Tag: Staines

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)

Dietary supplements, daily nutrient intake, and health-related quality of life among people with myalgic encephalomyelitis/chronic fatigue syndrome

There remains ambiguity surrounding the role of dietary supplementation and nutrient intake on the health status of myalgic encephalomyelitis (ME)/chronic fatigue syndrome (CFS) patients, yet supplement use and dietary modification appear to be common among people with the condition. This pilot cross-sectional study aimed to investigate if supplement use or nutrient intake was associated with self-reported health-related quality of life (HRQoL) scores among Australians with ME/CFS.

The eligibility criteria for this study included being a resident of Australia, being aged between 18 and 65 years, and having received a formal diagnosis of ME/CFS from a physician. Participants completed a series of self-administered questionnaires querying sociodemographic information, symptom presentation, HRQoL, routine supplement use, and nutrient intake. The 36-item Short-Form Health Survey version 2 (SF-36) was employed to assess participants’ HRQoL. Daily nutrient intake was estimated from participants’ responses to the Dietary Questionnaire for Epidemiological Studies (Cancer Council Victoria, Australia). Multiple linear regression analysis was performed for each of the eight SF-36 domains. Age, gender, body mass index, employment, education were controlled variables in each model, with supplement and nutrient variables entered in a stepwise manner.

Twenty-four Australians with ME/CFS, 54.2% of which met the International Consensus Criteria case definition for ME/CFS, participated in the study. Three of the eight regression models were statistically significant, being the ‘role limitations due to physical health problems’ (adjusted R 2 = 0.733, P < 0.001), ‘bodily pain’ (adjusted R 2 = 0.544, P = 0.004), and ‘general health perceptions’ (adjusted R 2 = 0.743, P < 0.001) SF-36 domains. Positive associations were observed between HRQoL and the routine use of vitamin C (ß = 0.300, P = 0.042) and herbal supplements (ß = 0.618, P < 0.001), as well as daily saturated fat (ß = 0.860, P < 0.001), total folate (ß = 0.710, P < 0.001), and calcium intake (ß = 0.897, P = 0.003). However, the routine use of evening primrose oil supplements (ß = -0.385, P = 0.006) and daily intakes of alpha-linolenic acid (ß = −0.543, P = 0.001), long chain omega-3 fatty acids (ß = −0.431, P = 0.017), and iodine (ß = −0.602, P = 0.034) were negatively associated with HRQoL scores. None of the supplements or nutrients studied had consistent associations with HRQoL across the three significant regression models.

The findings of this pilot study suggest that there may be links between dietary supplementation and nutrient intake with HRQoL among people with ME/CFS. Future studies should investigate supplement use, daily nutrient intake, and their relationships with HRQoL and symptom presentation among people with ME/CFS longitudinally and compared with healthy controls to further elucidate the role of supplements and nutrient intake in the management of ME/CFS.

Read the full study HERE.

Source: Weigel, B., Eaton-Fitch, N., Passmore, R., Cabanas, H., Staines, D., & Marshall-Gradisnik, S. (2022). Dietary supplements, daily nutrient intake, and health-related quality of life among people with myalgic encephalomyelitis/chronic fatigue syndrome. Proceedings of the Nutrition Society, 81(OCE3), E80. doi:10.1017/S0029665122001057 https://www.cambridge.org/core/journals/proceedings-of-the-nutrition-society/article/dietary-supplements-daily-nutrient-intake-and-healthrelated-quality-of-life-among-people-with-myalgic-encephalomyelitischronic-fatigue-syndrome/F837EC4FE783FFAEB44F66F7748C11F6 (Full text)

Alteration of Cortical Volume and Thickness in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Abstract:

Myalgic Encephalomyelitis/Chronic fatigue syndrome (ME/CFS) patients suffer from neurocognitive impairment. In this study, we investigated cortical volumetric and thickness changes in ME/CFS patients and healthy controls (HC). We estimated mean surface-based cortical volume and thickness from 18 ME/CFS patients who met International Consensus Criteria (ICC) and 26 HC using FreeSurfer. Vertex-wise analysis showed significant reductions in the caudal middle frontal gyrus (p = 0.0016) and precuneus (p = 0.013) thickness in ME/CFS patients compared with HC.

