Tag: hypothalamus

Hypothalamus Connectivity in Adolescent Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Abstract:

Adolescent Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a disabling illness of unknown etiology. Increasing evidence suggests hypothalamic involvement in ME/CFS pathophysiology, which has rarely been explored using magnetic resonance imaging (MRI) in the condition. This work aimed to use MRI to examine hypothalamus connectivity in adolescents with ME/CFS and explore how this relates to fatigue severity and illness duration.

25 adolescents with ME/CFS and 23 healthy controls completed a neuroimaging protocol consisting of structural and multishell diffusion-weighted imaging sequences, in addition to the PedsQL Multidimensional Fatigue Scale to assess fatigue severity. Information about illness duration was acquired at diagnosis. Preprocessing and streamlines tractography was performed using QSIPrep combined with a custom parcellation scheme to create structural networks. The number (degree) and weight (strength) of connections between lateralized hypothalamus regions and cortical and subcortical nodes were extracted, and relationships between connectivity measures, fatigue severity, and illness duration were performed using Bayesian regression models.

We observed weak-to-moderate evidence of increased degree, but not strength, of connections from the bilateral anterior-inferior (left: pd [%] = 99.18, median [95% CI] = -22.68[-40.96 to 4.45]; right: pd [%] = 99.86, median [95% CI] = -23.35[-38.47 to 8.20]), left anterior-superior (pd [%] = 99.33, median [95% CI] = -18.83[-33.45 to 4.07]) and total left hypothalamus (pd [%] = 99.44, median [95% CI] = -47.18[-83.74 to 11.03]) in the ME/CFS group compared with controls. Conversely, bilateral posterior hypothalamus degree decreased with increasing ME/CFS illness duration (left: pd [%] = 98.13, median [95% CI]: -0.47[-0.89 to 0.03]; right: pd [%] = 98.50, median [95% CI]:-0.43[-0.82 to 0.05]).

Finally, a weak relationship between right intermediate hypothalamus connectivity strength and fatigue severity was identified in the ME/CFS group (pd [%] = 99.35, median [95% CI] = -0.28[-0.51 to 0.06]), which was absent in controls. These findings suggest changes in hypothalamus connectivity may occur in adolescents with ME/CFS, warranting further investigation.

Source: Byrne H, Knight SJ, Josev EK, Scheinberg A, Beare R, Yang JYM, Oldham S, Rowe K, Seal ML. Hypothalamus Connectivity in Adolescent Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. J Neurosci Res. 2024 Oct;102(10):e25392. doi: 10.1002/jnr.25392. PMID: 39431934. https://onlinelibrary.wiley.com/doi/10.1002/jnr.25392 (Full text(

Low Vasopressin in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (P4-4.006)

Abstract:

Objective: To shed light on the pathophysiology of water homeostasis in patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), classified by WHO as a neurological disease (ICD 10 code G933).

Background: The complex symptomatology of ME/CFS includes signs suggesting abnormal water homeostasis and hypovolemia. Since many patients report polyuria-polydipsia, we conducted an observational series of plasma and urine osmolality as well as plasma levels of vasopressin (VP) in consecutive patients diagnosed with ME/CFS according to the Canadian Consensus Criteria.

Design/Methods: Plasma and urine osmolality (P-Osm and U-Osm, respectively) and plasma VP levels were measured in 111 patients after overnight fasting and 10-hour fluid deprivation. The clinical routine also included brain MRI and blood chemistry.

Results: Following the fluid deprivation P-Osm was above normal (>292 mOsm/kg) in 61 patients (55.0%) and U-Osm below normal (< 750 mOsm/kg) in 74 patients (66.7%). VP-levels were below the level of detection (<1.6 pg/mL) in 91 patients (82.0%). A normal level of VP in relation to their P-Osm was found in 11 patients (9.9 %). The state resembling a central type of diabetes insipidus (cDI) would in the absence of hypophyseal imaging findings and blood chemistry consistent with any other hypophyseal hormonal defect be classified as idiopathic.

