circadian rhythm – Page 2 – American ME and CFS Society

Convergent genomic studies identify association of GRIK2 and NPAS2 with chronic fatigue syndrome

Abstract:

BACKGROUND: There is no consistent evidence of specific gene(s) or molecular pathways that contribute to the pathogenesis, therapeutic intervention or diagnosis of chronic fatigue syndrome (CFS). While multiple studies support a role for genetic variation in CFS, genome-wide efforts to identify associated loci remain unexplored. We employed a novel convergent functional genomics approach that incorporates the findings from single-nucleotide polymorphism (SNP) and mRNA expression studies to identify associations between CFS and novel candidate genes for further investigation.

METHODS: We evaluated 116,204 SNPs in 40 CFS and 40 nonfatigued control subjects along with mRNA expression of 20,160 genes in a subset of these subjects (35 CFS subjects and 27 controls) derived from a population-based study.

RESULTS: Sixty-five SNPs were nominally associated with CFS (p<0.001), and 165 genes were differentially expressed (≥4-fold; p≤0.05) in peripheral blood mononuclear cells of CFS subjects. Two genes, glutamate receptor, ionotropic, kinase 2 (GRIK2) and neuronal PAS domain protein 2 (NPAS2), were identified by both SNP and gene expression analyses. Subjects with the G allele of rs2247215 (GRIK2) were more likely to have CFS (p=0.0005), and CFS subjects showed decreased GRIK2 expression (10-fold; p=0.015). Subjects with the T allele of rs356653 (NPAS2) were more likely to have CFS (p=0.0007), and NPAS2 expression was increased (10-fold; p=0.027) in those with CFS.

CONCLUSION: Using an integrated genomic strategy, this study suggests a possible role for genes involved in glutamatergic neurotransmission and circadian rhythm in CFS and supports further study of novel candidate genes in independent populations of CFS subjects.

Source: Smith AK, Fang H, Whistler T, Unger ER, Rajeevan MS. Convergent genomic studies identify association of GRIK2 and NPAS2 with chronic fatigue syndrome. Neuropsychobiology. 2011;64(4):183-94. doi: 10.1159/000326692. Epub 2011 Sep 9. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3701888/ (Full article)

Sleep-wake behavior in chronic fatigue syndrome

Abstract:

STUDY OBJECTIVES: Disturbances of the internal biological clock manifest as fatigue, poor concentration, and sleep disturbances-symptoms reminiscent of chronic fatigue syndrome (CFS) and suggestive of a role for circadian rhythm disturbance in CFS. We examined circadian patterns of activity, sleep, and cortisol secretion in patients with CFS.

DESIGN: Case-control study, 5-day behavioral observation.

SETTING: Natural setting/home environment

PARTICIPANTS: 15 patients with CFS and 15 healthy subjects of similar age, sex, body mass index (BMI), and activity levels.

INTERVENTIONS: N/A.

MEASUREMENTS: Self-report questionnaires were used to obtain medical history and demographic information and to assess health behaviors, somatic and psychological symptoms, and sleep quality. An actiwatch accelerometer recorded activity and sleep patterns over 5 days with concurrent activity and symptom logs. Diurnal salivary cortisol secretion was measured. Additionally, overnight heart rate monitoring and pain sensitivity assessment was undertaken.

RESULTS: Ratings of symptoms, disability, sleep disturbance, and pain sensitivity were greater in patients with CFS. No between-group differences were found in the pattern or amount of sleep, activity, or cortisol secretion. Afternoon activity levels significantly increased evening fatigue in patients but not control subjects. Low nocturnal heart rate variability was identified as a biological correlate of unrefreshing sleep.

CONCLUSIONS: We found no evidence of circadian rhythm disturbance in CFS. However, the role of autonomic activity in the experience of unrefreshing sleep warrants further assessment. The activity symptom-relationship modelled here is of clinical significance in the approach to activity and symptom management in the treatment of CFS.

Source: Rahman K, Burton A, Galbraith S, Lloyd A, Vollmer-Conna U. Sleep-wake behavior in chronic fatigue syndrome. Sleep. 2011 May 1;34(5):671-8. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3079947/ (Full article)

Effect of electroacupuncture at Shenshu (BL 23) and Zusanli (ST 36) on the event-related potentials of chronic fatigue syndrome

Abstract:

OBJECTIVE: To observe the effective mechanism of electroacupuncture for chronic fatigue syndrome (CFS).

METHODS: The dynamic detection of chronobiology was used to test the event-related potentials in 20 healthy subjects and 20 CFS patients. P3a and P3b latencies at 4 equidistant time points (8:00, 14:00, 20:00, 2:00) within 24 hours were collected and analyzed.