Region based analysis of sub-cortical volumes found that amygdala volume (p = 0.002) was significantly higher in ME/CFS patients compared with HC. We also performed interaction-with-group regressions with clinical measures to test for cortical volume and thickness correlations in ME/CFS with opposite slopes to HC (abnormal). ME/CFS cortical volume and thickness regressions with fatigue, heart-rate variability, heart rate, sleep disturbance score, respiratory rate, and cognitive performance were abnormal. Our study demonstrated different cortical volume and thickness in ME/CFS patients and showed abnormal cortical volume and thickness regressions with key symptoms of ME/CFS patients.

Source: Thapaliya Kiran, Marshall-Gradisnik Sonya, Staines Donald, Su Jiasheng, Barnden Leighton. Alteration of Cortical Volume and Thickness in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Frontiers in Neuroscience, Vol 16, 2022. DOI=10.3389/fnins.2022.848730 https://www.frontiersin.org/articles/10.3389/fnins.2022.848730/full   (Full text)

Volumetric differences in hippocampal subfields and associations with clinical measures in myalgic encephalomyelitis/chronic fatigue syndrome

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) patients suffer from a cognitive and memory dysfunction. Because the hippocampus plays a key role in both cognition and memory, we tested for volumetric differences in the subfields of the hippocampus in ME/CFS.

We estimated hippocampal subfield volumes for 25 ME/CFS patients who met Fukuda criteria only (ME/CFSFukuda ), 18 ME/CFS patients who met the stricter ICC criteria (ME/CFSICC ), and 25 healthy controls (HC). Group comparisons with HC detected extensive differences in subfield volumes in ME/CFSICC but not in ME/CFSFukuda . ME/CFSICC patients had significantly larger volume in the left subiculum head (p < 0.001), left presubiculum head (p = 0.0020), and left fimbria (p = 0.004).

Correlations of hippocampus subfield volumes with clinical measures were stronger in ME/CFSICC than in ME/CFSFukuda patients. In ME/CFSFukuda patients, we detected positive correlations between fatigue and hippocampus subfield volumes and a negative correlation between sleep disturbance score and the right CA1 body volume.

In ME/CFSICC patients, we detected a strong negative relationship between fatigue and left hippocampus tail volume. Strong negative relationships were also detected between pain and SF36 physical scores and two hippocampal subfield volumes (left: GC-ML-DG head and CA4 head).

Our study demonstrated that volumetric differences in hippocampal subfields have strong statistical inference for patients meeting the ME/CFSICC case definition and confirms hippocampal involvement in the cognitive and memory problems of ME/CFSICC patients.

Source: Thapaliya K, Staines D, Marshall-Gradisnik S, Su J, Barnden L. Volumetric differences in hippocampal subfields and associations with clinical measures in myalgic encephalomyelitis/chronic fatigue syndrome. J Neurosci Res. 2022 Mar 31. doi: 10.1002/jnr.25048. Epub ahead of print. PMID: 35355311. https://onlinelibrary.wiley.com/doi/10.1002/jnr.25048  (Full study)

Impaired TRPM3-dependent calcium influx and restoration using Naltrexone in natural killer cells of myalgic encephalomyelitis/chronic fatigue syndrome patients

Abstract:

Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a serious disorder of unknown aetiology. While the pathomechanism of ME/CFS remains elusive, reduced natural killer (NK) cell cytotoxic function is a consistent immunological feature. NK cell effector functions rely on long-term sustained calcium (Ca2+) influx. In recent years evidence of transient receptor potential melastatin 3 (TRPM3) dysfunction supports the hypothesis that ME/CFS is potentially an ion channel disorder. Specifically, reports of single nucleotide polymorphisms, low surface expression and impaired function of TRPM3 have been reported in NK cells of ME/CFS patients. It has been reported that mu (µ)-opioid receptor (µOR) agonists, known collectively as opioids, inhibit TRPM3. Naltrexone hydrochloride (NTX), a µOR antagonist, negates the inhibitory action of µOR on TRPM3 function. Importantly, it has recently been reported that NTX restores impaired TRPM3 function in NK cells of ME/CFS patients.