Conclusions: Our findings suggest that deficiency of vasopressin secretion is a fundamental measurable part of the disease mechanisms, which may underlie a number of symptoms in ME/CFS, including the common complaint of orthostatic intolerance.

Source: Helena Huhmar, Lauri Soinne, Per Sjögren, Bo Christer Bertilson, Per Hamid Ghatan, Björn Bragée, and Olli Polo. Low Vasopressin in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (P4-4.006) Neurology, April 9, 2024 issue 102 (17_supplement_1) https://doi.org/10.1212/WNL.000000000020576 https://www.neurology.org/doi/10.1212/WNL.0000000000205761

The Potential Role of Hypothalamic Phospholipid Liposomes in the Supportive Therapy of Some Manifestations of Post-COVID-19 Condition: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and Brain Fog

Abstract:

Post-COVID-19 condition (commonly known as Long COVID) is a heterogeneous clinical condition in which Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and brain fog stand out among the different clinical symptoms and syndromes. Cerebral metabolic alterations and neuroendocrine disorders seem to constitute an important part of the pathophysiology of Post-COVID-19 condition (PCC).

Given the substantial lack of specific drugs and effective therapeutic strategies, hypothalamic phospholipid liposomes, which have been on the market for several years as adjuvant therapy for cerebral metabolic alterations resulting from neuroendocrine disorders, might represent a potential option in an overall therapeutic strategy that aims to control PCC-associated symptoms and syndromes. Their pharmacological mechanisms and clinical effects strongly support their potential effectiveness in PCC. Our initial clinical experience seems to corroborate this rationale. Further controlled clinical research is warranted in order to verify this hypothesis.

Source: Menichetti F. The Potential Role of Hypothalamic Phospholipid Liposomes in the Supportive Therapy of Some Manifestations of Post-COVID-19 Condition: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and Brain Fog. J Clin Med. 2023 Aug 23;12(17):5478. doi: 10.3390/jcm12175478. PMID: 37685544; PMCID: PMC10488182. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10488182/ (Full text)

Hypothalamus volumes in adolescent Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Impact of self-reported fatigue and illness duration

Abstract:

Adolescent Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a complex illness of unknown aetiology. Emerging theories suggest ME/CFS may reflect a progressive, aberrant state of homeostasis caused by disturbances within the hypothalamus, yet few studies have investigated this using magnetic resonance imaging in adolescents with ME/CFS.

We conducted a volumetric analysis to investigate whether whole and regional hypothalamus volumes in adolescents with ME/CFS differed compared to healthy controls, and whether these volumes were associated with fatigue severity and illness duration. 48 adolescents (25 ME/CFS, 23 controls) were recruited. Lateralised whole and regional hypothalamus volumes, including the anterior superior, superior tubular, posterior, anterior inferior and inferior tubular subregions, were calculated from T1 weighted images.

When controlling for age, sex and intracranial volume, Bayesian linear regression revealed no evidence for differences in hypothalamus volumes between groups. However, in the ME/CFS group, a negative linear relationship between right anterior superior volumes and fatigue severity was identified, which was absent in controls. In addition, Bayesian ordinal regression revealed a likely-positive association between illness duration and right superior tubular volumes in the ME/CFS group.

While these findings suggest overall comparability in regional and whole hypothalamus volumes between adolescents with ME/CFS and controls, preliminary evidence was identified to suggest greater fatigue and longer illness duration were associated with greater right anterior superior and superior tubular volumes, respectively. These regions contain the anterior and superior divisions of the paraventricular nucleus, involved in the neuroendocrine response to stress, suggesting involvement in ME/CFS pathophysiology. However, replication in a larger, longitudinal cohort is required.

