NM  Vol.2 No.1 , March 2011
An Etiological Model for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
ABSTRACT
Kindling might represent a heuristic model for understanding the etiology of Myalgic Encephalomyelitis/chronic fatigue syndrome (ME/CFS). Kindling occurs when an organism is exposed repeatedly to an initially sub-threshold stimulus re-sulting in hypersensitivity and spontaneous seizure-like activity. Among patients with ME/CFS, chronically repeated low-intensity stimulation due to an infectious illness might cause kindling of the limbic-hypothalamic-pituitary axis. Kindling might also occur by high-intensity stimulation (e.g., brain trauma) of the limbic-hypothalamic-pituitary axis. Once this system is charged or kindled, it can sustain a high level of arousal with little or no external stimulus and eventually this could lead to hypocortisolism. Seizure activity may spread to adjacent structures of the limbic-hypothalamic-pituitary axis in the brain, which might be responsible for the varied symptoms that occur among patients with ME/CFS. In addition, kindling may also be responsible for high levels of oxidative stress, which has been found in patients with ME/CFS.

Cite this paper
nullL. Jason, M. Sorenson, N. Porter and N. Belkairous, "An Etiological Model for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome," Neuroscience and Medicine, Vol. 2 No. 1, 2011, pp. 14-27. doi: 10.4236/nm.2011.21003.
References
[1]   G. V. Goddard, “Development of Epileptic Seizures Thr- ough Brain Stimulation at Low Intensity,” Nature, Vol. 214, No. 5092, 1967, pp. 1020-1021. doi:10.1038/2141020a0

[2]   S. Lo, N. Pripuzova, B. Li, A.L. Komaroff, G. Hung, W.R. Richard and H.J. Alter, “Detection of MLV-related Virus Gene Sequences in Blood of Patients with Chronic Fatigue Syndrome and Healthy Blood Donors,” Pro-ceedings of the National Academy of Sciences, Vol. 107, No. 36, 2010, pp. 15874-15879. doi:10.1073/pnas.1006901107

[3]   V.C. Lombardi, F.W. Ruscetti, J.D. Gupta, M.A. Pfost, K.S. Hagen, D.L Peterson, S.K. Ruscetti, R.K. Bagni, C. Petrow-Sadowski, B. Gold, M. Dean, R.H. Silverman and J.A. Mikovits, “Detection of an Infectious Retrovirus, XMRV, in Blood Cells of Patients with Chronic Fatigue Syndrome,” Science.

[4]   G. Broderick, J. Fuite, A. Kreitz, S.D. Vernon, N. Klimas and M.A. Fletcher, “A Formal Analysis of Cytokine Networks in Chronic Fatigue Syndrome,” Brain, Behavior, and Immunity, 2010. [Epub ahead of print].

[5]   S.F.Maier, L.R Watkins and M. Fleshner, “Psychoneuroimmunology: The Interface Between Behavior, Brain, and Immunity.” American Psychologist, Vol.49, No. 12, 1994, pp. 1004-1017. doi:10.1037/0003-066X.49.12.1004

[6]   W. Loescher and U. Ebert, “The Role of the Piriform Cortex in Kindling,” Progress in Neurobiology, Vol. 50, No. 5, 1996, pp. 427-482. doi:10.1016/S0301-0082(96)00036-6

[7]   A. F. T. Arnsten, “Stress Signaling Pathways that Impair Preforntal Cortex Structure and Function,” Nature Revi-ews Neuroscience, Vol. 10, No. 6, 2009, pp. 410-422. doi:10.1038/nrn2648

[8]   D.A. Girdano, G.S. Everly Jr., and D.E. Dusek, Controlling Stress and Tension, Englewood Cliffs, N.J.: Prentice Hall, 1990.

[9]   B. Brouwer and T. Packer, “Corticospinal Excitability in Patients Diagnosed with Chronic Fatigue Syndrome,” Muscle and Nerve, Vol. 17, No. 101994, pp. 1210-1212.

[10]   J.W. Gow, C. Cannon, W.M.H. Behan, P. Herzyk, S. Keir, G. Riboldi-Tunnicliffe, et al., “Whole-Genome (33,000 genes) Affymetrix DNA Microarray Analysis of Gene Expression in Chronic Fatigue Syndrome,” Paper presented at the International Conference on Fatigue Science, Karuizawa, Japan, 2005.

