brain – Page 4 – American ME and CFS Society

Cerebral blood flow is reduced in chronic fatigue syndrome as assessed by arterial spin labeling

Abstract:

BACKGROUND: Chronic fatigue syndrome is diagnosed by a set of clinical criteria and therefore is probably heterogeneous. Earlier reports tested the hypothesis that the syndrome had a neurological substrate by doing studies of cerebral blood flow (CBF) but with discrepant results. One possible reason for the discrepancy was that relative CBF was assessed. We found reduced CBF in an earlier study of absolute CBF using xenon-CT. The purpose of this study was to use a second method of assessing CBF and to look within the study group for heterogeneity of responses.

METHOD: Eleven CFS patients and 10 age matched healthy controls underwent neuroimaging using arterial spin labeling to determine their regional and global absolute CBF. A template was constructed based on the control data, and individual patient montages were compared on a case by case basis to determine if differences in regions of interest occurred.

RESULTS: The patients as a group had significantly lower global CBF than the controls. The reduction in CBF occurred across nearly every region assessed. Nine of the 11 patients showed these reductions compared to the average control data, while two patients showed actual increases relative to the controls.

CONCLUSION: The data extend our earlier observation that CFS patients as a group have broad decreases in CBF compared to healthy controls. However, as expected, the effect was not homogeneous in that 2 of the 11 patients studied showed actual increases in CBF relative to controls.

Source: Biswal B, Kunwar P, Natelson BH. Cerebral blood flow is reduced in chronic fatigue syndrome as assessed by arterial spin labeling. J Neurol Sci. 2011 Feb 15;301(1-2):9-11. doi: 10.1016/j.jns.2010.11.018. Epub 2010 Dec 16.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3139492/ (Full article)

The increase of alpha-melanocyte-stimulating hormone in the plasma of chronic fatigue syndrome patients

Abstract:

BACKGROUND: Despite extensive research, no reliable biological marker for chronic fatigue syndrome (CFS) has yet been identified. However, hyperactivation of melanotrophs in the pituitary gland and increased levels of plasma alpha-melanocyte-stimulating hormone (alpha-MSH) have recently been detected in an animal model of chronic stress. Because CFS is considered to be caused partly by chronic stress events, increased alpha-MSH plasma levels may also occur in CFS patients. We therefore examined alpha-MSH levels in CFS patients.

METHODS: Fifty-five CFS patients, who were previously diagnosed within 10 years of with the disease, were enrolled in this study. Thirty healthy volunteers were studied as controls. Fasting bloods samples were collected in the morning and evaluated for their plasma levels of alpha-MSH, adrenocorticotropic hormone (ACTH), serum cortisol and dehydroepiandrosterone sulfate (DHEA-S). Mean levels of alpha-MSH were compared between the CFS and control groups using Welch’s t test.

RESULTS: The mean plasma alpha-MSH concentration in the CFS group (17.9 +/- 1.0 pg/mL) was significantly higher than that in healthy controls (14.5 +/- 1.0 pg/mL, p = 0.02). However, there was a wide range of values in the CFS group. The factors correlated with the plasma alpha-MSH values were analyzed using Spearman’s rank correlation. A negative correlation was found between the duration of the CFS and the plasma alpha-MSH values (p = 0.04, rs = -0.28), but no correlations with ACTH, cortisol or DHEA-S levels were identified (p = 0.55, 0.26, 0.33, respectively). The CFS patients were divided into two groups: patients diagnosed for <or= 5 years’ duration, and those diagnosed for 5-10 years’ duration. They were compared with the healthy controls using one-way ANOVA and Tukey-Kramer multiple comparison tests. The mean alpha-MSH concentration in the <or= 5 years group was 20.8 +/- 1.2 pg/mL, which was significantly higher than that in the healthy controls (p < 0.01). There was no significant difference between the 5-10 year group (15.6 +/- 1.4 pg/mL) and the healthy controls.

CONCLUSIONS:CFS patients with a disease duration of <or= 5 years had significantly higher levels of alpha-MSH in their peripheral blood. alpha-MSH could be a potent biological marker for the diagnosis of CFS, at least during the first 5 years after onset of the disease.

