Medial prefrontal cortex neurotransmitter abnormalities in posttraumatic stress disorder with and without comorbidity to major depression.

Posttraumatic stress disorder (PTSD) is a chronic psychiatric condition that follows exposure to a traumatic stressor. Though previous in vivo proton (1H) MRS) research conducted at 4 T or lower has identified alterations in glutamate metabolism associated with PTSD predisposition and/or progression, no prior investigations have been conducted at higher field strength. In addition, earlier studies have not extensively addressed the impact of psychiatric comorbidities such as major depressive disorder (MDD) on PTSD-associated 1H-MRS-visible brain metabolite abnormalities. Here we employ 7 T 1H MRS to examine concentrations of glutamate, glutamine, GABA, and glutathione in the medial prefrontal cortex (mPFC) of PTSD patients with MDD (PTSD+MDD+; N = 6) or without MDD (PTSD+MDD-; N = 5), as well as trauma-unmatched controls without PTSD but with MDD (PTSD-MDD+; N = 9) or without MDD (PTSD-MDD-; N = 18). Participants with PTSD demonstrated decreased ratios of GABA to glutamine relative to healthy PTSD-MDD- controls but no single-metabolite abnormalities. When comorbid MDD was considered, however, MDD but not PTSD diagnosis was significantly associated with increased mPFC glutamine concentration and decreased glutamate:glutamine ratio. In addition, all participants with PTSD and/or MDD collectively demonstrated decreased glutathione relative to healthy PTSD-MDD- controls. Despite limited findings in single metabolites, patterns of abnormality in prefrontal metabolite concentrations among individuals with PTSD and/or MDD enabled supervised classification to separate them from healthy controls with 80+% sensitivity and specificity, with glutathione, glutamine, and myoinositol consistently among the most informative metabolites for this classification. Our findings indicate that MDD can be an important factor in mPFC glutamate metabolism abnormalities observed using 1H MRS in cohorts with PTSD.

In vivo cortical glutathione response to oral fumarate therapy in relapsing-remitting multiple sclerosis: A single-arm open-label phase IV trial using 7-Tesla 1H MRS.

BACKGROUND: This is an open-label, single-arm, single-center pilot study using 7-Tesla in vivo proton magnetic resonance spectroscopy (1H MRS) to measure brain cortical glutathione concentration at baseline before and during the use of oral fumarates as a disease-modifying therapy for multiple sclerosis. The primary endpoint of this research was the change in prefrontal cortex glutathione concentration relative to a therapy-naïve baseline after one year of oral fumarate therapy. METHODS: Brain glutathione concentrations were examined by 1H MRS in single prefrontal and occipital cortex cubic voxels (2.5 × 2.5 × 2.5 cm3) before and during initiation of oral fumarate therapy (120 mg b.i.d. for 7 days and 240 mg b.i.d. thereafter). Additional measurements of related metabolites glutamate, glutamine, myoinositol, total N-acetyl aspartate, and total choline were also acquired in voxels centered on the same regions. Seven relapsing-remitting multiple sclerosis patients (4 f / 3 m, age range 28-50 years, mean age 40 years) naïve to fumarate therapy were scanned at pre-therapy baseline and after 1, 3, 6 and 12 months of therapy. A group of 8 healthy volunteers (4 f / 4 m, age range 33-48 years, mean age 41 years) was also scanned at baseline and Month 6 to characterize 1H-MRS measurement reproducibility over a comparable time frame. RESULTS: In the multiple sclerosis cohort, general linear models demonstrated a significant positive linear relationship between prefrontal glutathione and time either linearly across all time points (+0.05 ± 0.02 mM/month, t(27) = 2.6, p = 0.02) or specifically for factor variable Month 12 (+0.6 ± 0.3 mM/12 months, t(24) = 2.2, p = 0.04) relative to baseline. No such effects of time on glutathione concentration were demonstrated in the occipital cortex or in the healthy volunteer group. Changes in occipital total choline were further observed in the multiple sclerosis cohort as well as prefrontal total choline and occipital glutamine and myoinositol in the control cohort throughout the study duration. CONCLUSIONS: While the open-label single-arm pilot study design and abbreviated control series cannot support firm conclusions about the influence of oral fumarate therapy independent of test-retest factors or normal biological variation in a state of either health or disease, these results do justify further investigation at a larger scale into the potential relationship between prefrontal cortex glutathione increases and oral fumarate therapy in relapsing-remitting multiple sclerosis.