[11]   G. Kennedy, V. A. Spence, M. McLaren, A. Hill, C. Underwood and J. Belch, “Oxidative Stress Levels are Raised in Chronic Fatigue Syndrome and are Associated with Clinical Symptoms,” Free Radical Biology & Medicine, Vol. 39, No. 5, 2005, pp. 584-589. doi:10.1016/j.freeradbiomed.2005.04.020

[12]   M. Robinson, S. R. Gray, M.S.Watson, G. Kennedy, A. Hill, J.J. Belch, et al., “Plasma IL-6, its Soluble Receptors and F-Isoprostanes at Rest and During Exercise in Chronic Fatigue Syndrome,” Scandinavian Journal of Medicine & Science in Sports, Vol. 13, No. 3,2009, pp. 1-9. doi: 10.1111/j.1600-0838.2009.00895.x

[13]   L. A. Jason, T. Jessen, N. Porter, A. Boulton, M. G. Njoku, and F. Friedberg, “Examining Types of Fatigue Among Individuals with ME/CFS,” Disability Studies Quarterly, Vol. 29, No. 3, 2009. (available at http://www.dsq-sds org/article/view/938/1113).

[14]   B. M. Carruthers, A. K. Jain, K. L. DeMeirleir, D. L. Peterson, N. G. Klimas, A. M. Lerner, et al., “Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Clinical Working Case Definition, Diagnostic and Treatments Protocols,” Journal of Chronic Fatigue Syndrome, Vol. 11, No. 1, 2003, pp. 7-115. doi:10.1300/J092v11n01_02

[15]   H. Kuratsune and Y. Watanabe, “Chronic Fatigue Synd-rome. In: Y. Watanabe, B. Evengard, B. H. Natelson, L. A. Jason & H. Kuratsune, Eds., Fatigue Science for Human Health, 2007, pp.67-88, Tokyo: Springer.

[16]   T. Z. Baram and C. G. Hatalski, “Neuropeptide-Mediated Excitability: A Key Triggering Mechanism for Seizure Generation in the Developing Brain,” Trends in Neuro-science, Vol. 21, No. 11, 1998, pp. 471-476. doi:10.1016/S0166-2236(98)01275-2

[17]   S. C. Heinrichs and G. F. Koob, “Corticotropin-Releasing Factor in Brain: A Role in Activation, Arousal, and Affect Regulation,” Perspectives in Pharmacology, Vol. 311, No. 2, 2004, pp. 427-440.

[18]   A. J. Cleare, “The Neuroendocrinology of Chronic Fatigue Syndrome,” Endocrine Reviews, Vol. 24, No. 2, 2003, pp. 236-252.

[19]   T. G. Dinan, T. Majeed, E. Lavelle, L. V Scott, C. Berti and P. Behan, “Blunted Serotonin Mediated Activation of the Hypothalamic-Pituitary-Adrenal Axis in Chronic Fatigue Syndrome,” Psychoneu-roendocrinology, Vol. 22, No. 4, 1997, pp. 261-267. doi:10.1016/S0306-4530(97)00002-4

[20]   A. Kavelaars, W. Kuis, L. Knook, G. Sinnema, and C.J. Heijnen, “Disturbed Neuroendocrine-Immune Interacti-ons in Chronic Fatigue Syndrome,” Journal of Clinical Endocrinology and Metabolism, Vol. 85,No. 2,2000, pp. 692-696. doi:10.1210/jc.85.2.692

[21]   S. R. Torres-Harding, M. Sorenson, L. Jason, N. Rey- nolds, M. Brown, K. Maher, and M. A. Fletcher, “The Associ-ations between Basal Salivary Cortisol and Illness Symp-tomatology in Chronic Fatigue Syndrome,” Journal of Applied Biobehavioral Research, Vol. 13, No. 3, 2008, pp. 157-180. doi:10.1111/j.1751-9861.2008.00033.x

[22]   S. K. Johnson and J. DeLuca, “Chronic Fatigue Syndrome and the Brain,” In: J. DeLuca, Ed., Fatigue as a Window to the Brain, MIT Press: Cambridge, Vol. 1, No. 4, MA, 2005, pp. 137-156

[23]   A.V. Turnbull and C.L. Rivier, “Regulation of the Hypothalamic-Pituitary-Adrenal Axis by Cytokines: Actions and Mechanisms of Action,” Physiological Reviews, Vol. 79, No. 1, 1999, pp. 1-71.

[24]   M. Sorenson, N. Porter, L. A. Jason, A. Lerch and H. Matthews, “IL-8 Increased in Patients with CFS,” Manuscript Submitted for Publication, 2001.

[25]   A. J. Cleare, V. O. O’Keane and J. P. Miell, “Levels of DHEA and DHEAS and Responses to CRH Stimulation and Hydrocortisone Treatment in Chronic Fatigue Syndrome,” Psychoendocrinology, Vol. 29, No. 6, 2004, pp. 724-732. doi:10.1016/S0306-4530(03)00104-5

[26]   I. M. Adcock, B. Cosio, L. Tsaprouni, P. J. Barnes and K. Ito, “Redox Regulation of Histone Deacetylases and Glucocorticoid-Mediated Inhibition of the Inflammatory Response,” Antioxidants & Redox Signaling, Vol. 7, No. 1-2 2005, pp. 144-152. doi:10.1089/ars.2005.7.144

[27]   Z. Yuan, N. Rezai-Zadeh, X. Zhang and E. Seto, “Histone Deacetylase Activity Assay,” In: S. Chellappan, Ed., Chromatin Protocols, 2009, pp. 279-293. Springer.