Source: Shishioh-Ikejima N, Ogawa T, Yamaguti K, Watanabe Y, Kuratsune H, Kiyama H. The increase of alpha-melanocyte-stimulating hormone in the plasma of chronic fatigue syndrome patients. BMC Neurol. 2010 Aug 23;10:73. doi: 10.1186/1471-2377-10-73. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2933583/ (Full article)

Increased ventricular lactate in chronic fatigue syndrome measured by 1H MRS imaging at 3.0 T. II: comparison with major depressive disorder

Abstract:

Chronic fatigue syndrome (CFS), a complex illness characterized by fatigue, impaired concentration, and musculoskeletal pain, is often misdiagnosed as a psychiatric illness due to the overlap of its symptoms with mood and anxiety disorders. Using proton magnetic resonance spectroscopic imaging ((1)H MRSI), we previously measured levels of the major brain metabolites in CFS, in generalized anxiety disorder (GAD), and in healthy control subjects, and found significantly higher levels of ventricular cerebrospinal fluid (CSF) lactate in CFS compared to the other two groups.

In the present study, we sought to assess the specificity of this observation for CFS by comparing ventricular lactate levels in a new cohort of 17 CFS subjects with those in 19 healthy volunteers and in 21 subjects with major depressive disorder (MDD), which, like GAD, is a neuropsychiatric disorder that has significant symptom overlap with CFS.

Ventricular CSF lactate was significantly elevated in CFS compared to healthy volunteers, replicating the major result of our previous study. Ventricular lactate measures in MDD did not differ from those in either CFS or healthy volunteers. We found a significant correlation between ventricular CSF lactate and severity of mental fatigue that was specific to the CFS group.

In an exploratory analysis, we did not find evidence for altered levels of the amino acid neurotransmitters, gamma-aminobutyric acid (GABA) and glutamate + glutamine (‘Glx’), in CFS compared to MDD or healthy controls. Future (1)H MRS studies with larger sample sizes and well-characterized populations will be necessary to further clarify the sensitivity and specificity of neurometabolic abnormalities in CFS and MDD.

Source: Murrough JW, Mao X, Collins KA, Kelly C, Andrade G, Nestadt P, Levine SM, Mathew SJ, Shungu DC. Increased ventricular lactate in chronic fatigue syndrome measured by 1H MRS imaging at 3.0 T. II: comparison with major depressive disorder. NMR Biomed. 2010 Jul;23(6):643-50. doi: 10.1002/nbm.1512. https://www.ncbi.nlm.nih.gov/pubmed/20661876

A functional polymorphism in the disrupted-in schizophrenia 1 gene is associated with chronic fatigue syndrome

Abstract:

AIMS: Disrupted-in schizophrenia 1 (DISC1), identified in a pedigree with a familial psychosis with the chromosome translocation (1:11), is a putative susceptibility gene for psychoses such as schizophrenia and major depressive disorder (MDD). Patients with chronic fatigue syndrome (CFS) report having continuous severe fatigue and many overlapping symptoms with MDD; however, the mechanism and effective treatment of CFS are still unclear. We focused on the overlapping symptoms between CFS and MDD and performed an association study of the functional single-nucleotide polymorphism (SNP) in the DISC1 gene with CFS.

MAIN METHODS: Venous blood was drawn from CFS patients and controls and genomic DNA was extracted from the whole blood according to standard procedures. Ser704Cys DISC1 SNP was genotyped using the TaqMan 5′-exonuclease allelic discrimination assay.

KEY FINDINGS: We found that the Cys704 allele of Ser704Cys SNP was associated with an increased risk of CFS development compared with the Ser704 allele.

SIGNIFICANCE: DISC1 Ser704Cys might be a functional variant that affects one of the mechanisms implicated in the biology of CFS. Some patients with CFS showed a phenotype similar to that of patients with MDD, but further studies are needed to clarify the biological mechanism, because this study is of a rather preliminary nature. Despite the variety of patients with CFS, DISC1 Ser704Cys has an association with CFS, which may also suggest that DISC1 plays a central role in the induction of various psychiatric diseases.