Multiple sclerosis diagnosis and phenotype identification by multivariate classification of in vivo frontal cortex metabolite profiles.

Multiple sclerosis (MS) is a heterogeneous autoimmune disease for which diagnosis continues to rely on subjective clinical judgment over a battery of tests. Proton magnetic resonance spectroscopy (1H MRS) enables the noninvasive in vivo detection of multiple small-molecule metabolites and is therefore in principle a promising means of gathering information sufficient for multiple sclerosis diagnosis and subtype classification. Here we show that supervised classification using 1H-MRS-visible normal-appearing frontal cortex small-molecule metabolites alone can indeed differentiate individuals with progressive MS from control (held-out validation sensitivity 79% and specificity 68%), as well as between relapsing and progressive MS phenotypes (held-out validation sensitivity 84% and specificity 74%). Post hoc assessment demonstrated the disproportionate contributions of glutamate and glutamine to identifying MS status and phenotype, respectively. Our finding establishes 1H MRS as a viable means of characterizing progressive multiple sclerosis disease status and paves the way for continued refinement of this method as an auxiliary or mainstay of multiple sclerosis diagnostics.

In vivo evidence of differential frontal cortex metabolic abnormalities in progressive and relapsing-remitting multiple sclerosis.

The pathophysiology of progressive multiple sclerosis remains elusive, significantly limiting available disease-modifying therapies. Proton MRS (1 H-MRS) enables in vivo measurement of small molecules implicated in multiple sclerosis, but its application to key metabolites glutamate, γ-aminobutyric acid (GABA), and glutathione has been sparse. We employed, at 7 T, a previously validated 1 H-MRS protocol to measure glutamate, GABA, and glutathione, as well as glutamine, N-acetyl aspartate, choline, and myoinositol, in the frontal cortex of individuals with relapsing-remitting (N = 26) or progressive (N = 21) multiple sclerosis or healthy control adults (N = 25) in a cross-sectional analysis. Only individuals with progressive multiple sclerosis demonstrated reduced glutamate (F2,65 = 3.424, p = 0.04; 12.40 ± 0.62 mM versus control 13.17 ± 0.95 mM, p = 0.03) but not glutamine (F2,65 = 0.352, p = 0.7; 4.71 ± 0.35 mM versus control 4.84 ± 0.42 mM), reduced GABA (F2,65 = 3.89, p = 0.03; 1.29 ± 0.23 mM versus control 1.47 ± 0.25 mM, p = 0.05), and possibly reduced glutathione (F2,65 = 0.352, p = 0.056; 2.23 ± 0.46 mM versus control 2.51 ± 0.48 mM, p < 0.1). As a group, multiple sclerosis patients demonstrated significant negative correlations between disease duration and glutamate or GABA (ρ = -0.4, p = 0.02) but not glutamine or glutathione. Alone, only relapsing-remitting multiple sclerosis patients exhibited a significant negative correlation between disease duration and GABA (ρ = -0.5, p = 0.03). Taken together, these results indicate that frontal cortex metabolism is differentially disturbed in progressive and relapsing-remitting multiple sclerosis.

Potential mechanisms of the fatigue-reducing effect of cognitive-behavioral therapy in cancer survivors: Three randomized controlled trials.