[28]   M. Berthiaume, N. Boufaied, A. Moisan and L. Gaudreau, “High Levels of Oxidative Stress Globally Inhibit Gene Transcription and Histone Acetylation,” DNA Cell Biology, Vol. 25, No. 2, 2006, pp. 124-134.

[29]   K. A. Bode, K. Schroder, D. A. Hume, T. Ravasi, K. Heeg, M. J. Sweet and A. H. Dalpke, “Histone Deacetylase Inhibitors Decrease Toll-Like Receptor-Mediated Activation of Proinflammatory Gene Expression by Impairing Transcription Factor Recruitment,” Immunology, Vol. 122, No. 4, 2007, pp. 596-606. doi:10.1111/j.1365-2567.2007.02678.x

[30]   L. A. Jason, M. Sorenson, N. Porter, M. Brown, A. Lerch, J. Mikovits, L. J. Roberts, K. Sebally, D. Alkazemi and S. Kubow, “Increased HDAC is Associated with Hypocor-tisolism in Older Adults,” Manuscript Submitted for Publication, 2011.

[31]   J. R. Kerr, R. Petty, B. Burke, J. Gough, D. Fear, L. I. Sinclair, D. L. Mattey, S. C. Richards, J. Montgomery, D. A. Baldwin, P. Kellam, T. J. Harrison, G. E. Griffin, J. Main, D. Enlander, D. J. Nutt and S. T. Holgate, “Gene Expression Subtypes in Patients with Chronic Fatigue Syndrome/Myalgic Encephalomyelitis,” Journal of Infec-tious Diseases, Vol. 197, No. 8, 2008, pp. 1171-1184. doi:10.1086/533453

[32]   T. Saiki, T. Kawai, K. Morita, M. Ohta, T. Saito, K. Rokutan and N. Ban, “Identification of Marker Genes for Differential Diagnosis of Chronic Fatigue Syndrome,” Molecular Medicine, 2008. PMID: 18596870

[33]   M. S. Rajeevan, A. K. Smith, I. Dimulescu, E. R. Unger, S. D. Vernon, C. Heim, W. C. Reeves, “Glucocorticoid Receptor Polymorphisms and Haplotypes Associated with Chronic Fatigue Syndrome,” Genes, Brain,& Behavior, Vol. 6, 2006, 167-176. doi:10.1111/j.1601-183X.2006.00244.x

[34]   A. K. Smith, P.D. White, E. Aslakson, U. Vollmer-Conna and M.S. Rajeevan, “Polymorphisms in Genes Regulating the HPA Axis Associated with Empirically Delineated Classes of Unexplained Chronic Fatigue,” Pharma-cogenomics, Vol. 7, 2006, pp. 387-394. doi:10.2217/14622416.7.3.387

[35]   L. A. Jason, M. Sorenson, N. Porter, M. Brown, A. Lerch, C. Van der Eb and J. Mikovits, “Possible Genetic Dysregulation in Pediatric CFS,” Psychology, Vol. 1, 2010, pp. 247-251. doi:10.4236/psych.2010.14033

[36]   A. J. Dunn, “Cytokine Activation of the HPA Axis,” Annals New York Academy of Sciences, Vol. 917, 2006, pp. 608-617. doi:10.1111/j.1749-6632.2000.tb05426.x

[37]   S. Kizildere, T. Gluck, B. Zietz, J. Scholmerich and R. H. Straub, “During a Corticotropin-Releasing Hormone Test in Healthy Subjects, Administration of a Beta-Adrenergic Antagonist Induced Secretion of Cotisol and Dehydroepiandrosterone Sulfate and Inhibited Secretion of ACTH,” European Journal of Endocrinology, Vol. 148, 2003, pp. 45-53. doi:10.1530/eje.0.1480045

[38]   A. Chaudhuri, T. Majeed, T. Dinan and P. O. Behan, “Chronic Fatigue Syndrome: A Disorder of Central Cholinergic Transmission,” Journal of Chronic Fatigue Syndrome, Vol. 3, 1997, pp. 3-16. doi:10.1300/J092v03n01_02

[39]   M. C. Arnold, D. A. Papanicolaou, J. A. O’Grady, A. Lots-ikas, J. K. Dale, S. Straus.,et al., “Using an Interleukin-6 Challenge to Evaluate Neuropsychological Performance in Chronic Fatigue Syndrome. Psychological Medicine, Vol. 32, 2002, pp. 1075-1089. doi:10.1017/S0033291702006086

[40]   M. Pall and M, “Explaining "Unexplained Illnesses": Disease Paradigm for Chronic Fatigue Syndrome, Multiple Che-mical Sensitivity, Fibromyalgia, Posttraumatic Stress Disorder, Gulf War Syndrome and Others,” Bighamton, N.Y.: Haworth Press, 2007.