Source: Fukuda S, Hashimoto R, Ohi K, Yamaguti K, Nakatomi Y, Yasuda Y, Kamino K, Takeda M, Tajima S, Kuratsune H, Nishizawa Y, Watanabe Y. A functional polymorphism in the disrupted-in schizophrenia 1 gene is associated with chronic fatigue syndrome. Life Sci. 2010 May 8;86(19-20):722-5. doi: 10.1016/j.lfs.2010.03.007. Epub 2010 Mar 20. https://www.ncbi.nlm.nih.gov/pubmed/20227423

Longitudinal MRI shows no cerebral abnormality in chronic fatigue syndrome

Abstract:

MRI has previously provided conflicting results when used to search for brain abnormalities in sufferers of chronic fatigue syndrome (CFS). Eighteen CFS patients and nine healthy volunteers each underwent MRI on two occasions, one year apart. The resulting images were examined for abnormalities in brain atrophy, deep white matter hyperintensities (WMH) and cerebral blood and cerebrospinal fluid (CSF) flow.

Mean proportionate CSF volume was not significantly different between subject groups. All participants showed a slight increase in CSF between scans, but no significant difference was found between those with CFS and those without. Between-group comparisons of ventricular volume revealed no significant differences at study commencement and no significant change over the year. No significant inter-group differences were found for any of the cerebral blood and CSF flow parameters. Low levels of WMH were found in all participants. Objective scoring of WMH using Scheltens’ scale revealed no change in summary components (prosencephalic deep white matter hyperintensities, basal ganglia hyperintensities and infratentorial hyperintensities) or in individual component variables between the baseline and 1 year follow-up scans. No abnormal patterns in rate and extent of brain atrophy, ventricle volume, white matter lesions, cerebral blood flow or aqueductal CSF flow were detected in the CFS population.

These results throw open the debate into whether MRI scanning can reveal diagnostic signs of CFS and clinically questions the diagnoses of CFS made on the basis of previous research conclusions.

Source: Perrin R, Embleton K, Pentreath VW, Jackson A. Longitudinal MRI shows no cerebral abnormality in chronic fatigue syndrome. Br J Radiol. 2010 May;83(989):419-23. doi: 10.1259/bjr/85621779. Epub 2010 Mar 11. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3473570/ (Full article)

Cellular and molecular mechanisms of interaction between the neuroendocrine and immune systems under chronic fatigue syndrome in experiment

Abstract:

One of the main mechanisms of chronic fatigue syndrome development involves disturbances of interaction between the immune and neuroendocrine systems. The adequate experimental model for the search of these mechanisms is induction of fatigue in animals via the single intraperitoneal administration of synthetic double-stranded RNA – Poly I : C.

Investigation of alterations in cytotoxic and proliferation activities of splenocytcs, the intensity of immunomodulatory cytokines signaling via the sphingomyelin pathways in membrane P2 fraction of the brain cortex, as well as the activity of hypothalamic-pituitary adrenal (HP A) axis in the dynamics of chronic fatigue syndrome in rats has performed. Inhibition of both cytotoxic and proliferative activities of splenocytes during the period of fatigue development has been shown. Priority data concerning the suppression of the activity of neutral sphingomyelinase (nSMase) – the key enzyme of the sphingomyelin cascade – in membranes ofthe cells from the brain cortex on the 3d day after Poly I : C administration to rats have been obtained.

It was found that Poly I : C injection to rats led to disturbed HPA axis functions which was manifested by decreased corticosterone concentration in standard functional assays with ACTH and hydrocortisone administration.

It is suggested that disturbances in interaction between the immune and neuroendocrine systems during development of chronic fatigue syndrome, including alterations in HPA axis activity, are realized both on the level of changes in the activity of immune-competent cells and immediately on membranes of the brain cells.