OBJECTIVE: Fatigue is a common symptom among cancer survivors that can be successfully treated with cognitive-behavioral therapy (CBT). Insights into the working mechanisms of CBT are currently limited. The aim of this study was to investigate whether improvements in targeted cognitive-behavioral variables and reduced depressive symptoms mediate the fatigue-reducing effect of CBT. METHODS: We pooled data from three randomized controlled trials that tested the efficacy of CBT to reduce severe fatigue. In all three trials, fatigue severity (checklist individual strength) decreased significantly following CBT. Assessments were conducted pre-treatment and 6 months later. Classical mediation analysis testing a pre-specified model was conducted and its results compared to those of causal discovery, an explorative data-driven approach testing all possible causal associations and retaining the most likely model. RESULTS: Data from 250 cancer survivors (n = 129 CBT, n = 121 waitlist) were analyzed. Classical mediation analysis suggests that increased self-efficacy and decreased fatigue catastrophizing, focusing on symptoms, perceived problems with activity and depressive symptoms mediate the reduction of fatigue brought by CBT. Conversely, causal discovery and post-hoc analyses indicate that fatigue acts as mediator, not outcome, of changes in cognitions, sleep disturbance and depressive symptoms. CONCLUSIONS: Cognitions, sleep disturbance and depressive symptoms improve during CBT. When assessed pre- and post-treatment, fatigue acts as a mediator, not outcome, of these improvements. It seems likely that the working mechanism of CBT is not a one-way causal effect but a dynamic reciprocal process. Trials integrating intermittent assessments are needed to shed light on these mechanisms and inform optimization of CBT.

Elevated homocarnosine and GABA in subject on isoniazid as assessed through 1H MRS at 7T.

Typical magnetic resonance spectroscopy J-editing methods designed to quantify GABA suffer from contamination of both overlapping macromolecules and homocarnosine signal, introducing potential confounds. The aim of this study was to develop a novel method to assess accurately both the relative concentrations of homocarnosine as well as GABA free from overlapping creatine, homocarnosine and macromolecule signal. A novel method which utilized the combination of echo time STEAM and MEGA-sLASER magnetic resonance spectroscopy experiments at 7T were used to quantify the concentration of GABA and homocarnsoine independently, which are typically quantified in tandem. The metabolites GABA and homocarnosine were measured in brain of 6 healthy control subjects, and in a single subject medicated with isoniazid. It was found that (16.6±10.2)% of the supposed GABA signal in the brain originated from homocarnosine, and that isoniazid caused significantly elevated concentration of GABA and homocarnosine in a single subject compared to controls.

Interferon Gamma-Induced Protein (IP-10) as Potential Biomarker for Cancer-Related-Fatigue: Results from a 6-month Randomized Controlled Trial.

We examined if serum concentrations Interferon gamma-induced protein (IP-10) is a potential clinical biomarker for cancer-related-fatigue (CRF). Fatigue scores and IP-10 concentrations were measured from curatively treated fatigued cancer patients randomized to either cognitive behavioral therapy (CBT, n = 26) or waiting-list (WL, n = 13). No correlation was found between baseline IP-10 level and fatigue severity and no significant differences in IP-10 serum levels were observed between fatigued and matched non-fatigued patients (n = 22). Relative changes in IP-10 concentrations from baseline to six-month follow-up were not significantly different between the CBT and WL conditions. In this study, IP-10 showed low potential as clinical CRF biomarker. TRIAL REGISTRATION: This study is registered at ClinicalTrials.gov (NCT01096641).

Are the effects of cognitive behavior therapy for severe fatigue in cancer survivors sustained up to 14 years after therapy?

PURPOSE: Cognitive behavior therapy (CBT) reduces cancer-related fatigue (CRF) in cancer survivors in the short term. We examined fatigue levels up to 14 years after CBT. METHODS: Eligible participants of two randomized controlled trials who had completed CBT for CRF and a post-treatment assessment were contacted (n = 81). Fatigue was assessed with the subscale "fatigue severity" of the Checklist Individual Strength (CIS-fatigue). The course of fatigue over time was examined with linear mixed model analyses. Fatigue levels of participants were compared to matched population controls at long-term follow-up. We tested with multiple regression analysis if fatigue at follow-up was predicted by the patients' fatigue level and fatigue-perpetuating factors directly after CBT (post-CBT). RESULTS: Seventy-eight persons completed a follow-up assessment (response rate = 96%, mean time after CBT = 10 years). The mean level of fatigue increased from 23.7 (SD = 11.1) at post-CBT to 34.4 (SD = 12.4) at follow-up (p < 0.001). Population controls (M = 23,9, SD = 11.4) reported lower fatigue levels than participants. Half of the patients (52%) who were recovered from severe fatigue at post-CBT (CIS-fatigue < 35) were still recovered at long-term follow-up. Patients with lower fatigue levels at post-CBT were less likely to show relapse. CONCLUSION: Despite initial improvement after CBT, levels of fatigue deteriorated over time. Half of the patients who were recovered from severe fatigue after CBT still scored within normal ranges of fatigue at long-term follow-up. IMPLICATIONS FOR CANCER SURVIVORS: It should be explored how to help patients with a relapse of severe fatigue following an initially successful CBT. They may profit from CBT again, or another evidence-based intervention for fatigue (like mindfulness or exercise therapy). Future research to gain insight into reasons for relapse is warranted.

