Can light therapy help heal the brain?

When NIH doesn't fund research for your illness, what do you do? You look at results from studies on other diseases that have an overlap in symptoms. One such illness is Gulf War Illness, which shares so many symptoms with ME/CFS that Nancy Klimas has said it is clinically "identical."

The body has a limited number of ways it can respond to injury. It can produce inflammation, thereby isolating the injury. It can raise or lower pH and temperature to help eradicate a pathogen. But it cannot morph into another form, grow another limb, or start all over again. There are organisms that can do all these things, but we can't. We can, however, repair the injured part.

When the brain is injured, whether due to a toxin, inflammation, or hypoxia, it has the capacity for self-repair. It doesn't really matter to the brain how it was injured, because the self-repair mechanisms are the same. In the case of GWI vets, brain injury was generated by a toxin, but the resulting neurological symptoms and cognitive impairment are similar enough to ME/CFS to warrant a look at how the injury in GWI vets is being treated. In the procedure being investigated by Dr. Margaret Naeser, the mitochondria of the brain are stimulated by LED light to increase their function.

Given the known mitochondrial defects in patients with ME/CFS, coupled with hypoxic conditions in the CNS, a treatment that could stimulate repair of brain tissues would be of enormous benefit.

A follow-up study sponsored by the VA is currently recruiting.

Photo: A staffer in Dr. Margaret Naeser's lab demonstrates the equipment built especially for the research: an LED helmet (Photomedex), intranasal diodes (Vielight), and LED cluster heads placed on the ears (MedX Health). The real and sham devices look identical. Goggles are worn to block out the red light. The  near-infrared light is beyond the visible spectrum and cannot be seen. Credit: Naeser lab
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Can light therapy help the brain?

An innovative therapy that applies red and near-infrared light to the brain is being tested for GWI, traumatic brain injury, and PTSD.

Press Release: Veterans Affairs Research Communications, April 2, 2015. Following up on promising results from pilot work, researchers at the VA Boston Healthcare System are testing the effects of light therapy on brain function in veterans with Gulf War Illness.

Veterans in the study wear a helmet lined with light-emitting diodes that apply red and near-infrared light to the scalp. They also have diodes placed in their nostrils, to deliver photons to the deeper parts of the brain.

The light is painless and generates no heat. A treatment takes about 30 minutes.

The therapy, though still considered "investigational" and not covered by most health insurance plans, is already used by some alternative medicine practitioners to treat wounds and pain. The light from the diodes has been shown to boost the output of nitric oxide near where the LEDs are placed, which improves blood flow in that location.

"We are applying a technology that's been around for a while," says lead investigator Dr. Margaret Naeser, "but it's always been used on the body, for wound healing and to treat muscle aches and pains, and joint problems. We're starting to use it on the brain."

Naeser is a research linguist and speech pathologist for the Boston VA, and a research professor of neurology at Boston University School of Medicine (BUSM). She is also a licensed acupuncturist and has conducted past research on laser acupuncture to treat paralysis in stroke, and pain in carpal tunnel syndrome.

The LED therapy increases blood flow in the brain, as shown on MRI scans. It also appears to have an effect on damaged brain cells, specifically on their mitochondria. These are bean-shaped subunits within the cell that put out energy in the form of a chemical known as ATP. The red and near-infrared light photons penetrate through the skull and into brain cells and spur the mitochondria to produce more ATP. That can mean clearer, sharper thinking, says Naeser.

Naeser says brain damage caused by explosions, or exposure to pesticides or other neurotoxins--such as in the Gulf War--could impair the mitochondria in cells. She believes light therapy can be a valuable adjunct to standard cognitive rehabilitation, which typically involves "exercising" the brain in various ways to take advantage of brain plasticity and forge new neural networks.

"The light-emitting diodes add something beyond what's currently available with cognitive rehabilitation therapy," says Naeser. "That's a very important therapy, but patients can go only so far with it. And in fact, most of the traumatic brain injury and PTSD cases that we've helped so far with LEDs on the head have been through cognitive rehabilitation therapy. These people still showed additional progress after the LED treatments. It's likely a combination of both methods would produce the best results."

The LED approach has its skeptics, but Naeser's group has already published some encouraging results in the peer-reviewed scientific literature.

Last June in the Journal of Neurotrauma, they reported the outcomes of LED therapy in 11 patients with chronic TBI, ranging in age from 26 to 62. Most of the injuries occurred in car accidents or on the athletic field. One was a battlefield injury, from an improvised explosive device (IED).

