Tag: brainstem

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)

Mapping of pathological change in chronic fatigue syndrome using the ratio of T1- and T2-weighted MRI scans

Abstract:

Myalgic Encephalomyelitis or Chronic Fatigue Syndrome (ME/CFS) subjects suffer from a variety of cognitive complaints indicating that the central nervous system plays a role in its pathophysiology. Recently, the ratio T1w/T2w has been used to study changes in tissue myelin and/or iron levels in neurodegenerative diseases such as multiple sclerosis and schizophrenia. In this study, we applied the T1w/T2w method to detect changes in tissue microstructure in ME/CFS patients relative to healthy controls.

We mapped the T1w/T2w signal intensity values in the whole brain for forty-five ME/CFS patients who met Fukuda criteria and twenty-seven healthy controls and applied both region- and voxel-based quantification. We also performed interaction-with-group regressions with clinical measures to test for T1w/T2w relationships that are abnormal in ME/CFS at the population level.

Region-based analysis showed significantly elevated T1w/T2w values (increased myelin and/or iron) in ME/CFS in both white matter (WM) and subcortical grey matter. The voxel-based group comparison with sub-millimetre resolution voxels detected very significant clusters with increased T1w/T2w in ME/CFS, mostly in subcortical grey matter, but also in brainstem and projection WM tracts. No areas with decreased T1w/T2w were found in either analysis. ME/CFS T1w/T2w regressions with heart-rate variability, cognitive performance, respiration rate and physical well-being were abnormal in both gray and white matter foci. Our study demonstrates that the T1w/T2w approach is very sensitive and shows increases in myelin and/or iron in WM and basal ganglia in ME/CFS.

Source: Thapaliya K, Marshall-Gradisnik S, Staines D, Barnden L. Mapping of pathological change in chronic fatigue syndrome using the ratio of T1- and T2-weighted MRI scans [published online ahead of print, 2020 Jul 31]. Neuroimage Clin. 2020;28:102366. doi:10.1016/j.nicl.2020.102366 https://pubmed.ncbi.nlm.nih.gov/32777701/

Intra brainstem connectivity is impaired in chronic fatigue syndrome

Abstract:

In myalgic encephalomyelitis or chronic fatigue syndrome (ME/CFS), abnormal MRI correlations with symptom severity and autonomic measures have suggested impaired nerve signal conduction within the brainstem. Here we analyse fMRI correlations to directly test connectivity within and from the brainstem. Resting and task functional MRI (fMRI) were acquired for 45 ME/CFS (Fukuda criteria) and 27 healthy controls (HC).

We selected limited brainstem reticular activation system (RAS) regions-of-interest (ROIs) based on previous structural MRI findings in a different ME/CFS cohort (bilateral rostral medulla and midbrain cuneiform nucleus), the dorsal Raphe nucleus, and two subcortical ROIs (hippocampus subiculum and thalamus intralaminar nucleus) reported to have rich brainstem connections.

When HC and ME/CFS were analysed separately, significant correlations were detected for both groups during both rest and task, with stronger correlations during task than rest. In ME/CFS, connections were absent between medulla and midbrain nuclei, although hippocampal connections with these nuclei were enhanced.

When corresponding correlations from HC and ME/CFS were compared, ME/CFS connectivity deficits were detected within the brainstem between the medulla and cuneiform nucleus and between the brainstem and hippocampus and intralaminar thalamus, but only during task.

In CFS/ME, weaker connectivity between some RAS nuclei was associated with increased symptom severity. RAS neuron oscillatory signals facilitate coherence in thalamo-cortical oscillations. Brainstem RAS connectivity deficits can explain autonomic changes and diminish cortical oscillatory coherence which can impair attention, memory, cognitive function, sleep quality and muscle tone, all symptoms of ME/CFS.

Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.

Source: Barnden LR, Shan ZY, Staines DR, Marshall-Gradisnik S, Finegan K, Ireland T, Bhuta S. Intra brainstem connectivity is impaired in chronic fatigue syndrome. Neuroimage Clin. 2019 Oct 19;24:102045. doi: 10.1016/j.nicl.2019.102045. [Epub ahead of print] https://www.ncbi.nlm.nih.gov/pubmed/31671321

Hyperintense sensorimotor T1 spin echo MRI is associated with brainstem abnormality in chronic fatigue syndrome

Abstract:

We recruited 43 Chronic Fatigue Syndrome (CFS) subjects who met Fukuda criteria and 27 healthy controls and performed 3T MRI T1 and T2 weighted spin-echo (T1wSE and T2wSE) scans. T1wSE signal follows T1 relaxation rate (1/T1 relaxation time) and responds to myelin and iron (ferritin) concentrations. We performed MRI signal level group comparisons with SPM12. Spatial normalization after segmentation was performed using T2wSE scans and applied to the coregistered T1wSE scans.