Methods: Live cell immunofluorescent imaging was used to measure TRPM3-dependent Ca2+ influx in NK cells isolated from n = 10 ME/CFS patients and n = 10 age- and sex-matched healthy controls (HC) following modulation with TRPM3-agonist, pregnenolone sulfate (PregS) and TRPM3-antaognist, ononetin. The effect of overnight (24 h) NTX in vitro treatment on TRPM3-dependent Ca2+ influx was determined.

Results: The amplitude (p < 0.0001) and half-time of Ca2+ response (p < 0.0001) was significantly reduced at baseline in NK cells of ME/CFS patients compared with HC. Overnight treatment of NK cells with NTX significantly improved TRPM3-dependent Ca2+ influx in ME/CFS patients. Specifically, there was no significance between HC and ME/CFS patients for half-time response, and the amplitude of Ca2+ influx was significantly increased in ME/CFS patients (p < 0.0001).

Conclusion: TRPM3-dependent Ca2+ influx was restored in ME/CFS patients following overnight treatment of isolated NK cells with NTX in vitro. Collectively, these findings validate that TRPM3 loss of function results in altered Ca2+ influx supporting the growing evidence that ME/CFS is a TRP ion channel disorder and that NTX provides a potential therapeutic intervention for ME/CFS.

Source: Eaton-Fitch N, Du Preez S, Cabanas H, Muraki K, Staines D, Marshall-Gradisnik S. Impaired TRPM3-dependent calcium influx and restoration using Naltrexone in natural killer cells of myalgic encephalomyelitis/chronic fatigue syndrome patients. J Transl Med. 2022 Feb 16;20(1):94. doi: 10.1186/s12967-022-03297-8. PMID: 35172836. https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-022-03297-8  (Full text)

Characterization of IL-2 Stimulation and TRPM7 Pharmacomodulation in NK Cell Cytotoxicity and Channel Co-Localization with PIP 2 in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Patients

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex multisystemic disorder responsible for significant disability. Although a unifying etiology for ME/CFS is uncertain, impaired natural killer (NK) cell cytotoxicity represents a consistent and measurable feature of this disorder.

Research utilizing patient-derived NK cells has implicated dysregulated calcium (Ca2+) signaling, dysfunction of the phosphatidylinositol-4,5-bisphosphate (PIP2)-dependent cation channel, transient receptor potential melastatin (TRPM) 3, as well as altered surface expression patterns of TRPM3 and TRPM2 in the pathophysiology of ME/CFS. TRPM7 is a related channel that is modulated by PIP2 and participates in Ca2+ signaling. Though TRPM7 is expressed on NK cells, the role of TRPM7 with IL-2 and intracellular signaling mechanisms in the NK cells of ME/CFS patients is unknown.

This study examined the effect of IL-2 stimulation and TRPM7 pharmacomodulation on NK cell cytotoxicity using flow cytometric assays as well as co-localization of TRPM7 with PIP2 and cortical actin using confocal microscopy in 17 ME/CFS patients and 17 age- and sex-matched healthy controls. The outcomes of this investigation are preliminary and indicate that crosstalk between IL-2 and TRMP7 exists. A larger sample size to confirm these findings and characterization of TRPM7 in ME/CFS using other experimental modalities are warranted.

Source: Du Preez S, Eaton-Fitch N, Cabanas H, Staines D, Marshall-Gradisnik S. Characterization of IL-2 Stimulation and TRPM7 Pharmacomodulation in NK Cell Cytotoxicity and Channel Co-Localization with PIP2 in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Patients. Int J Environ Res Public Health. 2021 Nov 12;18(22):11879. doi: 10.3390/ijerph182211879. PMID: 34831634. https://pubmed.ncbi.nlm.nih.gov/34831634/

Network Analysis of Symptoms Co-Occurrence in Chronic Fatigue Syndrome

Abstract:

Chronic fatigue syndrome (CFS) is a heterogenous disorder of multiple disabling symptoms with complex manifestations. Network analysis is a statistical and interrogative methodology to investigate the prevalence of symptoms (nodes) and their inter-dependent (inter-nodal) relationships. In the present study, we explored the co-occurrence of symptoms in a cohort of Polish CFS patients using network analysis.