Quantification of glutathione transverse relaxation time T2 using echo time extension with variable refocusing selectivity and symmetry in the human brain at 7 Tesla.

Glutathione (GSH) is an endogenous antioxidant implicated in numerous biological processes, including those associated with multiple sclerosis, aging, and cancer. Spectral editing techniques have greatly facilitated the acquisition of glutathione signal in living humans via proton magnetic resonance spectroscopy, but signal quantification at 7 Tesla is still hampered by uncertainty about the glutathione transverse decay rate T2 relative to those of commonly employed quantitative references like N-acetyl aspartate (NAA), total creatine, or water. While the T2 of uncoupled singlets can be derived in a straightforward manner from exponential signal decay as a function of echo time, similar estimation of signal decay in GSH is complicated by a spin system that involves both weak and strong J-couplings as well as resonances that overlap those of several other metabolites and macromolecules. Here, we extend a previously published method for quantifying the T2 of GABA, a weakly coupled system, to quantify T2 of the strongly coupled spin system glutathione in the human brain at 7 Tesla. Using full density matrix simulation of glutathione signal behavior, we selected an array of eight optimized echo times between 72 and 322 ms for glutathione signal acquisition by J-difference editing (JDE). We varied the selectivity and symmetry parameters of the inversion pulses used for echo time extension to further optimize the intensity, simplicity, and distinctiveness of glutathione signals at chosen echo times. Pairs of selective adiabatic inversion pulses replaced nonselective pulses at three extended echo times, and symmetry of the time intervals between the two extension pulses was adjusted at one extended echo time to compensate for J-modulation, thereby resulting in appreciable signal-to-noise ratio and quantifiable signal shapes at all measured points. Glutathione signal across all echo times fit smooth monoexponential curves over ten scans of occipital cortex voxels in nine subjects. The T2 of glutathione was calculated to be 145.0 ±â€¯20.1 ms (mean ±â€¯standard deviation); this result was robust within one standard deviation to changes in metabolite fitting baseline corrections and removal of individual data points on the signal decay curve. The measured T2 of NAA (222.1 ±â€¯24.7 ms) and total creatine (153.0 ±â€¯19.9 ms) were both higher than that calculated for GSH. Apparent glutathione concentration quantified relative to both reference metabolites increased by up to 32% and 6%, respectively, upon correction with calculated T2 values, emphasizing the importance of considering T2 relaxation differences in the spectroscopic measurement of these metabolites, especially at longer echo times.

Elevated α-Hydroxybutyrate and Branched-Chain Amino Acid Levels Predict Deterioration of Glycemic Control in Adolescents.

