Natelson – Page 3 – American ME and CFS Society

Chronic fatigue syndrome and fibromyalgia in diagnosed sleep disorders: a further test of the ‘unitary’ hypothesis

Abstract:

BACKGROUND: Since chronic fatigue syndrome (CFS) and fibromyalgia (FM) often co-exist, some believe they reflect the same process, somatization. Against that hypothesis are data suggesting FM but not CFS was common in patients with sleep-disordered breathing (SDB). The presence of discrete case definitions for CFS and FM allowed us to explore rates of CFS alone, CFS with FM, and FM alone in SDB patients compared to those with sleep complaints that fulfilled criteria for insomnia.

METHODS: Participants were 175 sequential patients with sleep-related symptoms (122 had SDB and 21 had insomnia) and 39 healthy controls. Diagnoses were made by questionnaires, tender point count, and rule out labs; sleepiness was assessed with Epworth Sleepiness Scale and mood with Beck Depression Inventory.

RESULTS: Rates of CFS, FM or CFS + FM were high: 13% in SDB and 48% in insomnia. CFS occurred frequently in SDB and insomnia, but FM occurred frequently only in insomnia. SDB patients with CFS and/or FM had higher daytime sleepiness than those without these disorders.

CONCLUSION: CFS patients should complete Epworth scales, and sleep evaluation should be considered for those with scores ≥ 16 before receiving the diagnosis of CFS; the coexistence of depressed mood in these patients suggests some may be helped by treatment of their depression. That FM was underrepresented in SDB suggests FM and CFS may have different underlying pathophysiological causes.

Source: Pejovic S, Natelson BH, Basta M, Fernandez-Mendoza J, Mahr F, Vgontzas AN. Chronic fatigue syndrome and fibromyalgia in diagnosed sleep disorders: a further test of the ‘unitary’ hypothesis. BMC Neurol. 2015 Apr 12;15:53. doi: 10.1186/s12883-015-0308-2. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4405866/ (Full article)

The effects of exercise on dynamic sleep morphology in healthy controls and patients with chronic fatigue syndrome

Abstract:

Effects of exercise on dynamic aspects of sleep have not been studied. We hypothesized exercise altered dynamic sleep morphology differently for healthy controls relative to chronic fatigue syndrome (CFS) patients. Sixteen controls (38 ± 9 years) and 17 CFS patients (41 ± 8 years) underwent polysomnography on baseline nights and nights after maximal exercise testing. We calculated transition probabilities and rates (as a measure of relative and temporal transition frequency, respectively) between sleep stages and cumulative duration distributions (as a measure of continuity) of each sleep stage and sleep as a whole.

After exercise, controls showed a significantly greater probability of transition from N1 to N2 and a lower rate of transition from N1 to wake than at baseline; CFS showed a significantly greater probability of transition from N2 to N3 and a lower rate of transition from N2 to N1. These findings suggest improved quality of sleep after exercise. After exercise, controls had improved sleep continuity, whereas CFS had less continuous N1 and more continuous rapid eye movement (REM) sleep. However, CFS had a significantly greater probability and rate of transition from REM to wake than controls. Probability of transition from REM to wake correlated significantly with increases in subjective fatigue, pain, and sleepiness overnight in CFS – suggesting these transitions may relate to patient complaints of unrefreshing sleep.

Thus, exercise promoted transitions to deeper sleep stages and inhibited transitions to lighter sleep stages for controls and CFS, but CFS also reported increased fatigue and continued to have REM sleep disruption. This dissociation suggests possible mechanistic pathways for the underlying pathology of CFS.

Source: Kishi A, Togo F, Cook DB, Klapholz M, Yamamoto Y, Rapoport DM, Natelson BH. The effects of exercise on dynamic sleep morphology in healthy controls and patients with chronic fatigue syndrome. Physiol Rep. 2013 Nov;1(6):e00152. doi: 10.1002/phy2.152. Epub 2013 Nov 13. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3871467/ (Full article)

Attention network test: assessment of cognitive function in chronic fatigue syndrome

Abstract:

Information processing difficulties are common in patients with chronic fatigue syndrome (CFS). It has been shown that the time it takes to process a complex cognitive task, rather than error rate, may be the critical variable underlying CFS patients’ cognitive complaints. The Attention Network Task (ANT) developed by Fan and colleagues may be of clinical utility to assess cognitive function in CFS, because it allows for simultaneous assessment of mental response speed, also called information processing speed, and error rate under three conditions challenging the attention system.