A total of 110 patients with CFS were examined (75 females). The mean age of the total sample was 37.93 (8.5) years old while the mean duration of symptoms in years was 4.4 (4). Post-exertional malaise (PEM) was present in 75.45% of patients, unrefreshing sleep was noted in 89.09% and impaired memory or concentration was observed in 87.27% of patients. The least prevalent symptom was tender cervical or axillary lymph nodes, noted in 34.55% of the total sample.

Three of the most densely connected nodes were the total number of symptoms, sore throat and PEM. PEM was positively related with impairment in memory or concentration. Both PEM and impairment in memory or concentration presence are related to more severe fatigue measured by CFQ and FIS. PEM presence was positively related with the presence of multi-joint pain and negatively with tender lymph nodes and muscle pain. Sore throat was related with objective and subjective autonomic nervous system impairment. This study helps define symptom presentation of CFS with the pathophysiology of specific systems and links with multidisciplinary contemporary molecular pathology, including comparative MRI.

Source: Kujawski S, Słomko J, Newton JL, Eaton-Fitch N, Staines DR, Marshall-Gradisnik S, Zalewski P. Network Analysis of Symptoms Co-Occurrence in Chronic Fatigue Syndrome. Int J Environ Res Public Health. 2021 Oct 13;18(20):10736. doi: 10.3390/ijerph182010736. PMID: 34682478; PMCID: PMC8535251. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8535251/ (Full text)

Potential Implications of Mammalian Transient Receptor Potential Melastatin 7 in the Pathophysiology of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Review

Abstract:

The transient receptor potential (TRP) superfamily of ion channels is involved in the molecular mechanisms that mediate neuroimmune interactions and activities. Recent advancements in neuroimmunology have identified a role for TRP cation channels in several neuroimmune disorders including amyotropic lateral sclerosis, multiple sclerosis, and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). ME/CFS is a debilitating disorder with an obscure aetiology, hence considerable examination of its pathobiology is warranted. Dysregulation of TRP melastatin (TRPM) subfamily members and calcium signalling processes are implicated in the neurological, immunological, cardiovascular, and metabolic impairments inherent in ME/CFS.

In this review, we present TRPM7 as a potential candidate in the pathomechanism of ME/CFS, as TRPM7 is increasingly recognized as a key mediator of physiological and pathophysiological mechanisms affecting neurological, immunological, cardiovascular, and metabolic processes. A focused examination of the biochemistry of TRPM7, the role of this protein in the aforementioned systems, and the potential of TRPM7 as a molecular mechanism in the pathophysiology of ME/CFS will be discussed in this review. TRPM7 is a compelling candidate to examine in the pathobiology of ME/CFS as TRPM7 fulfils several key roles in multiple organ systems, and there is a paucity of literature reporting on its role in ME/CFS.

Source: Du Preez S, Cabanas H, Staines D, Marshall-Gradisnik S. Potential Implications of Mammalian Transient Receptor Potential Melastatin 7 in the Pathophysiology of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Review. Int J Environ Res Public Health. 2021 Oct 12;18(20):10708. doi: 10.3390/ijerph182010708. PMID: 34682454; PMCID: PMC8535478. https://pubmed.ncbi.nlm.nih.gov/34682454/ (Full text)

Impact of Life Stressors on Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Symptoms: An Australian Longitudinal Study

Abstract:

(1) Background: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a complex, multifaceted illness. The pathomechanism, severity and progression of this illness is still being investigated. Stressors have been implicated in symptom exacerbation for ME/CFS, however, there is limited information for an Australian ME/CFS cohort. The aim of this study was to assess the potential effect of life stressors including changes in work, income, or family scenario on symptom severity in an Australian ME/CFS cohort over five months;

(2) Methods: Australian residents with ME/CFS responded to questions relating to work, income, living arrangement, access to healthcare and support services as well as symptoms experienced;