[41]   A. Peckerman, R. Chemitiganti, C. Zhao, K. Dahl, B. H. Natelson, L. Zuckler, et al., “Left Ventricular Function in Chronic Fatigue Syndrome (CFS): Data from Nuclear Ventriculography Studies of Responses to Exercise and Portural Stress,” FASEB, Vol. 17 (F Suppl: Part 2), 2003, p. A853.

[42]   A. J. Cleare, J. Bearn, T. Allain, A. McGregor, S. Wessely, R.M. Murray, et al., “Contrasting Neuroendocrine Resp-onses in Depression and Chronic Fatigue Syndrome,” Journal of Affective Disorders, Vol. 34, 1995, pp. 283-289. doi:10.1016/0165-0327(95)00026-J

[43]   C. M. Vassallo, E. Feldman, T. Peto, L. Castell, A. L. Sharpley and P.J. Cowen, “Decreased Tryptophan Availability but Normal Post-Synaptic 5-HT Receptor Sensitivity in Chronic Fatigue Syndrome,” Psychological Medicine, Vol. 31, No. 4, 2001, pp. 585-591.

[44]   S. H. Vashadze, “Insomnia, Serotonin and Depression,” Georgian Medical News, Vol. 150, 2001, 22-24.

[45]   G. M. Shepherd, Neurobiology, 1988, pp. 517-528, Oxford University Press.

[46]   A. M. Bakheit, P.O Behan, T. G. Dinan and V. O’Keane, “Possible Upregulation of Hypothalantic 5-Hydroxytry-Ptamine Receptors in Patients with Postviral Fatigue Syndrome, British Medical Journal, Vol. 304, 1992, pp. 1010-1012. doi:10.1136/bmj.304.6833.1010

[47]   M. Spath, D. Welzel and L. Farber, “Treatment of Chr-onic Fatigue Syndrome with 5-HT3 Receptor Antagonists Preliminary Results,” Scandinavian Journal of Rheumatology Supplement, Vol. 113, 2000, 72-77.

[48]   A. B. Badawy, C. J. Morgan, M. B. Llewelyn, R.J. Selwyn, S. R. J. Albuquerque and A. Farmer, “Heterogeneity of Serum Tryptophan Concentration and Availability to the Brain in Patients with the Chronic Fatigue Syndrome,” Journal of Psychopharmacology, Vol. 19, 2005, pp. 385-391. doi:10.1177/0269881105053293

[49]   S. Yamamoto, Y. Ouchi, H. Onoe, E. Yoshikawa, H. Tsu-kada, H. Takahashi, et al., “Reduction of Serotonin Tran-sporters of Patients with Chronic Fatigue Syndrome,” Brain Imaging, Vol. 15, No. 17, 2004, pp. 2571-2574.

[50]   R. W. Fuller, “Role of Serotonin in Therapy of Depression and Related Disorders,” Journal of Clinical Psychiatry, Vol. 52, 1991, pp. 52-57.

[51]   A. J. Cleare, C. Messa, E. A. Rabiner and P. M. Grasby, “Brain 5-HT1A Receptor Binding in Chronic Fatigue Syndrome Measured Using Positron Emission Tomography and [11C]WAY-100635,” Biological Psychiatry, Vol. 57, No. 3, 2005, pp. 239-246.

[52]   V. R. Falkenberg, B.M. Gurbaxani, E. R. Unger and M. S. Rajeevan, “Functional Genomics of Serotonin Receptor 2a (HTR2A): Interaction of Polymorphism, Methylation, Expression and Disease Association,” Neuromolecural Medicine, 2010.

[53]   M. Tanaka and Y. Watanabe, “Mechanism of Fatigue Studied in a Newly Developed Animal Model of Combined (Mental and Physical) Fatigue,” In: Y. Watanabe, B. Evengard, B.H. Natelson, L. A. Jason, & H. Kuratsune, Eds., Fatigue Science for Human Health, 2007, pp. 203-212, Tokyo: Springer.

[54]   I. J. Elenkov, R.L. Wilder, G. P. Chrousos and E. S. Vizi, “The Sympathetic Nerve—An Integrative Interface Between Two Supersystems: The Brain and the Immune System,” Pharmacological Reviews, Vol. 52, No. 2, 2000, pp. 595-638.

