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
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Biswala, Bharat, Pratap Kunwarb, Benjamin H. Natelson.
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Caseras X, Mataix-Cols D, Giampietro V, Rimes KA, Brammer M,
Zelaya F, Chalder T, Godfrey EL. “Probing the working memory system in chronic
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