The recent national attention generated by Stanford's brain study of ME/CFS patients could not have come at a better time.
The news that people with ME/CFS have a problem in their brains is not really news (although medical studies proving it are always welcome). After all, the name myalgic encephalomyelitis is a clear indication that brain involvement is key to the disease.
What makes the Stanford study special is not that it shows several anomalies, but that it was accompanied by huge amount of press. Coincidentally, the news that "CFS is real" (to quote USA Today) comes at a time when HHS seems hell-bent on proving that it isn't.
In one month, the P2P panel will meet to decide the financial fate of ME/CFS research. If the panel decides that ME/CFS can be cured with "a talk and a walk" (CBT and GET), it will be going head-to-head with the Stanford University School of Medicine, which is not only one of the most prestigious institutions in the country, but one that leaves any panel or committee assembled by HHS in the dust.
Up until now, the P2P and IOM efforts to redefine ME/CFS have been primarily opposed by ME/CFS patients, advocates and specialists. But with the publicity generated by the Stanford study, it now appears as if at least one major institution is also tacitly weighing in.
And Stanford will be hard to ignore.
For those who are interested in previous studies that have shown CNS and brain anomalies in ME/CFS, I have posted an excerpt from Chronic Fatigue Syndrome: A Treatment Guide, 2nd Edition below. To get a sense of the quantity of research that has been done, I invite you to look at the research section. (The 2014 study, Neuroinflammation in Patients with Chronic Fatigue Syndrome/Myalgic Encephalomyelitis by Nakatomi et al. is not on the list.)
CNS Involvement and Goldstein's Limbic Hypothesis
In the early 1990s, Dr. Jay Goldstein, a psychiatrist and psychopharmacologist (now deceased), developed a theory in which he proposed that CFS/ME was the result of an insult to the limbic system, which is composed of structures relating to the hypothalamus, such as the hippocampus, amygdala, cingulate gyrus, and dentate gyrus. The limbic system is an area located deep in the brain just above the brainstem, and is involved with memory, emotion, and regulation of the autonomic nervous system. This last function is of critical importance to maintaining homeostasis in the body, as the autonomic nervous system regulates appetite, body temperature, blood pressure, blood sugar, sleep, wakefulness, heart rate, digestion – in short, nearly every physiological function necessary for maintaining life.
Dr. Goldstein's theory, as laid out in his book, Betrayal by the Brain, was that CFS/ME is essentially a communication problem between the limbic system and the rest of the nervous system. His “limbic hypothesis” essentially states that no matter what the underlying cause of CFS/ME, the result is an injury (encephalopathy) to the limbic system, which subsequently causes widespread neuroimmune dysfunction. He identified CFS/ME as a “neurosomatic” illness, that is, a disorder of central nervous system processing. Dr. Goldstein based his theory on what he knew of the brain, which was substantial, as well as what he had observed of his patients' reactions to various psychotropic medications. In one sense, Dr. Goldstein was old-fashioned; he followed a time-honored scientific practice – observation. Recent studies, however, have shown that Dr. Goldstein was actually far ahead of his time, if not prescient.
Currently, there seems to be no doubt of central nervous system (CNS) involvement in CFS/ME, and a variety of approaches have been used to measure its extent. Typically, psychologists have employed cognitive tests to measure the overall performance of patients, while neurologists have used brain scans: MRIs to locate structural damage, functional MRIs to measure brain activation, SPECT scans to measure blood flow, PET scans to measure glucose uptake, and MR Spectroscopy to measure biochemicals associated with inflammation inside the brain.
Cognitive deficits, because they among the most frequently reported causes of disability in CFS/ME patients, have received a considerable amount of attention from researchers. Dozens of studies have been performed in an effort to categorize the nature of these deficits, quantify them, and distinguish these cognitive deficits from those produced by other disorders (in most cases, depression). In general, the studies have revealed that patients with CFS/ME do, in fact, suffer from the very problems they report – slow processing of information, lack of concentration, and so forth. Researchers have found that people with CFS/ME have problems processing auditory information, experience mental fatigue quickly, and cannot multitask. These results are buttressed by studies such as those by Majer et al and Marcel et al, which show that cognitive impairment in people with CFS/ME is independent of depression, a disorder with which CFS/ME is often confused.