[55]   B. V. Van Houdenhove, F. Van Den Eede and P. Luyten, “Does Hypothalamic-Pituitary-Adrenal Axis Hypofunction in Chronic Fatigue Syndrome Reflect a ‘Crash in the Stress System?” Medical Hypothesis, Vol. 72, No. 6, 2009, pp. 701-705. doi:10.1016/j.mehy.2008.11.044

[56]   R. A. Van Konynenburg, Comments Posted on Esther Sternberg’s Presentation at the NIH CFS Workshop “Health Consequences of a Dysregulated Stress Response,” Posted on Co-Cure@LISTSERV. NODAK. EDU on July 1, 2003.

[57]   K. Inoue and T. Fushiki, “Exercise Fatigue,” In: Y. Watanabe, B. Evengard, B. H. Natelson, L. A. Jason, & H. Kuratsune, Eds., Fatigue Science for Human Health, 2007, pp. 187-201, Tokyo: Springer.

[58]   P. D. White, K. E. Nye, A. J. Pinching, T. M. Yap, N. Power, V. Vleck, D. J. Bentley, J. M. Thomas, M. Buckland and J. M. Parkin, “Immunological Changes After Both Exercise and Activity in Chronic Fatigue Syndrome: A Pilot Study,” Journal of Chronic Fatigue Syndrome, Vol. 12, No. 2, 2004, pp. 51-66. doi:10.1300/J092v12n02_06

[59]   J. N. Baraniuk, B. Casado, H. Maibach, D. J. Clauw, L. K. Pannell and S. S. Hess, “A Chronic Fatigue Syndrome-Related Proeome in Human Cerebrospinal Fluid,” BioMedCentral Neurology, Vol. 1, 2005, 5:22. PMCID: PMC 1326206

[60]   C. Johnson, “Proteins on the Brain: Spinal Tapping for ME/CFS,” Phoenix Rising Website, 2010, Retrieved on April 9, 2010. http://www.aboutmecfs.org/News/BrainPr-oteomeMar10.aspx.

[61]   F. P. de Lange, J.S. Kalkman, G. Bleijenberg, P. Hagoort, J. W. M. van der Meer and I. Toni, “Gray Matter Volume Reduction in the Chronic Fatigue Syndrome,” Neuro-Image, Vol. 26, No. 3, 2005, pp. 777-781. doi:10.1016/j.neuroimage.2005.02.037

[62]   L. A. Jason, N. Porter, J. Herrington, M. Sorenson and S. Kubow, “Kindling and Oxidative Stress as Contributors to Myalgic Encephalomyelitis/Chronic Fatigue Syndrome,” Journal of Behavioral and Neuroscience Research, Vol. 7, 2009, pp. 1-17.

[63]   B. Biswal, P. Kunwar and B. H. Natelson, “Cerebral Blood Flow is Reduced in Chronic Fatigue Syndrome as Assessed by Arterial Spin Labeling,” Journal of the Neurologic Sciences, 2010 [Epub ahead of print].

[64]   W. J. Shian and C. S. Chi, “Epstein-Barr virus Encephalitis and Encephalomyelitis: MR Findings,” Pediatric Radiology, Vol. 26, No. 9, 1996, pp. 690-693.

[65]   M. Hausler, V. T. Ramaekers, M. Doenges, K. Schweizer, K. Ritter and L. Schaade, “Neurological Complications of Acute and Persistent Epstein-Barr Virus Infection in Paediatric Patients,” Journal of Medical Virology, Vol. 68, No. 2, 2002, pp. 253-263. doi:10.1002/jmv.10201

[66]   A. Gupta, “Unconscious Amygdalar Fear Conditioning in a Subset of Chronic Fatigue Syndrome Patients,” Medical Hypotheses, Vol. 59, No. 6, 2002, pp. 727-735.

[67]   B. S. McEwen and M. Kalia, “The Role of Corticosteroids and Stress in Chronic Pain Conditions,” Metabolism, Vol. 59, 2010, pp. S9-15.

[68]   J. P. Neary, A. D. W. Roberts, N. Leavins, M. F. Harrison, J. C. Croll and J.R. Sexsmith, “Prefrontal Cortex Oxygenation During Incremental Exercise in Chronic Fatigue Syndrome,” Clinical Physiology and Functional Imaging, 2008.

[69]   X. Caseras, D. Mataix-Cols, K. A. Rimes, V. Giampietro, M. Brammer, F. Zelaya, et al., “The Neural Correlates of Fatigue: An Exploratory Imaginal Fatigue Provocation Study in Chronic Fatigue Syndrome,” Psychological Medicine, Vol. 38, No. 7, 2008, pp. 941-951.