(3) Results: thirty-six ME/CFS patients (age: 41.25 ± 12.14) completed all questionnaires (response rate 83.7%). Muscle pain and weakness, orthostatic intolerance and intolerance to extreme temperatures were experienced and fluctuated over time. Sleep disturbances were likely to present as severe. Work and household income were associated with worsened cognitive, gastrointestinal, body pain and sleep symptoms. Increased access to healthcare services was associated with improved symptom presentation;

(4) Conclusions: life stressors such as work and financial disruptions may significantly contribute to exacerbation of ME/CFS symptoms. Access to support services correlates with lower symptom scores.

Source: Balinas C, Eaton-Fitch N, Maksoud R, Staines D, Marshall-Gradisnik S. Impact of Life Stressors on Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Symptoms: An Australian Longitudinal Study. Int J Environ Res Public Health. 2021 Oct 11;18(20):10614. doi: 10.3390/ijerph182010614. PMID: 34682360; PMCID: PMC8535742.  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8535742/ (Full text)

The effect of IL-2 stimulation and treatment of TRPM3 on channel co-localisation with PIP 2 and NK cell function in myalgic encephalomyelitis/chronic fatigue syndrome patients

Abstract:

Background: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a serious multifactorial disorder. The origin remains ambiguous, however reduced natural killer (NK) cell cytotoxicity is a consistent immunological feature of ME/CFS. Impaired transient receptor potential melastatin 3 (TRPM3), a phosphatidylinositol dependent channel, and impaired calcium mobilisation have been implicated in ME/CFS pathology. This investigation aimed to examine the localisation of TRPM3 at the NK cell plasma membrane and co-localisation with phosphatidylinositol 4,5-bisphosphate (PIP2). The effect of IL-2 priming and treatment using pregnenolone sulfate (PregS) and ononetin on TRPM3 co-localisation and NK cell cytotoxicity in ME/CFS patients and healthy controls (HC) was also investigated.

Methods: NK cells were isolated from 15 ME/CFS patients and 15 age- and sex-matched HC. Immunofluorescent technique was used to determine co-localisation of TRPM3 with the NK cell membrane and with PIP2 of ME/CFS patients and HC. Flow cytometry was used to determine NK cell cytotoxicity. Following IL-2 stimulation and treatment with PregS and ononetin changes in co-localisation and NK cell cytotoxicity were measured.

Results: Overnight treatment of NK cells with PregS and ononetin resulted in reduced co-localisation of TRPM3 with PIP2 and actin in HC. Co-localisation of TRPM3 with PIP2 in NK cells was significantly reduced in ME/CFS patients compared with HC following priming with IL-2. A significant increase in co-localisation of TRPM3 with PIP2 was reported following overnight treatment with ononetin within ME/CFS patients and between groups. Baseline NK cell cytotoxicity was significantly reduced in ME/CFS patients; however, no changes were observed following overnight incubation with IL-2, PregS and ononetin between HC and ME/CFS patients. IL-2 stimulation significantly enhanced NK cell cytotoxicity in HC and ME/CFS patients.

Conclusion: Significant changes in co-localisation suggest PIP2-dependent TRPM3 function may be impaired in ME/CFS patients. Stimulation of NK cells with IL-2 significantly enhanced cytotoxic function in ME/CFS patients demonstrating normal function compared with HC. A crosstalk exists between IL-2 and TRPM3 intracellular signalling pathways which are dependent on Ca2+ influx and PIP2. While IL-2R responds to IL-2 binding in vitro, Ca2+ dysregulation and impaired intracellular signalling pathways impede NK cell function in ME/CFS patients.

Source: Eaton-Fitch N, Cabanas H, du Preez S, Staines D, Marshall-Gradisnik S. The effect of IL-2 stimulation and treatment of TRPM3 on channel co-localisation with PIP2 and NK cell function in myalgic encephalomyelitis/chronic fatigue syndrome patients. J Transl Med. 2021 Jul 15;19(1):306. doi: 10.1186/s12967-021-02974-4. PMID: 34266470.  https://pubmed.ncbi.nlm.nih.gov/34266470/