Neuropsychological testing before the therapy and at several points thereafter showed gains in areas such as executive function, verbal learning, and memory. The study volunteers also reported better sleep and fewer PTSD symptoms.

The study authors concluded that the pilot results warranted a randomized, placebo-controlled trial--the gold standard in medical research.

That's happening now, thanks to VA support. One trial, already underway, aims to enroll 160 Gulf War veterans. Half the veterans will get the real LED therapy for 15 sessions, while the others will get a mock version, using sham lights.

Then the groups will switch, so all the volunteers will end up getting the real therapy, although they won't know at which point they received it. After each veteran's last real or sham treatment, he or she will undergo tests of brain function.

Naeser points out that "because this is a blinded, controlled study, neither the participant nor the assistant applying the LED helmet and the intranasal diodes is aware whether the LEDs are real or sham. So they both wear goggles that block out the red LED light." The near-infrared light is invisible to begin with.

Besides the Gulf War study, other trials of the LED therapy are getting underway:

• Later this year, a trial will launch for veterans age 18 to 55 who have both traumatic brain injury (TBI) and posttraumatic stress disorder--a common combination in recent war veterans. The VA-funded study will be led by Naeser's colleague Dr. Jeffrey Knight, a psychologist with VA's National Center for PTSD and an assistant professor of psychiatry at BUSM.

• Dr. Yelena Bogdanova, a clinical psychologist with VA and assistant professor of psychiatry at BUSM, will lead a VA-funded trial looking at the impact of LED therapy on sleep and cognition in veterans with blast TBI.

• Naeser is collaborating on an Army study testing LED therapy, delivered via the helmets and the nose diodes, for active-duty soldiers with blast TBI. The study, funded by the Army's Advanced Medical Technology Initiative, will also test the feasibility and effectiveness of using only the nasal LED devices--and not the helmets--as an at-home, self-administered treatment. The study leader is Dr. Carole Palumbo, an investigator with VA and the Army Research Institute of Environmental Medicine, and an associate professor of neurology at BUSM.

Naeser hopes the work will validate LED therapy as a viable treatment for veterans and others with brain difficulties. She foresees potential not only for war injuries but for conditions such as depression, stroke, dementia, and even autism.

"There are going to be many applications, I think. We're just in the beginning stages right now."

Journal Reference: Margaret A. Naeser, Ross Zafonte, Maxine H. Krengel, Paula I. Martin, Judith Frazier, Michael R. Hamblin, Jeffrey A. Knight, William P. Meehan, Errol H. Baker.Significant Improvements in Cognitive Performance Post-Transcranial, Red/Near-Infrared Light-Emitting Diode Treatments in Chronic, Mild Traumatic Brain Injury: Open-Protocol Study. Journal of Neurotrauma, 2014; 31 (11): 1008 DOI: 10.1089/neu.2013.3244

The Elephant in the Room: Brain Studies, Politics, and ME/CFS

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.)

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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.”

RESOURCES

List of brain scan research studies: http://www.cfids-cab.org/cfs-inform/Brainscans/brainscans.html

RESEARCH

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

Stanford study finds brain abnormalities in ME/CFS patients

Image courtesy Pixabay

Press Release: Eurekalert, October 29, 2014. An imaging study by Stanford University School of Medicine investigators has found distinct differences between the brains of patients with chronic fatigue syndrome and those of healthy people.

The findings could lead to more definitive diagnoses of the syndrome and may also point to an underlying mechanism in the disease process.

It's not uncommon for CFS patients to face several mischaracterizations of their condition, or even suspicions of hypochondria, before receiving a diagnosis of CFS. The abnormalities identified in the study, to be published Oct. 29 in Radiology, may help to resolve those ambiguities, said lead author Michael Zeineh, MD, PhD, assistant professor of radiology.

"Using a trio of sophisticated imaging methodologies, we found that CFS patients' brains diverge from those of healthy subjects in at least three distinct ways," Zeineh said.

CFS affects between 1 million and 4 million individuals in the United States and millions more worldwide. Coming up with a more precise number of cases is tough because it's difficult to actually diagnose the disease. While all CFS patients share a common symptom — crushing, unremitting fatigue that persists for six months or longer — the additional symptoms can vary from one patient to the next, and they often overlap with those of other conditions.