Source: Rybakina EG, Shanin SN, Fomicheva EE, Korneva EA. Cellular and molecular mechanisms of interaction between the neuroendocrine and immune systems under chronic fatigue syndrome in experiment. Ross Fiziol Zh Im I M Sechenova. 2009 Dec;95(12):1324-35. [Article in Russian] https://www.ncbi.nlm.nih.gov/pubmed/20141043

EEG source analysis of chronic fatigue syndrome

Abstract:

Sixty-one dextral, unmedicated women with chronic fatigue syndrome (CFS) diagnosed according to the Fukuda criteria (1994) and referred for investigation by rheumatologists and internists were studied with quantitative EEG (43 channels) at rest with eyes open and during verbal and spatial cognitive activation. The EEGs from the patients were compared with recordings from 80 dextral healthy female controls. Only those subjects who could provide 20 1-s artefact-free segments of EEG were admitted into the study.

The analysis consisted of the identification of the spatial patterns in the EEGs that maximally differentiated the two groups and the estimation of the cortical source distributions underlying these patterns. Spatial patterns were analyzed in the alpha (8-13Hz) and beta (14-20Hz) bands and the source distributions were estimated using the Borgiotti-Kaplan BEAMFORMER algorithm.

The results indicate that the spatial patterns identified were effective in separating the two groups, providing a minimum correct retrospective classification rate of 72% in both frequency bands while the subjects were at rest to a maximum of 83% in the alpha band during the verbal cognitive condition.

Underlying cortical source distributions showed significant differences between the two groups in both frequency bands and in all cognitive conditions. Lateralized cortical differences were evident between the two groups in the both frequency bands during both the verbal and spatial cognitive conditions. During these active cognitive conditions, the CFS group showed significantly greater source-current activity than the controls in the left frontal-temporal-parietal regions of the cortex.

Source: Flor-Henry P, Lind JC, Koles ZJ. EEG source analysis of chronic fatigue syndrome. Psychiatry Res. 2010 Feb 28;181(2):155-64. doi: 10.1016/j.pscychresns.2009.10.007. Epub 2009 Dec 16. https://www.ncbi.nlm.nih.gov/pubmed/20006474

An in vivo proton neurospectroscopy study of cerebral oxidative stress in myalgic encephalomyelitis (chronic fatigue syndrome)

Abstract:

A particularly important family of antioxidant defence enzymes in the body are the glutathione peroxidases, which remove H(2)O(2) by coupling its reduction to H(2)O with oxidation of reduced glutathione (GSH) to oxidised glutathione (GSSG). There are suggestions that GSH in the peripheral blood may be reduced in myalgic encephalomyelitis, which is a highly disabling neurological disease of unknown aetiology.

Since many of the symptoms relate to cerebral functioning, it would seem probable that peripheral blood GSH findings would be reflected in lower cerebral GSH levels. The aim of this study was to carry out the first direct assessment of cerebral GSH levels in myalgic encephalomyelitis; the hypothesis being tested was that cerebral GSH levels would be reduced in myalgic encephalomyelitis.

Cerebral proton neurospectroscopy was carried out at a magnetic field strength of 3T in 26 subjects; spectra were obtained from 20x20x20mm(3) voxels using a point-resolved spectroscopy pulse sequence. The mean cerebral GSH level in the myalgic encephalomyelitis patients was 2.703 (SD 2.311) which did not differ significantly from that in age- and gender-matched normal controls who did not have any history of neurological or other major medical disorder (5.191, SD 8.984; NS). Therefore our study does not suggest that GSH is reduced in the brain in myalgic encephalomyelitis.

At the present time, based on the results of this study, there is no evidence to support the suggestion that, by taking glutathione supplements, an improvement in the brain-related symptomatology of myalgic encephalomyelitis may occur.

Source: Puri BK, Agour M, Gunatilake KD, Fernando KA, Gurusinghe AI, Treasaden IH. An in vivo proton neurospectroscopy study of cerebral oxidative stress in myalgic encephalomyelitis (chronic fatigue syndrome). Prostaglandins Leukot Essent Fatty Acids. 2009 Nov-Dec;81(5-6):303-5. doi: 10.1016/j.plefa.2009.10.002. Epub 2009 Nov 10.https://www.ncbi.nlm.nih.gov/pubmed/19906518

Change in grey matter volume cannot be assumed to be due to cognitive behavioural therapy

Comment on: Can CBT substantially change grey matter volume in chronic fatigue syndrome? [Brain. 2009]

Sir, In their reply to Dr Bramsen, De Lange et al. (2008) use a type of circular reasoning: cognitive behavioural therapy (CBT), they say, has previously been shown to be ‘effective’ for chronic fatigue syndrome (CFS) so the change they measured must be due to CBT.