The most informative cognitive studies are those which have measured brain function during the performance of tasks requiring mental effort. Tanaka et al, in 2006, used functional magnetic resonance imaging (fMRI) to demonstrate distractibility in CFS/ME patients. In this study, subjects were given a visual task to perform while listening to intermittent noise. Over the course of the task, people with CFS/ME showed reduced responsiveness in the areas of the brain associated with task performance, demonstrating an inability to focus on a task while receiving simultaneous input from competing stimuli. A previous study by de Lange et al showed that given a visual and simultaneous motor task, patients with CFS/ME solved the motor imagery task by using additional cerebral regions supporting visual processes. The authors suggested that CFS/ME patients might rely on visual imagery to compensate for dysfunctional motor planning.
Tests of working memory also show impairments. Caseras et al conducted an fMRI study to objectively compare brain activity in 17 CFS/ME patients with 12 controls during a test of working memory. The study revealed significant differences in brain activation between the two groups. CFS/ME patients showed greater activation than control subjects in areas associated with working memory (prefrontal regions). Under more challenging conditions, patients, but not controls, showed a significantly activated large cluster in the right inferior/medial temporal cortex (an area associated with working memory and attention). These findings are consistent with earlier studies demonstrating that patients with CFS/ME could perform as well as controls, but that the effort involved greater brain activity.
A subsequent functional MRI study conducted by Cook et al confirmed that several areas of the brain are activated to a greater extent in CFS/ME patients compared to controls during challenging cognitive tasks. During a task that required no mental effort (finger tapping), neither patients nor controls showed significant differences in activation or fatigue. However, when presented with a complex mental task involving attention, working memory, and executive function, patient perceptions of fatigue correlated with brain activation: the greater the brain activity, the greater the fatigue.
Given that fatigue is the result of work of any kind, whether physical or mental, the conclusion that CFS/ME patients are more easily fatigued by mental effort than healthy people seems obvious. However, most cognitive studies are based on the assumption that people with CFS/ME merely “feel” fatigued. There is a lingering suspicion that the mental exhaustion experienced by people with CFS/ME may be form of neurosis unless physiological correlates can be identified.
In this regard, brain scans have been of enormous interest to the CFS/ME community because they provide concrete proof of neurological impairment. Dr. Ismael Mena and Dr. Jay Goldstein pioneered the use of SPECT (Single-photon Emission Computed Tomography) to document brain abnormalities in CFS/ME patients. SPECT scans measure blood flow in the brain, as opposed to MRIs, which show structure. Studies in the 1990s by Mena, Goldstein, Richardson, and Costa showed brainstem hypoperfusion (low blood flow) in a high percentage of CFS/ME patients.
In 1998 the late John Richardson conducted SPECT scans on some of his patients suffering from ME. The scans showed hypoperfusion in 90% of the patients in several areas. These included the brainstem (62%), the caudate nuclei in the basal ganglia (51%), temporal lobes (62%), parietal lobes (31%), and frontal lobes (23%).
A group of Australian researchers led by R. Casse also found a deficit in regional cerebral blood flow in similar areas: the brainstem, left medial temporal lobe, right medial temporal lobe, frontal lobe, and anterior cingulate gyrus. These are the areas of the brain responsible for auditory processing, attention, autonomic nervous system regulation, memory, sleep and pain.
The most recent studies to show brain hypoperfusion in CFS/ME have not used SPECT scans, but a xenon-CT. This type of scan measures the uptake of xenon gas by the brain. (When the gas is inhaled, it is distributed through the brain via the bloodstream.) Using this technique, Yoshiuchi et al found that patients with CFS/ME have reduced absolute cortical blood flow in broad areas when compared with healthy controls. Non-depressed patients with CFS/ME had reduced cortical blood flow in both right and left middle cerebral arteries. The authors concluded that their data supported earlier findings that CFS/ME patients without depression are the group most at risk for having symptoms due to brain dysfunction. In a 2011 study by Biswal et al, 9 of 11 patients with CFS/ME showed broad decreases in cerebral blood flow compared to healthy controls. While these are small studies, they are significant in that they used a different tool to confirm hypoperfusion.