Comparison of data from two groups of CFS patients (those with and without comorbid major depressive disorder; n = 19 and 22, respectively) to controls (n = 29) consistently showed that error rates did not differ among groups across conditions, but speed of information processing did. Processing time was prolonged in both CFS groups and most significantly affected in response to the most complex task conditions. For simpler tasks, processing time was only prolonged in CFS participants with depression. The data suggest that the ANT may be a task that could be used clinically to assess information processing deficits in individuals with CFS.

Source: Togo F, Lange G, Natelson BH, Quigley KS. Attention network test: assessment of cognitive function in chronic fatigue syndrome. J Neuropsychol. 2015 Mar;9(1):1-9. doi: 10.1111/jnp.12030. Epub 2013 Sep 24. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4159443/ (Full article)

Exercise and sleep deprivation do not change cytokine expression levels in patients with chronic fatigue syndrome

Abstract:

A major hypothesis regarding the cause of chronic fatigue syndrome (CFS) is immune dysregulation, thought to be reflected in upregulated proinflammatory cytokines leading to the symptoms that are characteristic of this illness. Because the symptoms worsen with physical exertion or sleep loss, we hypothesized that we could use these stressors to magnify the underlying potential pathogenic abnormalities in the cytokine systems of people with CFS.

We conducted repeat blood sampling for cytokine levels from healthy subjects and CFS patients during both postexercise and total sleep deprivation nights and assayed for protein levels in the blood samples, mRNA activity in peripheral blood lymphocytes (PBLs), and function in resting and stimulated PBLs. We found that these environmental manipulations did not produce clinically significant upregulation of proinflammatory cytokines. These data do not support an important role of immune dysregulation in the genesis of stress-induced worsening of CFS.

Source: Nakamura T, Schwander S, Donnelly R, Cook DB, Ortega F, Togo F, Yamamoto Y, Cherniack NS, Klapholz M, Rapoport D, Natelson BH. Exercise and sleep deprivation do not change cytokine expression levels in patients with chronic fatigue syndrome. Clin Vaccine Immunol. 2013 Nov;20(11):1736-42. doi: 10.1128/CVI.00527-13. Epub 2013 Sep 11. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3837776/ (Full article)

Brain dysfunction as one cause of CFS symptoms including difficulty with attention and concentration

Abstract:

We have been able to reduce substantially patient pool heterogeneity by identifying phenotypic markers that allow the researcher to stratify chronic fatigue syndrome (CFS) patients into subgroups. To date, we have shown that stratifying based on the presence or absence of comorbid psychiatric diagnosis leads to a group with evidence of neurological dysfunction across a number of spheres.

We have also found that stratifying based on the presence or absence of comorbid fibromyalgia leads to information that would not have been found on analyzing the entire, unstratified patient group. Objective evidence of orthostatic intolerance (OI) may be another important variable for stratification and may define a group with episodic cerebral hypoxia leading to symptoms.

We hope that this review will encourage other researchers to collect data on discrete phenotypes in CFS to allow this work to continue more broadly. Finding subgroups of CFS suggests different underlying pathophysiological processes responsible for the symptoms seen. Understanding those processes is the first step toward developing discrete treatments for each.

Source: Natelson BH. Brain dysfunction as one cause of CFS symptoms including difficulty with attention and concentration. Front Physiol. 2013 May 20;4:109. doi: 10.3389/fphys.2013.00109. ECollection 2013. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3657628/ (Full article)

Heart rate variability during sleep and subsequent sleepiness in patients with chronic fatigue syndrome

Abstract:

We determined whether alterations in heart rate dynamics during sleep in patients with chronic fatigue syndrome (CFS) differed from controls and/or correlated with changes of sleepiness before and after a night in the sleep laboratory. We compared beat-to-beat RR intervals (RRI) during nocturnal sleep, sleep structure, and subjective scores on visual analog scale for sleepiness in 18 CFS patients with 19 healthy controls aged 25-55 after excluding subjects with sleep disorders. A short-term fractal scaling exponent (α1) of RRI dynamics, analyzed by the detrended fluctuation analysis (DFA) method, was assessed after stratifying patients into those who reported more or less sleepiness after the night’s sleep (a.m. sleepier or a.m. less sleepy, respectively).