Context: Traditional risk factors for type 2 diabetes mellitus are weak predictors of changes in glucose tolerance and insulin sensitivity in youth. Objective: To identify early metabolic features of insulin resistance (IR) in youth and whether they predict deterioration of glycemic control. Design and Setting: A cross-sectional and longitudinal study was conducted at the Yale Pediatric Obesity Clinic. Patients and Intervention: Concentrations of α-hydroxybutyrate, ß-hydroxybutyrate, lactate, and branched-chain amino acids (BCAAs) were measured by nuclear magnetic resonance spectroscopy in 78 nondiabetic adolescents during an oral glucose tolerance test (OGTT). Associations between baseline metabolic alterations and longitudinal changes in glucose control were tested in 16 subjects after a mean follow-up of 2.3 years. Main Outcome Measures: The relationship between metabolite levels, parameters of IR, and glycemic control, and their progression over time. Results: Elevated fasting α-hydroxybutyrate levels were observed in adolescents with reduced insulin sensitivity after adjusting for age, sex, ethnicity, Tanner stage, and body mass index z-score (P = 0.014). Plasma α-hydroxybutyrate and BCAAs were increased throughout the course of the OGTT in this group (P < 0.03). Notably, borderline IR was associated with a progressive α-hydroxybutyrate decrease from elevated baseline concentrations to normal levels (P = 0.02). Increased baseline α-hydroxybutyrate concentrations were further associated with progressive worsening of glucose tolerance and disposition index. Conclusion: α-Hydroxybutyrate and BCAA concentrations during an OGTT characterize insulin-resistant youth and predict worsening of glycemic control. These findings provide potential biomarkers for risk assessment of type 2 diabetes and new insights into IR pathogenesis.

Reproducibility measurement of glutathione, GABA, and glutamate: Towards in vivo neurochemical profiling of multiple sclerosis with MR spectroscopy at 7T.

PURPOSE: To determine the reproducibility of a comprehensive single-session measurement of glutathione (GSH), γ-aminobutyric acid (GABA), glutamate, and other biochemicals implicated in the pathophysiology of multiple sclerosis (MS) in the human brain with 1 H magnetic resonance spectroscopy (MRS). MATERIALS AND METHODS: Five healthy subjects were studied twice in separate 1-hour sessions at 7T. One MS patient was also scanned once. GSH and GABA were measured with J-difference editing using a semilocalized by adiabatic selective refocusing sequence (semi-LASER, TE = 72 msec). A stimulated echo acquisition mode sequence (STEAM, TE = 10 msec) was used to detect glutamate along with the overall biochemical profile. Spectra were quantified with LCModel. Quantification accuracy was assessed through Cramer-Rao lower bounds (CRLB). Reproducibility of the metabolite quantification was tested using coefficients of variation (CoV). RESULTS: CRLB were ≤7% for GSH, GABA, and glutamate and average CoV of 7.8 ± 3.2%, 9.5 ± 7.0%, and 3.2 ± 1.7% were achieved, respectively. The average test/retest concentration differences at this measurement reproducibility and quantification accuracy were smaller for GABA and glutamate than intersubject variations in metabolite content with CoV ratios of 0.6 and 0.8, respectively. As proof of principle, GSH, GABA, and glutamate were also detected in an MS patient. CONCLUSION: GSH, GABA, glutamate, and other metabolites relevant in MS can be quantified at 7T with high accuracy and reproducibility in a single 1-hour session. This methodology might serve as a clinical research tool to investigate biochemical markers associated with MS. LEVEL OF EVIDENCE: 2 J. Magn. Reson. Imaging 2017;45:187-198.

Quantification of 1H NMR Spectra from Human Plasma.

Human plasma is a biofluid that is high in information content, making it an excellent candidate for metabolomic studies. 1H NMR has been a popular technique to detect several dozen metabolites in blood plasma. In order for 1H NMR to become an automated, high-throughput method, challenges related to (1) the large signal from lipoproteins and (2) spectral overlap between different metabolites have to be addressed. Here diffusion-weighted 1H NMR is used to separate lipoprotein and metabolite signals based on their large difference in translational diffusion. The metabolite 1H NMR spectrum is then quantified through spectral fitting utilizing full prior knowledge on the metabolite spectral signatures. Extension of the scan time by 3 minutes or 15% per sample allowed the acquisition of a 1H NMR spectrum with high diffusion weighting. The metabolite 1H NMR spectra could reliably be modeled with 28 metabolites. Excellent correlation was found between results obtained with diffusion NMR and ultrafiltration. The combination of minimal sample preparation together with minimal user interaction during processing and quantification provides a metabolomics technique for automated, quantitative 1H NMR of human plasma.

Humoral and cellular immune responses after influenza vaccination in patients with postcancer fatigue.