Scientific Challenge

"CFS is one of the greatest scientific and medical challenges of our time," said the study's senior author, Jose Montoya, MD, professor of infectious diseases and geographic medicine. "Its symptoms often include not only overwhelming fatigue but also joint and muscle pain, incapacitating headaches, food intolerance, sore throat, enlargement of the lymph nodes, gastrointestinal problems, abnormal blood-pressure and heart-rate events, and hypersensitivity to light, noise or other sensations."

The combination of symptoms can devastate a patient's life for 10, 20 or even 30 years, said Montoya, who has been following 200 CFS patients for several years in an effort to identify the syndrome's underlying mechanisms. He hopes to accelerate the development of more-effective treatments than now exist. (A new Stanford Medicine magazine story describes the study in more detail.)

"In addition to potentially providing the CFS-specific diagnostic biomarker we've been desperately seeking for decades, these findings hold the promise of identifying the area or areas of the brain where the disease has hijacked the central nervous system," Montoya said.

"If you don't understand the disease, you're throwing darts blindfolded," said Zeineh. "We asked ourselves whether brain imaging could turn up something concrete that differs between CFS patients' and healthy people's brains. And, interestingly, it did."

The Stanford investigators compared brain images of 15 CFS patients chosen from the group Montoya has been following to those of 14 age- and sex-matched healthy volunteers with no history of fatigue or other conditions causing symptoms similar to those of CFS.

Three Key Findings

The analysis yielded three noteworthy results, the researchers said. First, an MRI showed that overall white-matter content of CFS patients' brains, compared with that of healthy subjects' brains, was reduced. The term "white matter" largely denotes the long, cablelike nerve tracts carrying signals among broadly dispersed concentrations of "gray matter." The latter areas specialize in processing information, and the former in conveying the information from one part of the brain to another.

That finding wasn't entirely unexpected, Zeineh said. CFS is thought to involve chronic inflammation, quite possibly as a protracted immunological response to an as-yet unspecified viral infection. Inflammation, meanwhile, is known to take a particular toll on white matter.

But a second finding was entirely unexpected. Using an advanced imaging technique — diffusion-tensor imaging, which is especially suited to assessing the integrity of white matter — Zeineh and his colleagues identified a consistent abnormality in a particular part of a nerve tract in the right hemisphere of CFS patients' brains. This tract, which connects two parts of the brain called the frontal lobe and temporal lobe, is called the right arcuate fasciculus, and in CFS patients it assumed an abnormal appearance.

Furthermore, there was a fairly strong correlation between the degree of abnormality in a CFS patient's right arcuate fasciculus and the severity of the patient's condition, as assessed by performance on a standard psychometric test used to evaluate fatigue.

Right vs. Left

Although the right arcuate fasciculus's function is still somewhat mysterious, its counterpart in the brain's left hemisphere has been extensively explored. The left arcuate fasciculus connects two critical language areas of the left side of the brain termed Wernicke's and Broca's areas, which are gray-matter structures several centimeters apart. These two structures are important to understanding and generating speech, respectively. Right-handed people almost always have language organized in this fashion exclusively in the left side of the brain, but the precise side (left or right) and location of speech production and comprehension are not so clear-cut in left-handed people. (It's sometimes said that every left-hander's brain is a natural experiment.) So, pooling left- and right-handed people's brain images can be misleading. And, sure enough, the finding of an abnormality in the right arcuate fasciculus, pronounced among right-handers, was murky until the two left-handed patients and four left-handed control subjects' images were exempted from the analysis.

Bolstering these observations was the third finding: a thickening of the gray matter at the two areas of the brain connected by the right arcuate fasciculus in CFS patients, compared with controls. Its correspondence with the observed abnormality in the white matter joining them makes it unlikely that the two were chance findings, Zeineh said.

Although these results were quite robust, he said, they will need to be confirmed. "This study was a start," he said. "It shows us where to look." The Stanford scientists are in the planning stages of a substantially larger study.

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Additional Stanford co-authors are former medical fellow James Kang, MD, now a neuroradiologist in Hawaii; former professor of radiology and chief of neuroradiology Scott Atlas, MD, now a senior fellow at the Stanford-affiliated Hoover Institution; professor of radiology and of psychiatry and behavioral sciences Allan Reiss, MD; lead scientific programmer Mira Raman; physician assistant Jane Norris; and social-science research assistant Ian Valencia.