Patients in the a.m. sleepier group showed significantly (p<0.05) higher fractal scaling index α1 during non-rapid eye movement (non-REM) sleep (Stages 1, 2, and 3 sleep) than healthy controls, although standard polysomnographic measures did not differ between the groups. The fractal scaling index α1 during non-REM sleep was significantly (p<0.05) higher than that during awake periods after sleep onset for healthy controls and patients in the a.m. less sleepy group, but did not differ between sleep stages for patients in the a.m. sleepier group. For patients, changes in self-reported sleepiness before and after the night correlated positively with the fractal scaling index α1 during non-REM sleep (p<0.05). These results suggest that RRI dynamics or autonomic nervous system activity during non-REM sleep might be associated with disrupted sleep in patients with CFS.

Source: Togo F, Natelson BH. Heart rate variability during sleep and subsequent sleepiness in patients with chronic fatigue syndrome. Auton Neurosci. 2013 Jun;176(1-2):85-90. doi: 10.1016/j.autneu.2013.02.015. Epub 2013 Mar 15. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4100066/ (Full article)

Is chronic fatigue syndrome the same illness as fibromyalgia: evaluating the ‘single syndrome’ hypothesis

Abstract:

Chronic fatigue syndrome (CFS) and fibromyalgia (FM) are medically unexplained syndromes that can and often do co-occur. For this reason, some have posited that the two are part of the same somatic syndrome–examples of symptom amplification. This hypothesis would suggest that few differences exist between the two syndromes. To evaluate this interpretation, we have searched the literature for articles comparing CFS to FM, reviewing only those articles which report differences between the two. This review presents data showing differences across a number of parameters–implying that the underlying pathophysiology in CFS may differ from that of FM. We hope that our review encourages other groups to look for additional differences between CFS and FM. By continuing to preserve the unique illness definitions of the two syndromes, clinicians will be able to better identify, understand and provide treatment for these individuals.

Source: Abbi B, Natelson BH. Is chronic fatigue syndrome the same illness as fibromyalgia: evaluating the ‘single syndrome’ hypothesis. QJM. 2013 Jan;106(1):3-9. doi: 10.1093/qjmed/hcs156. Epub 2012 Aug 26. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3527744/ (Full article)

Increased ventricular lactate in chronic fatigue syndrome. III. Relationships to cortical glutathione and clinical symptoms implicate oxidative stress in disorder pathophysiology

Abstract:

Chronic fatigue syndrome (CFS) is a complex illness, which is often misdiagnosed as a psychiatric illness. In two previous reports, using (1)H MRSI, we found significantly higher levels of ventricular cerebrospinal fluid (CSF) lactate in patients with CFS relative to those with generalized anxiety disorder and healthy volunteers (HV), but not relative to those with major depressive disorder (MDD). In this third independent cross-sectional neuroimaging study, we investigated a pathophysiological model which postulated that elevations of CSF lactate in patients with CFS might be caused by increased oxidative stress, cerebral hypoperfusion and/or secondary mitochondrial dysfunction.

Fifteen patients with CFS, 15 with MDD and 13 HVs were studied using the following modalities: (i) (1)H MRSI to measure CSF lactate; (ii) single-voxel (1)H MRS to measure levels of cortical glutathione (GSH) as a marker of antioxidant capacity; (iii) arterial spin labeling (ASL) MRI to measure regional cerebral blood flow (rCBF); and (iv) (31)P MRSI to measure brain high-energy phosphates as objective indices of mitochondrial dysfunction.

We found elevated ventricular lactate and decreased GSH in patients with CFS and MDD relative to HVs. GSH did not differ significantly between the two patient groups. In addition, we found lower rCBF in the left anterior cingulate cortex and the right lingual gyrus in patients with CFS relative to HVs, but rCBF did not differ between those with CFS and MDD. We found no differences between the three groups in terms of any high-energy phosphate metabolites.

In exploratory correlation analyses, we found that levels of ventricular lactate and cortical GSH were inversely correlated, and significantly associated with several key indices of physical health and disability. Collectively, the results of this third independent study support a pathophysiological model of CFS in which increased oxidative stress may play a key role in CFS etiopathophysiology.