The aim of this study was to compare humoral and cellular immune responses to influenza vaccination in cancer survivors with and without severe symptoms of fatigue. Severely fatigued (n = 15) and non-fatigued (n = 12) disease-free cancer survivors were vaccinated against seasonal influenza. Humoral immunity was evaluated at baseline and post-vaccination by a hemagglutination inhibition assay. Cellular immunity was evaluated at baseline and post-vaccination by lymphocyte proliferation and activation assays. Regulatory T cells were measured at baseline by flow cytometry and heat-shock protein 90 alpha levels by ELISA. Comparable humoral immune responses were observed in fatigued and non-fatigued patients, both pre- and post-vaccination. At baseline, fatigued patients showed a significantly diminished cellular proliferation upon virus stimulation with strain H3N2 (1414 ± 1201 counts), and a trend in a similar direction with strain H1N1 (3025 ± 2339 counts), compared to non-fatigued patients (3099 ± 2401 and 5877 ± 4604 counts, respectively). The percentage of regulatory T lymphocytes was significantly increased (4.4 ± 2.1% versus 2.4 ± 0.8%) and significantly lower amounts of interleukin 2 were detected prior to vaccination in fatigued compared to non-fatigued patients (36.3 ± 44.3 pg/ml vs. 94.0 ± 45.4 pg/ml with strain H3N2 and 28.4 ± 44.0 pg/ml versus 74.5 ± 56.1 pg/ml with strain H1N1). Pre-vaccination heat-shock protein 90 alpha concentrations, post-vaccination cellular proliferation, and post-vaccination cytokine concentrations did not differ between both groups. In conclusion, influenza vaccination is favorable for severely fatigued cancer survivors and should be recommended when indicated. However, compared to non-fatigued cancer survivors, fatigued cancer survivors showed several significant differences in immunological reactivity at baseline, which warrants further investigation.

The role of central and peripheral muscle fatigue in postcancer fatigue: a randomized controlled trial.

CONTEXT: Postcancer fatigue is a frequently occurring problem, impairing quality of life. Little is known about (neuro)physiological factors determining postcancer fatigue. It may be hypothesized that postcancer fatigue is characterized by low peripheral muscle fatigue and high central muscle fatigue. OBJECTIVES: The aims of this study were to examine whether central and peripheral muscle fatigue differ between fatigued and non-fatigued cancer survivors and to examine the effect of cognitive behavioral therapy (CBT) on peripheral and central muscle fatigue of fatigued cancer survivors in a randomized controlled trial. METHODS: Sixteen fatigued patients in the intervention group (CBT) and eight fatigued patients in the waiting list group were successfully assessed at baseline and six months later. Baseline measurements of 20 fatigued patients were compared with 20 non-fatigued patients. A twitch interpolation technique and surface electromyography were applied, respectively, during sustained contraction of the biceps brachii muscle. RESULTS: Muscle fiber conduction velocity (MFCV) and central activation failure (CAF) were not significantly different between fatigued and non-fatigued patients. Change scores of MFCV and CAF were not significantly different between patients in the CBT and waiting list groups. Patients in the CBT group reported a significantly larger decrease in fatigue scores than patients in the waiting list group. CONCLUSION: Postcancer fatigue is neither characterized by abnormally high central muscle fatigue nor by low peripheral muscle fatigue. These findings suggest a difference in the underlying physiological mechanism of postcancer fatigue vs. other fatigue syndromes.

Magnetic resonance spectroscopic imaging and volumetric measurements of the brain in patients with postcancer fatigue: a randomized controlled trial.