[70]   T. Okada, M. Tanaka, H. Kuratsune, Y. Watanabe and N. Sadato, “Mechanisms Underlying Fatigue: A Voxel-Based Morphometric Study of Chronic Fatigue Syndrome,” BioMedCentral Neurology, Vol. 4, No. 1, 2004, pp. 14-20. doi:10.1186/1471-2377-4-14

[71]   F. P. de Lange, H. Knoop, G. Bleijenberg and J. W. van der Meer, “The Experience of Fatigue in the Brain (Letter to the Editor),” Psychological Medicine, Vol. 38, 2008, pp. 523-524.

[72]   K. M. Billiot, T. H. Budzynski and F. Andrasik, “EEG Patterns and Chronic Fatigue Syndrome,” Journal of Neurotherapy, Vol. 2, 1997, pp. 20-30. http://www.snr-jnt.org/JournalNT/JNT(22)4.html.8004844 doi:10.1300/J184v02n02_04

[73]   L. Sherlin, T. Budzynski, H. Kogan-Budzynski, M. Con-gedo, M. E. Fischer and D. Buchwald, “Low-Resolution Brain Tomography (LORETA) of Monozygotic Twins Disconcordant for Chronic Fatigue Syndrome,” Neuro-Image, Vol. 34, No. 4, 2006, pp. 1438-1442.

[74]   P. Flor-Henry, J. C. Lind and Z. J. Koles, “EEG Source Analysis of Chronic Fatigue Syndrome,” Psychiatric Research, 2009. PMID: 20006474.

[75]   F. Donati, L. Fagioli, A. L. Komaroff and F. H. Duffy, “Quantified EEG Findings in Patients with Chronic Fatigue Syndrome,” Paper Presented at the American Association for Chronic Fatigue Syndrome, Ft. Lauderdale, Florida, 1994.

[76]   F. H. Duffy, G. B. McAnulty, M. McCreary, M. S. Albert, G. Cucharal, A. Shatzberg, et al., “Electroencephalogra-phic Data Distinguish Patients with CFS from Healthy and Depressed Controls,” Paper Presented at the 9th International Association of CFS/ME, Reno, NV, March, 2009.

[77]   A. Kishi, B. H. Natelson, F. Togo, Z. R. Struzik, D. M. Rapoport and Y. Yamamoto, “Sleep Stage Transitions in Chronic Fatigue Syndrome Patients With or Without Fibromyalgia,” Proceedings of the International Conference of the IEEE Engineering in Medicine and Biology Society, Vol. 1, 2010, pp. 5391-5394.

[78]   A. R. Spitzer and M. Broadman, “Treatment of the Narcoleptiform Sleep Disorder in Chronic Fatigue Syndrome and Fibromyalgia with Sodium Oxybate,” Pain Practice, Vol. 10, No. 1, 2010, pp. 54-59.

[79]   H. Moldofsky, N. H. Inhaber, D. R. Guinta and S. B. Alvarez-Horine, “Effects of Sodium Oxybate (Xyrem) on Sleep Physiology and Sleep/Wake-Related Symptoms in Patients with Fibromyalgia Syndrome: A Double-Blind, Randomized, Placebo-Controlled Study,” Journal of Rheumatology, 2010 [Epub ahead of print].

[80]   I. Blanco, N. Béritze, M. Argüelles, V. Cárcaba, F. Fern-ández, S. Janciauskiene, K. Oikonomopoulou, F.J. de Serres, E. Fernández-Bustillo and M. D. Hollenberg, “Abnormal Overexpression of Mastocytes in Skin Biop-sies of Fibromyalgia Patients,” Clinical Rheumatology, 2010. (Epub ahead of print). doi:10.1007/s10067-010-1474-7

[81]   I. Hickie, T. Davenport, D. Wakefield, U. Vollmer-Conna, B. Cameron, S. D. Vernon, et al., “Post-Infective and Chronic Fatigue Syndromes Precipitated by Viral and Non-Viral Pathogens: Prospective Cohort Study,” British Medical Journal, Vol. 333, No. 7568, 2006, pp. 575-578. doi:10.1136/bmj.38933.585764.AE

[82]   C. R. Plata-Salaman, S. E. Ilyin, P. Nicolas, N. P. Turrin, D. Gayle, M. C. Flynn, et al., “Kindling Modulates the IL-1b System, TNF-a, TGF-b1 and Neuropeptide mRNAs in Specific Brain Regions,” Molecular Brain Research, Vol. 75, No. 2, 2000, pp. 248-258.