After global signal-level normalization of individual scans, the T1wSE group comparison detected decreased signal-levels in CFS in a brainstem region (cluster-based inference controlled for family wise error rate, PFWE= 0.002), and increased signal-levels in large bilateral clusters in sensorimotor cortex white matter (cluster PFWE < 0.0001). Moreover, the brainstem T1wSE values were negatively correlated with the sensorimotor values for both CFS (R2 = 0.31, P = 0.00007) and healthy controls (R2= 0.34, P = 0.0009), and the regressions were co-linear.

This relationship, previously unreported in either healthy controls or CFS, in view of known thalamic projection-fibre plasticity, suggests brainstem conduction deficits in CFS may stimulate the upregulation of myelin in the sensorimotor cortex to maintain brainstem – sensorimotor connectivity. VBM did not find group differences in regional grey matter or white matter volumes. We argued that increased T1wSE observed in sensorimotor WM in CFS indicates increased myelination which is a regulatory response to deficits in the brainstem although the causality cannot be tested in this study. Altered brainstem myelin may have broad consequences for cerebral function and should be a focus of future research.

Source: Barnden LR, Shan ZY, Staines DR, Marshall-Gradisnik S, Finegan K, Ireland T, Bhuta S. Hyperintense sensorimotor T1 spin echo MRI is associated with brainstem abnormality in chronic fatigue syndrome. Neuroimage Clin. 2018;20:102-109. doi: 10.1016/j.nicl.2018.07.011. Epub 2018 Jul 11. https://www.ncbi.nlm.nih.gov/pubmed/30497131

Autonomic correlations with MRI are abnormal in the brainstem vasomotor centre in Chronic Fatigue Syndrome

Abstract:

Autonomic changes are often associated with the chronic fatigue syndrome (CFS), but their pathogenetic role is unclear and brain imaging investigations are lacking. The vasomotor centre and, through it, nuclei in the midbrain and hypothalamus play a key role in autonomic nervous system regulation of steady state blood pressure (BP) and heart rate (HR).

In this exploratory cross-sectional study, BP and HR, as indicators of autonomic function, were correlated with volumetric and T1- and T2-weighted spin-echo (T1w and T2w) brain MRI in 25 CFS subjects and 25 normal controls (NC). Steady state BP (systolic, diastolic and pulse pressure) and HR in two postures were extracted from 24 h blood pressure monitoring. We performed (1) MRI versus autonomic score interaction-with-group regressions to detect locations where regression slopes differed in the CFS and NC groups (collectively indicating abnormality in CFS), and (2) MRI regressions in the CFS and NC groups alone to detect additional locations with abnormal correlations in CFS.

Significant CFS regressions were repeated controlling for anxiety and depression (A&D). Abnormal regressions were detected in nuclei of the brainstem vasomotor centre, midbrain reticular formation and hypothalamus, but also in limbic nuclei involved in stress responses and in prefrontal white matter. Group comparisons of CFS and NC did not find MRI differences in these locations.

We propose therefore that these regulatory nuclei are functioning correctly, but that two-way communication between them is impaired in CFS and this affects signalling to/from peripheral effectors/sensors, culminating in inverted or magnified correlations. This single explanation for the diverse abnormal correlations detected here consolidates the conclusion for a brainstem/midbrain nerve conduction deficit inferred earlier (Barnden et al., 2015). Strong correlations were also detected in isolated NC regressions.

 

Source: Barnden LR, Kwiatek R, Crouch B, Burnet R, Del Fante P. Autonomic correlations with MRI are abnormal in the brainstem vasomotor centre in Chronic Fatigue Syndrome. Neuroimage Clin. 2016 Mar 31;11:530-7. doi: 10.1016/j.nicl.2016.03.017. ECollection 2016. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4833047/ (Full article)

 

Brainstem conundrum: the Chiari I malformation

Abstract:

PURPOSE: To describe the Chairi I Malformation in relation to the anatomy of the brain and spinal cord, the common manifestations of the condition, diagnostic considerations, and management for the primary care provider.

DATA SOURCES: Extensive review of the world-wide scientific literature on the condition, supplemented with actual case studies.

CONCLUSIONS: The adult Chairi I Malformation is an insidious congenital brainstem anomaly that consists of caudal displacement of the cerebellar tonsils, brainstem and fourth ventricle into the upper cervical space, resulting in overcrowding of the posterior fossa.