BACKGROUND: Postcancer fatigue is a frequently occurring problem, impairing quality of life. Until now, little is known about (neuro) physiological factors determining postcancer fatigue. For non-cancer patients with chronic fatigue syndrome, certain characteristics of brain morphology and metabolism have been identified in previous studies. We investigated whether these volumetric and metabolic traits are a reflection of fatigue in general and thus also of importance for postcancer fatigue. METHODS: Fatigued patients were randomly assigned to either the intervention condition (cognitive behavior therapy) or the waiting list condition. Twenty-five patients in the intervention condition and fourteen patients in the waiting list condition were assessed twice, at baseline and six months later. Baseline measurements of 20 fatigued patients were compared with 20 matched non-fatigued controls. All participants had completed treatment of a malignant, solid tumor minimal one year earlier. Global brain volumes, subcortical brain volumes, metabolite tissue concentrations, and metabolite ratios were primary outcome measures. RESULTS: Volumetric and metabolic parameters were not significantly different between fatigued and non-fatigued patients. Change scores of volumetric and metabolic parameters from baseline to follow-up were not significantly different between patients in the therapy and the waiting list group. Patients in the therapy group reported a significant larger decrease in fatigue scores than patients in the waiting list group. CONCLUSIONS: No relation was found between postcancer fatigue and the studied volumetric and metabolic markers. This may suggest that, although postcancer fatigue and chronic fatigue syndrome show strong resemblances as a clinical syndrome, the underlying physiology is different. TRIAL REGISTRATION: ClinicalTrials.gov NCT01096641.

Humoral and cellular immune responses after influenza vaccination in patients with chronic fatigue syndrome.

BACKGROUND: Chronic fatigue syndrome (CFS) is a clinical condition characterized by severe and disabling fatigue that is medically unexplained and lasts longer than 6 months. Although it is possible to effectively treat CFS, the nature of the underlying physiology remains unclear. Various studies have sought evidence for an underlying disturbance in immunity. The aim of this study was to compare the humoral and cellular immune responses upon influenza vaccination in CFS patients and healthy controls. RESULTS: Identical antibody titers were observed in CFS patients and healthy controls. Patients and controls demonstrated similar seroprotection rates against all three virus-strains of the influenza vaccine, both pre- and post-vaccination. Functional T cell reactivity was observed in both CFS patients and healthy controls. CFS patients showed a non-significant, numerically lower cellular proliferation at baseline compared to controls. Vaccination induced a significant increase in cellular proliferation in CFS patients, but not in healthy controls. Cytokine production and the number of regulatory T cells were comparable in patients and controls. CONCLUSIONS: The humoral and cellular immune responses upon influenza vaccination were comparable in CFS patients and healthy controls. Putative aberrations in immune responses in CFS patients were not evident for immunity towards influenza. Standard seasonal influenza vaccination is thus justified and, when indicated, should be recommended for patients suffering from CFS.

Physiological and neurophysiological determinants of postcancer fatigue: design of a randomized controlled trial.

BACKGROUND: Postcancer fatigue is a frequently occurring, severe, and invalidating problem, impairing quality of life. Although it is possible to effectively treat postcancer fatigue with cognitive behaviour therapy, the nature of the underlying (neuro)physiology of postcancer fatigue remains unclear. Physiological aspects of fatigue include peripheral fatigue, originating in muscle or the neuromuscular junction; central fatigue, originating in nerves, spinal cord, and brain; and physical deconditioning, resulting from a decreased cardiopulmonary function. Studies on physiological aspects of postcancer fatigue mainly concentrate on deconditioning. Peripheral and central fatigue and brain morphology and function have been studied for patients with fatigue in the context of chronic fatigue syndrome and neuromuscular diseases and show several characteristic differences with healthy controls. METHODS/DESIGN: Fifty seven severely fatigued and 21 non-fatigued cancer survivors will be recruited from the Radboud University Nijmegen Medical Centre. Participants should have completed treatment of a malignant, solid tumour minimal one year earlier and should have no evidence of disease recurrence. Severely fatigued patients are randomly assigned to either the intervention condition (cognitive behaviour therapy) or the waiting list condition (start cognitive behaviour therapy after 6 months). All participants are assessed at baseline and the severely fatigued patients also after 6 months follow-up (at the end of cognitive behaviour therapy or waiting list). Primary outcome measures are fatigue severity, central and peripheral fatigue, brain morphology and function, and physical condition and activity. DISCUSSION: This study will be the first randomized controlled trial that characterizes (neuro)physiological factors of fatigue in disease-free cancer survivors and evaluates to which extent these factors can be influenced by cognitive behaviour therapy. The results of this study are not only essential for a theoretical understanding of this invalidating condition, but also for providing an objective biological marker for fatigue that could support the diagnosis and follow-up of treatment. TRIAL REGISTRATION: The study is registered at http://ClinicalTrials.gov (NCT01096641).