The study was supported by GE Healthcare and by the CFS Fund, which is housed in the Stanford Department of Medicine's Division of Infectious Diseases. Information about Stanford's Department of Radiology, which also supported this work, is available at http://radiology.stanford.edu/.

Basal Ganglia Implicated in Chronic Fatigue Syndrome

This study by Andrew Miller (see below) builds on previous work by Chaudhuri (Chaudhuri and Behan, 2000, Chaudhuri et al., 2003) and by Unger et al. (2012) linking fatigue to the basal ganglia in patients with ME/CFS.

The basal ganglia are a collection of nuclei found on both sides of the thalamus, outside and above the limbic system. Among other things, the basal ganglia control automatic coordinated activity (such as riding a bike or walking), eye movements, and reward circuits. Damage to this area would not only produce fatigue, but would account for the nystagmus (quick involuntary eye movements) as well as difficulty walking found in so many ME/CFS patients.
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Brain imaging reveals clues about chronic fatigue syndrome

Eurekalert, May 23, 2014

A brain imaging study shows that patients with chronic fatigue syndrome may have reduced responses, compared with healthy controls, in a region of the brain connected with fatigue. The findings suggest that chronic fatigue syndrome is associated with changes in the brain involving brain circuits that regulate motor activity and motivation.

Compared with healthy controls, patients with chronic fatigue syndrome had less activation of the basal ganglia, as measured by fMRI (functional magnetic resonance imaging). This reduction of basal ganglia activity was also linked with the severity of fatigue symptoms.

According to the Centers for Disease Control and Prevention, chronic fatigue syndrome is a debilitating and complex disorder characterized by intense fatigue that is not improved by bed rest and that may be worsened by exercise or mental stress.

The results are scheduled for publication in the journal PLOS One.

"We chose the basal ganglia because they are primary targets of inflammation in the brain," says lead author Andrew Miller, MD. "Results from a number of previous studies suggest that increased inflammation may be a contributing factor to fatigue in CFS patients, and may even be the cause in some patients."

Miller is William P. Timmie professor of psychiatry and behavioral sciences at Emory University School of Medicine. The study was a collaboration among researchers at Emory University School of Medicine, the CDC's Chronic Viral Diseases Branch, and the University of Modena and Reggio Emilia in Italy. The study was funded by the CDC.

The basal ganglia are structures deep within the brain, thought to be responsible for control of movements and responses to rewards as well as cognitive functions. Several neurological disorders involve dysfunction of the basal ganglia, including Parkinson's disease and Huntington's disease, for example.

In previous published studies by Emory researchers, people taking interferon alpha as a treatment for hepatitis C, which can induce severe fatigue, also show reduced activity in the basal ganglia. Interferon alpha is a protein naturally produced by the body, as part of the inflammatory response to viral infection. Inflammation has also been linked to fatigue in other groups such as breast cancer survivors.

"A number of previous studies have suggested that responses to viruses may underlie some cases of CFS," Miller says. "Our data supports the idea that the body's immune response to viruses could be associated with fatigue by affecting the brain through inflammation. We are continuing to study how inflammation affects the basal ganglia and what effects that has on other brain regions and brain function. These future studies could help inform new treatments."

Treatment implications might include the potential utility of medications to alter the body's immune response by blocking inflammation, or providing drugs that enhance basal ganglia function, he says.

The researchers compared 18 patients diagnosed with chronic fatigue syndrome with 41 healthy volunteers. The 18 patients were recruited [not referred] based on an initial telephone survey followed by extensive clinical evaluations. The clinical evaluations, which came in two phases, were completed by hundreds of Georgia residents. People with major depression or who were taking antidepressants were excluded from the imaging study, although those with anxiety disorders were not.

For the brain imaging portion of the study, participants were told they'd win a dollar if they correctly guessed whether a preselected card was red or black. After they made a guess, the color of the card was revealed, and at that point researchers measured blood flow to the basal ganglia.

The key measurement was: how big is the difference in activity between a win or a loss?

Participants' scores on a survey gauging their levels of fatigue were tied to the difference in basal ganglia activity between winning and losing. Those with the most fatigue had the smallest changes, especially in the right caudate and the right globus pallidus, both parts of the basal ganglia.

Ongoing studies at Emory are further investigating the impact of inflammation on the basal ganglia, including studies using anti-inflammatory treatments to reduce fatigue and loss of motivation in patients with depression and other disorders with inflammation including cancer.