IMPLICATIONS FOR PRACTICE: Due to the vague, and often ambiguous presenting symptoms of Chiari I Malformation, many patients are misdiagnosed with conditions such as multiple sclerosis, fibromyalgia, chronic fatigue syndrome, or psychiatric disorders. Patients frequently experience symptoms months to years prior to accurate diagnosis and often incur irreversible neurologic deficits.

 

Source: Mueller D. Brainstem conundrum: the Chiari I malformation. J Am Acad Nurse Pract. 2001 Apr;13(4):154-9. http://www.ncbi.nlm.nih.gov/pubmed/11930527

 

Brain positron emission tomography (PET) in chronic fatigue syndrome: preliminary data

Abstract:

Chronic fatigue syndrome (CFS) has been widely studied by neuroimaging techniques in recent years with conflicting results. In particular, using single-photon emission computed tomography (SPECT) and perfusion tracers, hypoperfusion has been found in several brain regions, although the findings vary across research centers. The objective of this study was to investigate brain metabolism of patients affected by CFS, using [18F]fluorine-deoxyglucose (18FDG) positron emission tomography (PET).

We performed 18FDG PET in 18 patients who fulfilled the criteria of the working case definition of CFS. Twelve of the 18 patients were females; the mean age was 34 +/- 15 years (range, 15-68) and the median time from CFS diagnosis was 16 months (range, 9-138). Psychiatric diseases and anxiety/neurosis were excluded in all CFS patients.

CFS patients were compared with a group of 6 patients affected by depression (according to DSM IV-R) and 6 age-matched healthy controls. The CFS patients were not taking any medication at the time of PET, and depressed patients were drug-free for at least 1 week before the PET examination. The PET images examined 22 cortical and subcortical areas.

CFS patients showed a significant hypometabolism in right mediofrontal cortex (P = 0.010) and brainstem (P = 0.013) in comparison with the healthy controls. Moreover, comparing patients affected by CFS and depression, the latter group showed a significant and severe hypometabolism of the medial and upper frontal regions bilaterally (P = 0.037-0.001), whereas the metabolism of brain stem was normal.

Brain 18FDG PET showed specific metabolism abnormalities in patients with CFS in comparison with both healthy controls and depressed patients. The most relevant result of our study is the brain stem hypometabolism which, as reported in a perfusion SPECT study, seems to be a marker for the in vivo diagnosis of CFS.

 

Source: Tirelli U, Chierichetti F, Tavio M, Simonelli C, Bianchin G, Zanco P, Ferlin G. Brain positron emission tomography (PET) in chronic fatigue syndrome: preliminary data. Am J Med. 1998 Sep 28;105(3A):54S-58S. http://www.ncbi.nlm.nih.gov/pubmed/9790483

 

“Prolonged” decay test and auditory brainstem responses in the clinical diagnosis of the chronic fatigue syndrome

Abstract:

The chronic fatigue syndrome (CFS) was formally defined to describe disabling fatigue of unknown etiology with immunologic disfunctions. In most cases occur abnormalities of neurophysiological tests.

In this paper the Authors use the low (11 pps) and high (51-71 pps) frequency ABR for detecting the electrophysiological function of auditory brainstem responses and propose the “Prolonged Decay Test”, a modified impedenzometric technique that explores any alterations of the stapedial contraction, as a new diagnostic test for CFS.

Twenty-one patients with suspected CFS, with an age between 17 and 50 years, were examined and the instrumental data were correlated with the clinical findings. The results of the ABR study showed in the examined subjects no many abnormalities in the 11 pps frequency test. The high frequency stimulation trials (with 51 and 71 pps) proved many alterations in 10 patients (absence of the first wave in 6 cases, in 5 many wave latency delay and in 1 patient absence of the first wave and many wave latency delay). The high frequency trials showed no abnormalities in the 11 remaining patients.

The clinical-audiological correlation showed a 61.9% of comparison with 33.3% of false negatives and 4.8% of false positives. The Prolonged Decay Test showed a 71.4% of clinical-audiological comparison with 23.8% of false negatives and 4.8% of false positives. The Prolonged Decay Test together with the ABR showed a 81.8% of clinical-audiological comparison with 18.2% of false negatives and 0% of false positives.

These preliminary data show that the stapedial reflex together with the ABR test could be useful for the diagnosis of CFS.

 

Source: Neri G, Bianchedi M, Croce A, Moretti A. “Prolonged” decay test and auditory brainstem responses in the clinical diagnosis of the chronic fatigue syndrome. Acta Otorhinolaryngol Ital. 1996 Aug;16(4):317-23. [Article in Italian] http://www.ncbi.nlm.nih.gov/pubmed/9082825