Source: Hollie Byrne, Elisha K Josev, Sarah J Knight, Adam Scheinberg, Katherine Rowe, Lionel Lubitz, Marc L Seal. Hypothalamus volumes in adolescent Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Impact of self-reported fatigue and illness duration. medRxiv 2023.05.16.23290031; doi: https://doi.org/10.1101/2023.05.16.23290031 (Full text available as PDF file)

Cortical Grey matter volume depletion links to neurological sequelae in post COVID-19 “long haulers”

Abstract:

Objective: COVID-19 (SARS-CoV-2) has been associated with neurological sequelae even in those patients with mild respiratory symptoms. Patients experiencing cognitive symptoms such as “brain fog” and other neurologic sequelae for 8 or more weeks define “long haulers”. There is limited information regarding damage to grey matter (GM) structures occurring in COVID-19 “long haulers”. Advanced imaging techniques can quantify brain volume depletions related to COVID-19 infection which is important as conventional Brain MRI often fails to identify disease correlates. 3-dimensional voxel-based morphometry (3D VBM) analyzes, segments and quantifies key brain volumes allowing comparisons between COVID-19 “long haulers” and normative data drawn from healthy controls, with values based on percentages of intracranial volume.

Methods: This is a retrospective single center study which analyzed 24 consecutive COVID-19 infected patients with long term neurologic symptoms. Each patient underwent Brain MRI with 3D VBM at median time of 85 days following laboratory confirmation. All patients had relatively mild respiratory symptoms not requiring oxygen supplementation, hospitalization, or assisted ventilation. 3D VBM was obtained for whole brain and forebrain parenchyma, cortical grey matter (CGM), hippocampus, and thalamus.

Results: The results demonstrate a statistically significant depletion of CGM volume in 24 COVID-19 infected patients. Reduced CGM volume likely influences their long term neurological sequelae and may impair post COVID-19 patient’s quality of life and productivity.

Conclusion: This study contributes to understanding effects of COVID-19 infection on patient’s neurocognitive and neurological function, with potential for producing serious long term personal and economic consequences, and ongoing challenges to public health systems.

Source: Rothstein TL. Cortical Grey matter volume depletion links to neurological sequelae in post COVID-19 “long haulers”. BMC Neurol. 2023 Jan 17;23(1):22. doi: 10.1186/s12883-023-03049-1. PMID: 36647063; PMCID: PMC9843113. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9843113/ (Full text)

Anti-Correlated Myelin-Sensitive MRI Levels in Humans Consistent with a Subcortical to Sensorimotor Regulatory Process-Multi-Cohort Multi-Modal Evidence

Abstract:

Differential axonal myelination synchronises signalling over different axon lengths. The consequences of myelination processes described at the cellular level for the regulation of myelination at the macroscopic level are unknown. We analysed multiple cohorts of myelin-sensitive brain MRI. Our aim was to (i) confirm a previous report of anti-correlation between myelination in subcortical and sensorimotor areas in healthy subjects, (ii) and thereby test our hypothesis for a regulatory interaction between them.

We analysed nine image-sets across three different human cohorts using six MRI modalities. Each image-set contained healthy controls (HC) and ME/CFS subjects. Subcortical and Sensorimotor regions of interest (ROI) were optimised for the detection of anti-correlations and the same ROIs were used to test the HC in all image-sets. For each cohort, median MRI values were computed in both regions for each subject and their correlation across the cohort was computed.

We confirmed negative correlations in healthy controls between subcortical and sensorimotor regions in six image-sets: three T1wSE (p = 5 × 10-8, 5 × 10-7, 0.002), T2wSE (p =2 × 10-6), MTC (p = 0.01), and WM volume (p = 0.02). T1/T2 was the exception with a positive correlation (p = 0.01). This myelin regulation study is novel in several aspects: human subjects, cross-sectional design, ROI optimization, spin-echo MRI and reproducible across multiple independent image-sets.