RESULTS: (1) Latency of P3a in CFS group was obviously prolonged at 14:00 compared to health group with statistical significance (P < 0.05), latency of P3b was decreased at 14:00 after electroacupuncture treatment with statistical significance compared to that of pre-treatment (P < 0.01). (2) There were obviously circadian rhythm in latency of P3a and P3b in health group (P < 0.05), which were not seen in CFS group (P > 0.05); the circadian rhythm latency of P3b restored after treatment (P < 0.05). (3) The latency acrophase of P3a and P3b pre-treatment obviously shifted backward compared to that of healthy subjects (P < 0.05), shifted forward after electroacupuncture treatment (P < 0.05).

CONCLUSION: The event-related potential circadian rhythms are lost in CFS patients. Electroacupuncture at Shenshu (BL 23) and Zusanli (ST 36) can regulate the circadian rhythm of P3a and P3b latency and improve the cognition of the patients in daytime.

Source: Cheng CS, Zhu YH, Liang FR, Wu X, Jin SG, Wu FP. Effect of electroacupuncture at Shenshu (BL 23) and Zusanli (ST 36) on the event-related potentials of chronic fatigue syndrome. Zhongguo Zhen Jiu. 2010 Apr;30(4):309-12. [Article in Chinese] https://www.ncbi.nlm.nih.gov/pubmed/20568438

Lower ambulatory blood pressure in chronic fatigue syndrome

Abstract:

OBJECTIVE: To examine blood pressure circadian rhythm in subjects with chronic fatigue syndrome (CFS) and appropriate normal and fatigued controls to correlate parameters of blood pressure regulation with perception of fatigue in an observational cohort study. The cause of CFS remains unknown and there are no effective treatments.

METHODS: To address whether inactivity was a confounder, we performed a 24-hour ambulatory blood pressure monitoring in the following three subject groups: 1) CFS patients (Fukuda Diagnostic criteria) (n = 38); 2) normal controls (n = 120); and 3) a fatigue comparison group (n = 47) with the autoimmune liver disease primary biliary cirrhosis (PBC). All patients completed a measure of fatigue severity (Fatigue Impact Scale). In view of the different demographics between the patient groups, patients were age- and sex-matched on a case-by-case basis to normal controls and blood pressure parameters were compared.

RESULTS: Compared with the control population, the CFS group had significantly lower systolic blood pressure (p < .0001) and mean arterial blood pressure (p = .0002) and exaggerated diurnal variation (p = .009). There was a significant inverse relationship between increasing fatigue and diurnal variation of blood pressure in both the CFS and PBC groups (p < .05).

CONCLUSION: Lower blood pressure and abnormal diurnal blood pressure regulation occur in patients with CFS. We would suggest the need for a randomized, placebo-controlled trial of agents to increase blood pressure such as midodrine in CFS patients with an autonomic phenotype.

Source: Newton JL, Sheth A, Shin J, Pairman J, Wilton K, Burt JA, Jones DE. Lower ambulatory blood pressure in chronic fatigue syndrome. Psychosom Med. 2009 Apr;71(3):361-5. doi: 10.1097/PSY.0b013e31819ccd2a. Epub 2009 Mar 17. https://www.ncbi.nlm.nih.gov/pubmed/19297309

24-hour pituitary and adrenal hormone profiles in chronic fatigue syndrome

Abstract:

OBJECTIVES: Disturbances of neuroendocrine function, particularly the hypothalamo-pituitary-adrenal (HPA) axis, have been implicated in the pathophysiology of chronic fatigue syndrome (CFS). However, few studies have attempted to measure blood levels of pituitary or adrenal hormones across a whole 24-hour period in CFS, and those that did so have used infrequent sampling periods. Our aim was to assess 24-hour pituitary and adrenal function using frequent blood sampling.

METHODS: We recruited 15 medication-free patients with CFS without comorbid psychiatric disorder and 10 healthy control subjects. Blood samples were collected over 24 hours and assayed for cortisol, corticotropin (ACTH), growth hormone (GH), and prolactin (PRL) levels on an hourly basis during daytime hours (10 am to 10 pm) and every 15 minutes thereafter (10 pm to 10 am).

RESULTS: Repeated-measures analyses of variance were undertaken using hormone levels averaged over 2-hour blocks to smooth curves by reducing the influence of sample timing relative to secretory burst. For ACTH, there was both a main effect of group, suggesting reduced mean ACTH secretion in patients with CFS over the whole monitoring period, and a group-by-time interaction, suggesting a differential pattern of ACTH release. Post hoc analysis showed reduced ACTH levels in CFS during the 8 am to 10 am period. In contrast, there were no significant abnormalities in the levels of cortisol, GH, and PRL in patients with CFS over the full cycle compared with control subjects. Cosinor analysis found no differences in the cortisol circadian rhythm parameters, but the ACTH rhythm did differ, patients with CFS showing an earlier acrophase.