[83]   A. A. Shandra, L. S. Godlevsky, R. S. Vastyanov, A. A. Oleinik, V. L. Konovalenko, E.N. Rapoport, et al., “The Role of TNF-Alpha in Amygdala Kindled Rats. Neuroscience Research, Vol. 42, No. 2, 2002, pp. 147-153. doi:10.1016/S0168-0102(01)00309-1

[84]   U. Vollmer-Conna, C. Fazou, B. Cameron, H. Li, C. Brennan, L. Luck, et al., “Production of Pro-Inflammatory Cytokines Correlates with Symptoms of Acute Sickness Behaviour in Humans,” Psychological Medicine, Vol. 34, 2004, pp. 1-9. doi:10.1017/S0033291704001953

[85]   U. Vollmer-Conna, B. F. Piraino, B. Cameron, T. Davenport, I. Hickie, D. Wakefield, et al., “Cytokine Polymorphisms Have a Synergistic Effect on Severity of the Acute Sickness Response to Infection,” Clinical Infectious Diseases, Vol. 47, 2008, pp. 1418-25. doi:10.1086/592967

[86]   M. Meeus, I. Van Eupen, J. Hondequin, L. De Hauwere, D. Kos and J. Nijs, “Nitric Oxide Concentrations are Normal and Unrelated to Activity Level in Chronic Fatigue Syndrome: A Case-Control Study,” In Vivo, Vol. 24, No. 6,2010, pp. 865-869.

[87]   T. R. Minor and A. M Hunter, “Stressor Controllability and Learned Helplessness Research in the United States: Sensitization and Fatigue Processes,” Integrative Physiological & Behavioral Science, Vol. 37, No. 1, 2002, pp. 44-58. doi:10.1007/BF02688805

[88]   T. Doi, Y. Ueda, K. Nagatomo and L. J. Willmore, “Role of Glutamate and GABA Transporters in Development of Pentylenetetrazol-Kindling,” Neurochemistry Research, Vol. 34, 2009, pp. 1324-1331.doi:10.1007/s11064-009-9912-0

[89]   J. W. Winkelman, O. M. Buxton, J. E. Jensen, K. L. Benson, S. P. O'Connor, W. Wang and P. F. Renshaw, “Reduced Brain GABA in Primary Insomnia: Preliminary Data from 4T Proton Magnetic Resonance Spectroscopy (1H-MRS),” Sleep, Vol. 31, No. 11,2008, pp. 1499-1506.

[90]   M. M. Halassa, C. Florian, T. Fellin, J. R. Munoz, S. Y. Lee, T. Abel, P. Haydon and M. G. Frank, “Astrocytic Modulation of Sleep Homeostasis and Cognitive Consequences of Sleep Loss,” Neuron, Vol. 61, No. 2, 2009, pp. 213-219. doi:10.1016/j.neuron.2008.11.024

[91]   Z. Y. Hong, Z. L. Huang, W. M. Qu, N. Eguchi, Y. Urade and O. Hayaishi, "An Aadenosine A Receptor Agonist Induces Sleep by Increasing GABA Release in the Tuberomammillary Nucleus to Inhibit Histaminergic Systems in Rats,” Journal of Neurochemistry, Vol. 92, 2005, pp. 1542-1549. doi:10.1111/j.1471-4159.2004.02991.x

[92]   J. Krueger, “The Brain that Never Fully Sleeps,” Fibromyalgia Network, Vol. 85, 2009, pp. 12-15.

[93]   J. M. Glass, A. K. Lyden, F. Petzke, P. Stein, G. Whalen, K. Ambrose, et al., “The Effect of Brief Exercise Cessation on Pain, Fatigue and Mood Symptom Development in Healthy, Fit Individuals,” Journal of Psychosomatic Research, Vol. 57, 2004, pp. 391-398.

[94]   K. W. Haug, M. Warnstedt, Alekov, T. Sander, A. Ramirez, B. Poser, S. Maljevic, S. Hebeisen, C. Kubisch, J. Rebstock, S. Horvath, K. Hallmann, J. S. Dullinger, B. Rau, F. Haverkamp, S. Beyenburg, H. Schulz, D. Janz, B. Geise, G. Muller-Newen, P. Propping, C. E. Elger, C. Fahlke, H. Lerche and A. Heils, “Mutations in Clcn2 Encoding a Voltage-Gated Chloride Channel are Associated with Idiopathic Generalized Epilepsies,” Nature Genetics, Vol. 33, 2003.