Small lesions, called “unidentified bright objects” (UBOs), often appear on the MRIs of CFS/ME patients. UBOs are often ignored by radiologists unless they are profuse and accompanied by signs of MS or other neurological injury, such as stroke. However, CFS/ME researchers have repeatedly stressed the significance of UBOs, which have appeared on the MRIs of CFS/ME patients since the first scans were performed in the 1980s.
Coincidentally, the first MRI scanner in Reno, Nevada was being set up by Dr. Royce Biddle just as the Lake Tahoe outbreak occurred. From 1985 to 1988 Dr. Biddle performed hundreds of MRI scans on patients seen by Dr. Peterson and Dr. Cheney. In conjunction with Dr. Buchwald, and Drs. Komaroff and Jolesz of Harvard, scans of 142 patients were analyzed. UBOs were found in 79% of the scans. While Dr. Biddle could not definitively state that the UBOs were pathological, he theorized that the disease might involve edema in perivascular spaces.
As far as brain structure in CFS/ME is concerned, the most dramatic studies have been those showing loss of brain matter. In 2004 Okada et al found that patients with CFS/ME had reduced gray matter volume in the bilateral prefrontal cortex. Furthermore, the volume reduction in the right prefrontal cortex paralleled the severity of the fatigue of the subjects (the lower the volume, the more fatigued the subject). The researchers concluded that the fatigue experienced by people with CFS/ME was central, that is, the difficulty in the initiation of and the ability to sustain voluntary activities was generated in the brain.
In 2006 a group of researchers in Holland led by de Lange, mapped structural brain structure and volume in two cohorts of CFS patients (28 patients total) and 28 healthy controls with high-resolution structural magnetic resonance images using voxel-based morphometry, a form of statistical analysis that measures the shape, size and position of brain structures. The de Lange study found “substantial and consistent” reductions in gray matter volume in two groups of CFS/ME patients as compared with controls.
A subsequent study in 2011 by Barnden et al found reductions in both white and gray matter. In the midbrain, white matter volume was decreased, while vascular abnormalities were observed in the brainstem, midbrain gray matter, deep prefrontal white matter, caudal basal pons, and hypothalamus. According to the authors, their findings were consistent with an injury to the midbrain at the onset of the illness, which could affect many feedback control loops, resulting in suppressed CNS motor and cognitive activity and a disruption of homeostasis.
Significantly, this type of injury would include resetting some elements of the autonomic nervous system, which might account for why people with CFS/ME experience increased sympathetic nervous system arousal. In line with the findings of this study, Claypoole et al found that sudden onset was predictive of cognitive impairment, particularly reduced speed in processing information.
In the same year, Puri et al conducted a large voxel-based morphometry study comparing 26 CFS/ME patients with 26 healthy volunteers matched for age and gender. Reduced gray matter volume in the CFS/ME group was noted in the occipital lobes (right and left occipital poles; left lateral occipital cortex, superior division; and left supracalcrine cortex), the right angular gyrus and the posterior division of the left parahippocampal gyrus. Reduced white matter volume in the CFS/ME group was also noted in the left occipital lobe. The authors concluded that their data supported the hypothesis that “significant neuroanatomical changes occur in CFS, and are consistent with the complaint of impaired memory that is common in this illness.” Their data also indicated that “subtle abnormalities in visual processing, and discrepancies between intended actions and consequent movements, may occur in CFS/ME.”