CONCLUSIONS: Patients with CFS demonstrated subtle alterations in HPA axis activity characterized by reduced ACTH over a full circadian cycle and reduced levels during the usual morning physiological peak ACTH secretion. This provides further evidence of subtle dysregulation of the HPA axis in CFS. Whether this dysregulation is a primary feature of the illness or instead represents a biologic effect secondary to having the illness itself remains unclear.

Source: Di Giorgio A, Hudson M, Jerjes W, Cleare AJ. 24-hour pituitary and adrenal hormone profiles in chronic fatigue syndrome. Psychosom Med. 2005 May-Jun;67(3):433-40. http://www.ncbi.nlm.nih.gov/pubmed/15911907

Chronic fatigue syndrome impairs circadian rhythm of activity level

Abstract:

Some of the symptoms of chronic fatigue syndrome (CFS) are the same as for disrupted circadian rhythm. Activity level is frequently used to study circadian rhythm. Continuous waist activity measurements taken every minute 24 h/day for from 5 to 7 days in 10 controls and from 2 to 7 days in 8 patients with CFS yielded two primary findings: (a) lower daytime activity and (b) less regular activity-rest cycles in persons with CFS than in controls.

Source: Tryon WW, Jason L, Frankenberry E, Torres-Harding S. Chronic fatigue syndrome impairs circadian rhythm of activity level. Physiol Behav. 2004 Oct 15;82(5):849-53. http://www.ncbi.nlm.nih.gov/pubmed/15451649

Basal circadian and pulsatile ACTH and cortisol secretion in patients with fibromyalgia and/or chronic fatigue syndrome

Abstract:

The objective of this study was to evaluate and compare the basal circadian and pulsatile architecture of the HPA axis in groups of patients with FMS, CFS, or both syndromes with individually matched control groups.

Forty patients with either FMS (n = 13), FMS and CFS (n = 12), or CFS (n = 15) were matched by age (18-65), sex, and menstrual status to healthy controls. Subjects were excluded if they met criteria for major Axis I psychiatric disorders by structured clinical interview (SCID). Subjects were admitted to the General Clinical Research Center where meals and activities were standardized. Blood was collected from an intravenous line every 10 min over 24 h for analysis of ACTH and cortisol. Samples were evaluable for ACTH in 36 subject pairs and for cortisol in 37 subject pairs.

There was a significant delay in the rate of decline from acrophase to nadir for cortisol levels in patients with FMS (P <.01). Elevation of cortisol in the late evening quiescent period was evident in half of the FMS patients compared with their control group, while cortisol levels were numerically, but not significantly, lower in the overnight period in patients with CFS compared with their control group. Pulsatility analyses did not reveal statistically significant differences between patient and control groups.

We conclude that the pattern of differences for basal circadian architecture of HPA axis hormones differs between patients with FMS and CFS compared to their matched control groups. The abnormalities in FMS patients are consistent with loss of HPA axis resiliency.

Source: Crofford LJ, Young EA, Engleberg NC, Korszun A, Brucksch CB, McClure LA, Brown MB, Demitrack MA. Basal circadian and pulsatile ACTH and cortisol secretion in patients with fibromyalgia and/or chronic fatigue syndrome. Brain Behav Immun. 2004 Jul;18(4):314-25. http://www.ncbi.nlm.nih.gov/pubmed/15157948

Therapy of circadian rhythm disorders in chronic fatigue syndrome: no symptomatic improvement with melatonin or phototherapy

Abstract:

BACKGROUND: Patients with chronic fatigue syndrome (CFS) show evidence of circadian rhythm disturbances. We aimed to determine whether CFS symptoms were alleviated by melatonin and bright-light phototherapy, which have been shown to improve circadian rhythm disorders and fatigue in jet-lag and shift workers.

DESIGN: Thirty patients with unexplained fatigue for > 6 months were initially assessed using placebo and then received melatonin (5 mg in the evening) and phototherapy (2500 Lux for 1 h in the morning), each for 12 weeks in random order separated by a washout period. Principal symptoms of CFS were measured by visual analogue scales, the Shortform (SF-36) Health Survey, Mental Fatigue Inventory and Hospital Anxiety and Depression Scale. We also determined the circadian rhythm of body temperature, timing of the onset of melatonin secretion, and the relationship between these.

RESULTS: Neither intervention showed any significant effect on any of the principal symptoms or on general measures of physical or mental health. Compared with placebo, neither body temperature rhythm nor onset of melatonin secretion was significantly altered by either treatment, except for a slight advance of temperature phase (0.8 h; P = 0.04) with phototherapy.