[95]   S. F. Berkovic, R. A. Howell, D. A. Hay and J. L. Hopper, “Epilepsies in Twins: Genetics of the Major Epilepsy Syndromes,” Annals of Neurology, Vol. 43, 1998, 435-445. doi:10.1002/ana.410430405

[96]   A. N. Vgontzas, V. M. Zoumakis D. A. Papanicolaou, E. O. Bixler, P. Prolo, H. M. Lin, A. Vela-Bueno, A. Kales and G. P. Chrousos, “Chronic Insomnia is Associated with a Shift of Interleukin-6 and Tumor Necrosis Factor Secretion from Nighttime to Daytime,” Metabolism, Vol. 51, 2002, pp. 887-892. doi:10.1053/meta.2002.33357

[97]   M. Demitrack and L. Crofford, “Evidence For and Pathophysiologic Implications of Hypothalamic-Pituitary -Adrenal Axis Dysregulation in Fibromyalgia and Chronic Fatigue Syndrome,” Annals of the New York Academy of Sciences, Vol. 840, 1998, pp. 684-697. doi:10.1111/j.1749-6632.1998.tb09607.x

[98]   L. V. Scott, S. Medbak and T. G. Dinan, “Blunted Adrenocorticotropin and Cortisol Responses to Cortic-otropin-Releasing Hormone Stimulation in Chronic Fati-gue Syndrome,” Acta Psychiatrica Scandinavica, Vol. 97, 1998, pp. 450-457. doi: 10.1111/j.1600-0447.1998. tb10030.x

[99]   D. B. Cook, P. J. O’Connor, G. Lange and J. Steffener, “Functional Neuroimaging Correlates of Mental Fatigue Induced by Cognition Among Chronic Fatigue Syndrome Patients and Controls,” NeuroImage, Vol. 36, 2007, pp. 108-122.doi:10.1016/j.neuroimage.2007.02.033

[100]   M. P. Kaufman and S. G. Hayes, “The Exercise Pressor Reflex,” Clinical Autonomic Research, Vol. 12, 2002, pp. 429-439. doi:10.1007/s10286-002-0059-1

[101]   A. R. Light, A. T. White, R. W. Hughen and K. C. Light, “Moderate Exercise Increases Expression for Sensory, Adrenergic and Immune Genes in Chronic Fatigue Syndrome Patients but not in Normal Subjects,” The Journal of Pain, Vol. 10, No. 10, 2009, pp. 1099-1112.

[102]   L. A. Jason, M. Benton, S. Torres-Harding and K. Muldowney, “The Impact of Energy Modulation on Physical Functioning and Fatigue Severity Among Patients with ME/CFS,” Patient Education and Counseling, Vol. 77, No. 8, 2009, pp. 237-241. PMCID: PMC2767446

[103]   K. Dursun, D. Ermutlu and K. Karamursel, “Neurofeedback Intervention in Fibromyalgia Syndrome: A Randomized, Controlled, Rater Blind Clinical Trial,” Applied Psychophysiology Biofeedback, 2010.

[104]   J. C. Mulley, I. E. Scheffer, S. Petrou and S. F. Berkovic, “Channelopathies as a Genetic Cause of Epilepsy,” Current Opinion in Neurobiology, Vol. 16, No. 2, 2003, pp. 171-176. doi:10.1097/00019052-200304000-00009

[105]   K. Cadwell, K. K. Patel, N. S. Maloney, T. C. Liu, A. C. Y. Ng, C. E. Storer, R. D. Head, R. Xavier, T. S. Stappenbeck and H. W. Virgin, “Virus Plus Susceptibility Gene Interaction Determines Crohn’s Disease Gene Atg16L1 Phenotypes in Intestine,” Cell, 2010.

[106]   B. Y. Chow, X. Han, A. S. Dobry, X. Qian, A. S. Chuong, M. Li, M. A. Henninger, G. M. Belfort, Y. Lin, P. E. Monahan and E. S. Boyden, “High-Performance Genetically-Targetable Optical Neural Silencing by Light-Driven Proton Pumps,” Nature, Vol. 463, No. 7277, 2010, pp. 98-102. doi:10.1038/nature08652

[107]   H. Landmark-H?yvik, K. V. Reinertsen, J. H. Loge, V. N. Kristensen, V. Dumeaux, S. Doss?, A. L. B?rresen-Dale and H. Edvardsen, “The Genetics and Epigenetics of Fatigue,” Physical Medicine and Rehabilitation, Vol. 2, No. 5, 2010, pp. 456-65.

[108]   S. Gupta, E. Aslakson, B. M. Gurbaxani and S. D. Vernon, “The Inclusion of the Glucocorticoid in a Hypothalamic Pituitary Adrenal Axis Model Reveals Bistability,” Theo-retical Biology and Medical Modeling, Vol. 4, 2007. PMID: 17300722.

[109]   J. Visser, E. Lentjes, I. Haspels, W. Graffelman, B. Blauw, R. DeKloet and L. Nagelkerken, “Increased Sen-sitivity to Glucocorticoids in Peripheral Blood Mono-nuclear Cells of Chronic Fatigue Syndrome Patients, Without Evidence for Altered Density or Affinity of Glucocorticoid Receptors,” Journal of Investigative Medicine, Vol. 49, No. 2, 2001, pp. 195-204.

 
 
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