Source: Shungu DC, Weiduschat N, Murrough JW, Mao X, Pillemer S, Dyke JP, Medow MS, Natelson BH, Stewart JM, Mathew SJ. Increased ventricular lactate in chronic fatigue syndrome. III. Relationships to cortical glutathione and clinical symptoms implicate oxidative stress in disorder pathophysiology. NMR Biomed. 2012 Sep;25(9):1073-87. doi: 10.1002/nbm.2772. Epub 2012 Jan 27. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3896084/ (Full article)

Responses to exercise differ for chronic fatigue syndrome patients with fibromyalgia

Abstract:

Chronic fatigue syndrome (CFS) and fibromyalgia (FM) are chronic multisymptom illnesses with substantial clinical and diagnostic overlap. We have previously shown that, when controlling for aerobic fitness and accounting for comorbid FM, CFS patients do not exhibit abnormal cardiorespiratory responses during maximal aerobic exercise compared with healthy controls, despite differences in pain and exertion.

PURPOSE: The purpose of the present study was to examine cardiac and perceptual responses to steady-state submaximal exercise in CFS patients and healthy controls.

METHODS: Twenty-one CFS patients (13 CFS with comorbid FM (CFS + FM)) and 14 controls completed 20 min of submaximal cycling exercise. Impedance cardiography was used to determine cardiac responses during exercise. Systolic blood pressure (SBP), RPE, and leg muscle pain were also measured. Data were analyzed using a doubly multivariate, repeated-measures MANOVA to model the exercise response.

RESULTS: There was a significant multivariate time-by-group interaction (P < 0.05). The CFS + FM group exhibited an exercise response characterized by higher stroke index, ventilatory equivalents for oxygen and carbon dioxide and RPE, lower SBP, and similar HR responses compared to controls.

CONCLUSIONS: The present results extend on our previous work with maximal exercise and show that CFS and CFS + FM differ in their responses to steady-state exercise. These results highlight the importance of accounting for comorbid conditions when conducting CFS research, particularly when examining psychophysiological responses to exercise.

Source: Cook DB, Stegner AJ, Nagelkirk PR, Meyer JD, Togo F, Natelson BH. Responses to exercise differ for chronic fatigue syndrome patients with fibromyalgia. Med Sci Sports Exerc. 2012 Jun;44(6):1186-93. doi: 10.1249/MSS.0b013e3182417b9a. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3319493/ (Full article)

Sleep-stage dynamics in patients with chronic fatigue syndrome with or without fibromyalgia

Abstract:

STUDY OBJECTIVES: Chronic fatigue syndrome (CFS) and fibromyalgia (FM) are medically unexplained conditions that often have overlapping symptoms, including sleep-related complaints. However, differences between the 2 conditions have been reported, and we hypothesized that dynamic aspects of sleep would be different in the 2 groups of patients.

PARTICIPANTS: Subjects were 26 healthy control subjects, 14 patients with CFS but without FM (CFS alone), and 12 patients with CFS and FM (CFS+FM)-all women.

MEASUREMENTS AND RESULTS: We studied transition probabilities and rates between sleep stages (waking, rapid eye movement [REM] sleep, stage 1 [S1], stage 2 [S2], and slow-wave sleep [SWS]) and duration distributions of each sleep stage. We found that the probability of transition from REM sleep to waking was significantly greater in subjects with CFS alone than in control subjects, which may be the specific sleep problem for people with CFS alone. Probabilities of (a) transitions from waking, REM sleep, and S1 to S2 and (b) those from SWS to waking and S1 were significantly greater in subjects with CFS+FM than in control subjects; in addition, rates of these transitions were also significantly increased in subjects with CFS+FM. Result (a) might indicate increased sleep pressure in subjects with CFS+FM whereas result (b) may be the specific sleep problem of subjects with CFS+FM. We also found that shorter durations of S2 sleep are specific to patients with CFS+FM, not to CFS alone.

CONCLUSIONS: These results suggest that CFS and FM may be different illnesses associated with different problems of sleep regulation.

Source: Kishi A, Natelson BH, Togo F, Struzik ZR, Rapoport DM, Yamamoto Y. Sleep-stage dynamics in patients with chronic fatigue syndrome with or without fibromyalgia. Sleep. 2011 Nov 1;34(11):1551-60. doi: 10.5665/sleep.1396. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3198210/ (Full article)