Neurosci. 2021 Feb 4;12(4):573–80. doi: 10.1021/acschemneuro.0c00793. Epub ahead of print. PMID: 33538586; PMCID: PMC7874499. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7874499/ (Full text)