First, it needs to be pointed out that CBT is far from a panacea for CFS. A recent meta-analysis (Malouff et al., 2008) of the efficacy of CBT in treating CFS found an effect size of d = 0.48 (95% CI 0.27–0.69).

In their letter, De Lange et al. (2008) refer to a review by Whiting et al. (2001) as part-evidence for their claim that CBT is effective for CFS. However, this review recommended the use of objective outcome measures e.g.

Outcomes such as ‘improvement,’ in which participants were asked to rate themselves as better or worse than they were before the intervention began, were frequently reported. However, the person may feel better able to cope with daily activities because they have reduced their expectations of what they should achieve, rather than because they have made any recovery as a result of the intervention. A more objective measure of the effect of any intervention would be whether participants have increased their working hours, returned to work or school, or increased their physical activities’.

Given one of the aims of CBT (for CFS) has been said to be ‘increased confidence in exercise and physical activity’ (O’Dowd et al.), we cannot have complete confidence that the improvements recorded in CBT trials thus far represent objective improvements [such as improvements in grey matter volume (GMV)], rather than simply being due to altering how patients answer questionnaires. An INAMI report (2006) on the use of CBT (combined with GET) in over 600 CFS patients in Belgium found that while patients reported improvements on their fatigue scores, there was negligible change on the tests of exercise capacity and there was actually a worsening of their employment status (as measured by the amount of hours worked per week), both at the end of the intervention and at follow-up.

You can read the rest of this comment here: http://brain.oxfordjournals.org/content/132/7/e119.long

Source: Kindlon T. Change in grey matter volume cannot be assumed to be due to cognitive behavioural therapy. Brain. 2009 Jul;132(Pt 7):e119; author reply e120. doi: 10.1093/brain/awn358. Epub 2009 Jan 29. http://brain.oxfordjournals.org/content/132/7/e119.long (Full article)

Ventricular cerebrospinal fluid lactate is increased in chronic fatigue syndrome compared with generalized anxiety disorder: an in vivo 3.0 T (1)H MRS imaging study

Abstract:

Chronic fatigue syndrome (CFS) is a controversial diagnosis because of the lack of biomarkers for the illness and its symptom overlap with neuropsychiatric, infectious, and rheumatological disorders. We compared lateral ventricular volumes derived from tissue-segmented T(1)-weighted volumetric MRI data and cerebrospinal fluid (CSF) lactate concentrations measured by proton MRS imaging ((1)H MRSI) in 16 subjects with CFS (modified US Centers for Disease Control and Prevention criteria) with those in 14 patients with generalized anxiety disorder (GAD) and in 15 healthy volunteers, matched group-wise for age, sex, body mass index, handedness, and IQ.

Mean lateral ventricular lactate concentrations measured by (1)H MRSI in CFS were increased by 297% compared with those in GAD (P < 0.001) and by 348% compared with those in healthy volunteers (P < 0.001), even after controlling for ventricular volume, which did not differ significantly between the groups. Regression analysis revealed that diagnosis accounted for 43% of the variance in ventricular lactate.

CFS is associated with significantly raised concentrations of ventricular lactate, potentially consistent with recent evidence of decreased cortical blood flow, secondary mitochondrial dysfunction, and/or oxidative stress abnormalities in the disorder.

Source: Mathew SJ, Mao X, Keegan KA, Levine SM, Smith EL, Heier LA, Otcheretko V, Coplan JD, Shungu DC. Ventricular cerebrospinal fluid lactate is increased in chronic fatigue syndrome compared with generalized anxiety disorder: an in vivo 3.0 T (1)H MRS imaging study. NMR Biomed. 2009 Apr;22(3):251-8. doi: 10.1002/nbm.1315. https://www.ncbi.nlm.nih.gov/pubmed/18942064