In multiple independent image-sets we confirmed an anti-correlation between subcortical and sensorimotor myelination which supports a previously unreported regulatory interaction. The subcortical region contained the brain’s primary regulatory nuclei. We suggest a mechanism has evolved whereby relatively low subcortical myelination in an individual is compensated by upregulated sensorimotor myelination to maintain adequate sensorimotor performance.

Source: Barnden L, Crouch B, Kwiatek R, Shan Z, Thapaliya K, Staines D, Bhuta S, Del Fante P, Burnet R. Anti-Correlated Myelin-Sensitive MRI Levels in Humans Consistent with a Subcortical to Sensorimotor Regulatory Process-Multi-Cohort Multi-Modal Evidence. Brain Sci. 2022 Dec 9;12(12):1693. doi: 10.3390/brainsci12121693. PMID: 36552153; PMCID: PMC9776387. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9776387/ (Full text)

Clinical characteristics of patients with unexplainable hypothalamic disorder diagnosed by the corticotropin-releasing hormone challenge test: a retrospective study

Abstract

Background: The corticotropin-releasing hormone (CRH) challenge test can distinguish the disorders of the hypothalamus from those of the pituitary. However, the pathophysiology of hypothalamic disorder (HD) has not been fully understood. This study aimed to elucidate the clinical characteristics of patients with unexplainable HD, diagnosed by the CRH challenge test.

Methods: We retrospectively reviewed patients who underwent the CRH challenge test. Patients were categorized into four groups as follows: patients with peak serum cortisol ≥18 μg/dL were assigned to the normal response (NR) group (n = 18), among patients with peak serum cortisol < 18 μg/dL and peak adrenocorticotropic hormone (ACTH) increase ≥two-fold, patients without obvious background pathology were assigned to the unexplainable-HD group (n = 18), whereas patients with obvious background pathology were assigned to the explainable-HD group (n = 38), and patients with peak serum cortisol < 18 μg/dL and peak ACTH increase <two-fold were assigned to the pituitary disorder (PD) group (n = 15). Inter-group comparisons were performed based on clinical characteristics.

Results: In the CRH challenge test, the peak plasma ACTH levels were significantly lower in the unexplainable-HD group than in the NR group, despite more than two-fold increase compared to basal levels. The increase in serum cortisol was significantly higher in the unexplainable-HD group than in the explainable-HD and PD groups. Although patients in the unexplainable-HD group showed a clear ACTH response in the insulin tolerance test, some patients had peak serum cortisol levels of < 18 μg/dL. Furthermore, attenuated diurnal variations and low normal levels of urinary free cortisol were observed. Most patients in the unexplainable-HD group were young women with chronic fatigue. However, supplementation with oral hydrocortisone at physiological doses reduced fatigue only in some patients.

Conclusions: Patients with unexplainable HD diagnosed by the CRH challenge test had hypothalamic-pituitary-adrenal (HPA) axis dysfunction and some patients had mild central adrenal insufficiency. Hydrocortisone supplementation reduced fatigue only in some patients, suggesting that HPA axis dysfunction may be a physiological adaptation. Further investigation of these patients may help elucidate the pathophysiology of myalgic encephalitis/chronic fatigue syndrome.

Source: Hataya Y, Okubo M, Hakata T, Fujimoto K, Iwakura T, Matsuoka N. Clinical characteristics of patients with unexplainable hypothalamic disorder diagnosed by the corticotropin-releasing hormone challenge test: a retrospective study. BMC Endocr Disord. 2022 Dec 9;22(1):312. doi: 10.1186/s12902-022-01237-7. PMID: 36494805; PMCID: PMC9733005. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9733005/ (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)

Dissecting the Molecular Mechanisms Surrounding Post-COVID-19 Syndrome and Neurological Features

Abstract:

Many of the survivors of the novel coronavirus disease (COVID-19) are suffering from persistent symptoms, causing significant morbidity and decreasing their quality of life, termed “post-COVID-19 syndrome” or “long COVID”. Understanding the mechanisms surrounding PCS is vital to developing the diagnosis, biomarkers, and possible treatments.