List of brain scan research studies: http://www.cfids-cab.org/cfs-inform/Brainscans/brainscans.html
Barnden LR, Crouch B, Kwiatek R, Burnet R, Mernone A, Chryssidis A, Scroop G, Del Fante P. “A brain MRI study of chronic fatigue syndrome: evidence of brainstem dysfunction and altered homeostasis.” NMR Biomed. 2011 Dec;24(10):1302-12. http://www.ncbi.nlm.nih.gov/pubmed/21560176 (Abstract)
Biswala, Bharat, Pratap Kunwarb, Benjamin H. Natelson. “Cerebral blood flow is reduced in chronic fatigue syndrome as assessed by arterial spin labeling.” J Neurol Sci. 2011 Feb 15;301(1-2):9-11. http://www.sciencedirect.com/science/article/pii/S0022510X10005666
Capuron L, Welberg L, Heim C, Wagner D, Solomon L, Papanicolaou DA, Craddock RC, Miller AH, Reeves WC. “Cognitive dysfunction relates to subjective report of mental fatigue in patients with chronic fatigue syndrome.” Neuropsychopharmacology. 2006 Aug;31(8):1777-84. http://www.ncbi.nlm.nih.gov/pubmed/16395303 (Abstract)
Caseras X, Mataix-Cols D, Giampietro V, Rimes KA, Brammer M, Zelaya F, Chalder T, Godfrey EL. “Probing the working memory system in chronic fatigue syndrome: a functional magnetic resonance imaging study using the n-back task.” Psychosom Med. 2006 Nov-Dec;68(6):947-55. http://www.ncbi.nlm.nih.gov/pubmed/17079703 (Abstract)
Casse R, P Delfante, L Barnden, R Burnett, M Kitchener, R Kwiatek. “Regional cerebral bloodflow in chronic fatigue syndrome (CFS).” Abstracts Sydney Conf. (20/35) http://www.cfids-cab.org/cfs-inform/Brainscans/casse.etal01.txt
Claypoole KH, Noonan C, Mahurin RK, Goldberg J, Erickson T, Buchwald D. “A twin study of cognitive function in chronic fatigue syndrome: the effects of sudden illness onset.” Neuropsychology. 2007 Jul;21(4):507-13. http://www.ncbi.nlm.nih.gov/pubmed/17605583 (Abstract)
Constant EL, Adam S, Gillain B, Lambert M, Masquelier E, Seron X. “Cognitive deficits in patients with chronic fatigue syndrome compared to those with major depressive disorder and healthy controls.” Clin Neurol Neurosurg. 2011 Jan 19. http://www.ncbi.nlm.nih.gov/pubmed/21255911 (Abstract)
Cook, Dane B., Patrick J. O’Connor, Gudrun Lange, and Jason Steffener. “Functional neuroimaging correlates of mental fatigue induced by cognition among chronic fatigue syndrome patients and controls.” NeuroImage. Volume 36, Issue 1, 15 May 2007, Pages 108–122 http://www.cfids-cab.org/rc/Cook-2.pdf
Costa DC, Tannock C, Brostoff J. “Brainstem perfusion is impaired in chronic fatigue syndrome.” QJM. 1995 Nov;88(11):767-73. http://www.ncbi.nlm.nih.gov/pubmed/8542261 (Abstract)
Daly E, Komaroff AL, Bloomingdale K, Wilson S, Albert MS. “Neuropsychological function in patients with chronic fatigue syndrome, multiple sclerosis, and depression.” Appl Neuropsychol. 2001;8(1):12-22.http://www.ncbi.nlm.nih.gov/pubmed/11388119 (Abstract)
Davey NJ, Puri BK, Catley M, Main J, Nowicky AV, Zaman R. “Deficit in motor performance correlates with changed corticospinal excitability in patients with chronic fatigue syndrome.” Int J Clin Pract. 2003 May;57(4):262-4. http://www.ncbi.nlm.nih.gov/pubmed/12800454 (Abstract)
de Lange, Floris P., Joke S. Kalkman, Gijs Bleijenberg, Peter Hagoort, Sieberen P. vd Werf, Jos W. M. van der Meer and Ivan Toni. “Neural correlates of the chronic fatigue syndrome—an fMRI study.” Brain (2004), 127, 1948–1957. http://brain.oxfordjournals.org/content/127/9/1948.full.pdf