CONCLUSION: Melatonin and bright-light phototherapy appear ineffective in CFS. Both treatments are being prescribed for CFS sufferers by medical and alternative practitioners. Their unregulated use should be prohibited unless, or until, clear benefits are convincingly demonstrated.

Source: Williams G, Waterhouse J, Mugarza J, Minors D, Hayden K. Therapy of circadian rhythm disorders in chronic fatigue syndrome: no symptomatic improvement with melatonin or phototherapy. Eur J Clin Invest. 2002 Nov;32(11):831-7. http://www.ncbi.nlm.nih.gov/pubmed/12423324

Activity rhythm degrades after strenuous exercise in chronic fatigue syndrome

Abstract:

Post-exertional exacerbation of symptoms is one of the major characteristics of chronic fatigue syndrome (CFS). In this study, we evaluated the hypothesis that disturbances in circadian chronobiological regulation may play a role in generating this phenomenon.

We recorded physical activity for 6-day periods in 16 women (10 CFS and 6 sedentary healthy controls, CON) before and after performing a maximal treadmill test. We calculated activity rhythms by computing autocorrelation coefficients by cutting 1 day apart from the data as a template and sliding it sequentially through each of the other days; all of 6 days were used as the templates. The peak value of autocorrelation coefficient (R) and the time between peak R’s (circadian period, CP) were calculated. CFS patients had a lengthening (P < .05) of mean circadian period (MCP) that was longer than 24 h (P < .05), while MCP in CON remained unchanged. No difference was found in the standard error of each subject’s MCP (circadian period variability, CPV) before and after exercise for both groups.

We interpret this increase in circadian rest-activity period seen in CFS patients following exercise to indicate that exhaustive exercise interferes with normal entrainment to 24-h zeitgeber(s). This effect may be associated in part with the common patient complaint of symptom worsening following exertion.

Source: Ohashi K, Yamamoto Y, Natelson BH. Activity rhythm degrades after strenuous exercise in chronic fatigue syndrome. Physiol Behav. 2002 Sep;77(1):39-44. http://www.ncbi.nlm.nih.gov/pubmed/12213500

Circadian rhythm of core body temperature in subjects with chronic fatigue syndrome

Abstract:

The pathophysiological basis for chronic fatigue syndrome (CFS) remains poorly understood. Certain symptoms of CFS, namely fatigue, neurocognitive symptoms and sleep disturbance, are similar to those of acute jet lag and shift work syndromes thus raising the possibility that CFS might be a condition associated with disturbances in endogenous circadian rhythms.

In this study, we tested this hypothesis by examining the circadian rhythm of core body temperature (CBT) in CFS and control subjects. Continuous recordings of CBT were obtained every 5 min over 48 h in a group of 10 subjects who met the Center for Disease Control (CDC) definition of CFS and 10 normal control subjects. Subjects in the two groups were age, sex and weight-matched and were known to have normal basal metabolic rates and thyroid function.

CBT recordings were performed under ambulatory conditions in a clinical research centre with the use of an ingestible radio frequency transmitter pill and a belt-worn receiver-logger. CBT time series were analysed by a cosinor analysis and by a harmonic-regression-plus-correlated-noise model to estimate the mean, amplitude and phase angle of the rhythm. The goodness of fit of each model was also compared using the Akaike Information Criterion (AIC) and sigma2. Average parameters for each group were compared by Student’s t-test.

By cosinor analysis, the only significant difference between CFS and control groups was in the phase angle of the third harmonic (P=0.02). The optimal harmonic-regression-plus-correlated-noise models selected were ARMA(1,1): control 7, CFS 6; ARMA(2,0): control 1, CFS 4; and ARMA(2,1): control 2 subjects. The optimal fit ARMA model contained two harmonics in eight of 10 control subjects but was more variable in the CFS subjects (1 harmonic: 5 subjects; 2 harmonics: 1 subject; 3 harmonics: 4 subjects). The goodness of fit measures for the optimal ARMA model were also better in the control than the CFS group, but the differences were not statistically significant.

We conclude that, measured under ambulatory conditions, the circadian rhythm of CBT in CFS is nearly indistinguishable from that of normal control subjects although there was a tendency for greater variability in the rhythm. Hence, it is unlikely that the symptoms of CFS are because of disturbance in the circadian rhythm of CBT.

Source: Hamilos DL, Nutter D, Gershtenson J, Ikle D, Hamilos SS, Redmond DP, Di Clementi JD, Schmaling KB, Jones JF. Circadian rhythm of core body temperature in subjects with chronic fatigue syndrome. Clin Physiol. 2001 Mar;21(2):184-95. http://www.ncbi.nlm.nih.gov/pubmed/11318826