Here, we describe the prevalence and manifestations of PCS, and similarities with previous SARS epidemics. Furthermore, we look at the molecular mechanisms behind the neurological features of PCS, where we highlight important neural mechanisms that may potentially be involved and pharmacologically targeted, such as glutamate reuptake in astrocytes, the role of NMDA receptors and transporters (EAAT2), ROS signaling, astrogliosis triggered by NF-κB signaling, KNDy neurons, and hypothalamic networks involving Kiss1 (a ligand for the G-protein-coupled receptor 54 (GPR54)), among others. We highlight the possible role of reactive gliosis following SARS-CoV-2 CNS injury, as well as the potential role of the hypothalamus network in PCS manifestations.

Source: Mohamed MS, Johansson A, Jonsson J, Schiöth HB. Dissecting the Molecular Mechanisms Surrounding Post-COVID-19 Syndrome and Neurological Features. Int J Mol Sci. 2022 Apr 12;23(8):4275. doi: 10.3390/ijms23084275. PMID: 35457093. https://www.mdpi.com/1422-0067/23/8/4275/htm (Full text)

A compromised paraventricular nucleus within a dysfunctional hypothalamus: A novel neuroinflammatory paradigm for ME/CFS

[Editor’s comment: While nicely explored in this article, the idea that the limbic system is the main driver behind ME/CFS symptoms is hardly new. Jay Goldstein in his 286-page book, Chronic Fatigue Syndromes: The Limbic Hypothesis (June 1993), examines the important role of the limbic system, and in particular the hypothalamus, in ME/CFS pathophysiology. The authors of this article fail to give him a mention.]

Abstract:

A neuroinflammatory paradigm is presented to help explain the pathophysiology of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). The hypothalamic paraventricular nucleus (PVN) is responsible for absorbing and processing multiple, incoming and convergent ‘stress’ signals, and if this cluster of neurons were affected (by neuroinflammation), the ongoing hypersensitivity of ME/CFS patients to a wide range of ‘stressors’ could be explained. Neuroinflammation that was chronic and fluctuating, as ‘inflammatory-marker’ studies support, could reflect a dynamic change in the hypothalamic PVN’s threshold for managing incoming ‘stress’ signals.

This may not only be a mechanism underpinning the characteristic feature of ME/CFS, post-exertional malaise, and its associated debilitating relapses, but could also be responsible for mediating the long-term perpetuation of the disease. Triggers (sustained physiological ‘stressors’) of ME/CFS, such as a particular viral infection, toxin exposure, or a traumatic event, could also target the hypothalamic PVN, a potentially vulnerable site in the brains of ME/CFS susceptible people, and disruption of its complex neural circuitry could account for the onset of ME/CFS. In common with the different ‘endogenous factors’ identified in the early ‘neuroinflammatory’ stages of the ‘neurodegenerative’ diseases, an as yet, unidentified factor within the brains and central nervous system (CNS) of ME/CFS patients might induce both an initial and then sustained ‘neuroinflammatory’ response by its ‘innate immune system’.

Positron emission tomography/magnetic resonance imaging has reinforced evidence of glial cell activation centred on the brain’s limbic system of ME/CFS patients. Neuroinflammation causing dysfunction of the limbic system and its hypothalamus together with a consequently disrupted autonomic nervous system could account for the diverse range of symptoms in ME/CFS relating, in particular to fatigue, mood, cognitive function, sleep, thermostatic control, gastrointestinal disturbance, and hypotension.

Source: Angus Mackay, Warren P Tate. A compromised paraventricular nucleus within a dysfunctional hypothalamus: A novel neuroinflammatory paradigm for ME/CFS. International Journal of Immunopathology and Pharmacology. First Published December 6, 2018. https://doi.org/10.1177/2058738418812342  https://journals.sagepub.com/doi/full/10.1177/2058738418812342 (Full article)