de Lange, Floris P., Joke S. Kalkman, Gijs Bleijenberg, Peter Hagoort, Jos W. M. van der Meer and Ivan Toni. “Gray matter volume reduction in the chronic fatigue syndrome.” NeuroImage 26 (2005) 777 – 78. http://pubman.mpdl.mpg.de/pubman/item/escidoc:60205:5/component/escidoc:60206/DeLange_2005_gray.pdf
DeLuca J, Johnson SK, Natelson BH. “Information processing efficiency in chronic fatigue syndrome and multiple sclerosis.” Arch Neurol. 1993 Mar;50(3):301-4 http://www.ncbi.nlm.nih.gov/pubmed/8442710 (Abstract)
DeLuca J, Johnson SK, Ellis SP, Natelson BH. “Cognitive functioning is impaired in patients with chronic fatigue syndrome devoid of psychiatric disease.” J Neurol Neurosurg Psychiatry. 1997 Feb;62(2):151-5. http://www.ncbi.nlm.nih.gov/pubmed/9048715 (Abstract)
DeLuca J, Johnson SK, Ellis SP, Natelson BH. “Sudden vs gradual onset of chronic fatigue syndrome differentiates individuals on cognitive and psychiatric measures.” J Psychiatr Res. 1997 Jan-Feb;31(1):83-90. http://www.ncbi.nlm.nih.gov/pubmed/9201650 (Abstract)
Friedberg F, Dechene L, McKenzie MJ 2nd, Fontanetta R. Symptom patterns in long duration chronic fatigue syndrome. J Psychosom Res. 2000 Jan;48(1):59-68. http://www.ncbi.nlm.nih.gov/pubmed/10750631 (Abstract)
Glass JM. “Cognitive dysfunction in fibromyalgia and chronic fatigue syndrome: new trends and future directions.” Curr Rheumatol Rep. 2006 Dec;8(6):425-9. http://www.ncbi.nlm.nih.gov/pubmed/17092441 (Abstract)
Goldstein, J.A. “Chronic Fatigue Syndrome: Limbic encephalopathy in a dysfunctional neuroimmune network.” In B.M. Hyde, J. Goldstein and P. Levine, eds. The Clinical and Scientific Basis of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Ottawa, Ontario, Canada: Nightingale Research Foundation Press. 1992.
Johnson SK, DeLuca J, Fiedler N, Natelson BH. “Cognitive functioning of patients with chronic fatigue syndrome.” Clin Infect Dis. 1994 Jan;18 Suppl 1:S84-5. http://www.ncbi.nlm.nih.gov/pubmed/8148459 (Abstract)
Johnson SK, DeLuca J, Diamond BJ, Natelson BH. “Selective impairment of auditory processing in chronic fatigue syndrome: a comparison with multiple sclerosis and healthy controls.” Percept Mot Skills. 1996 Aug;83(1):51-62. http://www.ncbi.nlm.nih.gov/pubmed/8873173 (Abstract)
Joyce E, Blumenthal S, Wessely S. “Memory, attention, and executive function in chronic fatigue syndrome.” J Neurol Neurosurg Psychiatry. 1996 May;60(5):495-503. http://www.ncbi.nlm.nih.gov/pubmed/8778252 (Abstract)
Kadota Y, Cooper G, Burton AR, Lemon J, Schall U, Lloyd A, Vollmer-Conna U. “Autonomic hyper-vigilance in post-infective fatigue syndrome.” Biol Psychol. 2010 Sep; 85(1):97-103. http://www.ncbi.nlm.nih.gov/pubmed/20678991 (Abstract)
Majer M, Welberg LA, Capuron L, Miller AH, Pagnoni G, Reeves WC. “Neuropsychological performance in persons with chronic fatigue syndrome: results from a population-based study.” Psychosom Med. 2008 Sep;70(7):829-36. http://www.ncbi.nlm.nih.gov/pubmed/18606722 (Abstract)
Marcel B, Komaroff AL, Fagioli LR, Kornish RJ 2nd, Albert MS. “Cognitive deficits in patients with chronic fatigue syndrome.” Biol Psychiatry. 1996 Sep 15;40(6):535-41. http://www.ncbi.nlm.nih.gov/pubmed/8879474 (Abstract)
Mena, Ismael, and Javier Villanueva-Meyer. “Study of Cerebral Perfusion by NeuroSPECT in Patients with Chronic Fatigue Syndrome.” In B.M. Hyde, J. Goldstein and P. Levine, eds. The Clinical and Scientific Basis of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Ottawa, Ontario, Canada: Nightingale Research Foundation Press. 1992.
Michiels V, Cluydts R, Fischler B, Hoffmann G, Le Bon O, De Meirleir K. “Cognitive functioning in patients with chronic fatigue syndrome.” J Clin Exp Neuropsychol. 1996 Oct;18(5):666-77. http://www.ncbi.nlm.nih.gov/pubmed/8941852 (Abstract)
Okada T, Tanaka M, Kuratsune H, Watanabe Y, Sadato N. “Mechanisms underlying fatigue: a voxel-based morphometric study of chronic fatigue syndrome.” BMC Neurol. 2004 Oct 04;4(1):14. http://www.cfids-cab.org/cfs-inform/Brainscans/okada.etal04.txt
Puri BK, Jakeman PM, Agour M, Gunatilake KD, Fernando KA, Gurusinghe AI, Treasaden IH, Waldman AD, Gishen P. “Regional grey and white matter volumetric changes in myalgic encephalomyelitis (chronic fatigue syndrome): a voxel-based morphometry 3-T MRI study.” Br J Radiol. 2011 Nov 29. http://www.ncbi.nlm.nih.gov/pubmed/22128128
Richardson, John, Durval Campos Costa. “Relationship Between SPECT Scans and Buspirone Tests in Patients with ME/CFS.” Journal of Chronic Fatigue Syndrome, Vol. 4(3) 1998. http://www.cfids-cab.org/cfs-inform/Brainscans/richardson.costa98.txt
Sandman CA, Barron JL, Nackoul K, Goldstein J, Fidler F. “Memory deficits associated with chronic fatigue immune dysfunction syndrome.” Biological Psychiatry. 1993 Apr 15-May 1;33(8-9):618-23. http://www.ncbi.nlm.nih.gov/pubmed/8329493 (Abstract)
Scheffers MK, Johnson R Jr, Grafman J, Dale JK, Straus SE. “Attention and short-term memory in chronic fatigue syndrome patients: an event-related potential analysis.” Neurology. 1992 Sep;42(9):1667-75. http://www.ncbi.nlm.nih.gov/pubmed/1513453 (Abstract)
Schrijvers D, Van Den Eede F, Maas Y, Cosyns P, Hulstijn W, Sabbe BG. “Psychomotor functioning in chronic fatigue syndrome and major depressive disorder: a comparative study.” J Affect Disord. 2009 May;115(1-2):46-53. http://www.ncbi.nlm.nih.gov/pubmed/18817977 (Abstract)
Schillings ML, Kalkman JS, van der Werf SP, van Engelen BG, Bleijenberg G, Zwarts MJ. “Diminished central activation during maximal voluntary contraction in chronic fatigue syndrome.” Clin Neurophysiol. 2004 Nov;115(11):2518-24. http://www.ncbi.nlm.nih.gov/pubmed/15465441 (Abstract)
Tanaka M, Sadato N, Okada T, Mizuno K, Sasabe T, Tanabe HC, Saito DN, Onoe H, Kuratsune H, Watanabe Y. “Reduced responsiveness is an essential feature of chronic fatigue syndrome: a fMRI study.” BMC Neurol. 2006 Feb 22;6:9. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1397862/
Thomas M, Smith A. “An investigation into the cognitive deficits associated with chronic fatigue syndrome.” Open Neurol J. 2009 Feb 27;3:13-23. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2682840/
Yoshiuchi, Kazuhiro, Jeffrey Farkas,and Benjamin H. Natelson. “Patients with chronic fatigue syndrome have reduced absolute cortical blood flow.” Clin Physiol Funct Imaging. 2006 Mar;26(2):83-6. http://www.cfids-cab.org/MESA/Yoshiuchi-1.pdf