The Montoya Effect
Jose Montoya’s enthusiasm and sense of urgency is clearly catching on at Stanford. You don’t often see sentences like the one below in the first part of the latest Stanford study on ME/CFS:
“The high prevalence … in the United States, combined with profound disability and poor prognosis motivates urgent scientific investigation.”
Prevalence figures are often bandied about in the first part of a research paper, but rarely do researchers explicitly refer to the urgency of their investigations.
Then again this was a study of firsts. This is the first time diffusion tensor imaging (DTI) has been used in Chronic Fatigue Syndrome. By tracking the motion of water in the brain, DTI is able to pick up microstructural abnormalities other brain imaging techniques cannot. DTI has been effective in exploring neurodegeneration in a number of disorders, including a recent Gulf War Syndrome study by Baraniuk. Zeineh also used an MRI to look for more obvious structural problems and for arterial spin labeling (ASL) to assess perfusion (blood flow) through the brain.
They used a “validated instrument” (except see the AHRQ report) – the Multidimensional Fatigue Inventory (MFI) – to assess fatigue severity.
This select group of patients had to have severe enough cognitive problems for doctors to feel the need to do MRIs to rule out other diagnoses. The researchers had to plow through three hundred patient charts to find fifteen who met this criteria.
Overall white matter volume was significantly reduced globally ME/CFS patients brains, with a trend towards a specific reduction in the thalamus. Because the white matter, or the wiring in the brain, is particularly susceptible to inflammation, inflammation – perhaps sparked by a viral infection – was likely causing the global white matter reductions found.
The thalamus, interestingly enough, relays sensory and motor signals – two big problems in ME/CFS – to the cerebral cortex. Watanabe’s ME/CFS neuroinflammation study suggesting increased microglial activity was present in the thalamus would appear to fit Zeineh’s results. (Katanabe’s small study found from 45%-200% increases in activity in the cingulate cortex, hippocampus, amygdala, thalamus, midbrain, and pons of ME/CFS patients.) Check out the image to the left to see what appears to be a pretty dramatic reduction in white matter in one person in the study.
The diffusion tensor imaging picked up the major finding of the study – a pattern of increased fractional anisotropy (FA) in the right anterior arcuate fasciculus. FA refers to the degree to which the water in brain tissues flows in a certain direction. Five small sections of the brain connected with the right arcuate fasciculus also displayed increased cortical thickness.
In contrast to some other studies, neither prefrontal cortex nor gray matter volume was reduced.
“Most CFS patients at some point in time have been accused of being hypochondriacs and their symptoms dismissed by others. And there is still skepticism in the medical community about the diagnosis. That’s one of the reasons these findings are important.” – Michael Zeineh
The arcuate fasciculus is part of the white matter “wiring” that connects different parts of the brain – in this case the temporal and frontal lobes. The arcuate fasciculus finding stuck out for several reasons.
The finding was very consistent, showing up in no less than 13 of the 16 ME/CFS subjects and none of the controls. That was a remarkably specific finding given that the abnormality occurred in only 10% of one small slice of the brain. If Zeineh started out surveying the whole brain, as it appears he did, having this one part of the brain jump out again and again in the brains of subjects with ME/CFS was encouraging.
Note that this is an opposite kind of finding compared to the increased numbers of white matter hyperintensities found years ago in the brains of Chronic Fatigue Syndrome patients. Because different patients had these hyperintensities in different parts of their brains, it was hard to tie them to anything specific.
The increased rather than decreased FAs bucked the trend found in neurodegenerative disorders, and Zeineh et al. clearly expected reduced FAs given the cognitive problems in the ME/CFS group. Increased FAs are, however, also found in Alzheimer’s, and Baraniuk’s finding of a trend toward increased FAs in a different “wire” ( the right inferior occipital fasciculus) in the brains of people with GWS perhaps suggested that increased FAs in the fasciculus are the norm in these kinds of disorders.
The fact the most severely fatigued ME/CFS had the highest FA values suggested the right arcuate fasciculus changes were associated with fatigue.
While the left side of the arcuate fasciculus – the part that was not affected in ME/CFS – is clearly associated with speech production, it’s not clear what part the right anterior arcuate fasciculus plays.
[The arcuate fasciculus does, however, mostly terminate in a diffuse manner in the premotor cortex – the part of the brain associated with “motor planning”. That’s intriguing given the recent basal ganglia findings and the slowed motor responses documented in ME/CFS, the data suggesting motor cortex excitability may be reduced in ME/CFS.
Miller’s recent findings of reduced basal ganglia activity in ME/CFS patients followed earlier studies by Chaudhuri and Behans suggesting inflammation or ischemia was present. Given those findings, it was interesting that Zeineh found fatigue scores were significantly correlated (p<.03) with basal ganglia volume in his group. The basal ganglia were the only section of the brain to be associated with fatigue scores in the volumetric part of the study.]
Zeineh’s study contradicted several findings suggesting reduced grey matter volume and perfusion is present in ME/CFS. He chalked up the different study results to his more precise equipment and his better controlling of confounding factors. (Perhaps it’s no big loss: one of the arguments for CBT was its supposed ability to normalize grey matter volumes. If Zeineh wasn’t able to find grey matter volume reductions in this very cognitively challenged group of patients, perhaps they’re not there.)
Using an analysis that the AHRQ panel appears to recommend, the Stanford researchers were able to correctly identify 80% of the ME/CFS patients.
This was a small study – just 15 ME/CFS patients – too small, Montoya acknowledged, to prove anything – but it definitely opened a door, and it demonstrated that when Stanford does something, people listen.
By the end of the day many media outlets across the U.S. and outside including CNN, Bloomberg News, the San Francisco Chronicle, and WebMD had led with the story line “Chronic Fatigue Syndrome is Real”.
A New Beginning?
The background section of the paper highlighted the heterogeneous brain imaging findings found in ME/CFS prior to this study, including grey matter abnormalities in three different parts of the brain, reduced perfusion in the brain in some studies, but no reduced perfusion in another.
That heterogeneity has been disappointing, but Zeineh’s use of diffusion tensor imaging (DTI) brought a more accurate technology to bear.
Zeineh noted that what he found was “not something you could see with conventional imaging.” Having access to some of the best technology is, of course, one of the advantages of getting an “in” at Stanford.
Zeineh suggested, in effect, that researchers were starting the search over with their more precise equipment:
“If you don’t understand the disease, you’re throwing darts blindfolded. We asked ourselves whether brain imaging could turn up something concrete that differs between [chronic fatigue syndrome] patients’ and healthy people’s brains. And, interestingly, it did.”
Pilot Study Takes Flight
“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.
At the Stanford Symposium, Dr. Byron Hyde stood up and said Zeineh’s presentation was the best he had seen on brain imaging on ME/CFS.
This was just a pilot study, but it was a very good pilot study and appears to be making waves in the research world. One radiologist stated:
“It suggests an actual organic basis for the symptoms of chronic fatigue syndrome. And I think it will definitely spark other research.” – Dr. Paolo Nucifora, University of Pennsylvania School of Medicine. “
The brain is becoming an ever more interesting place in ME/CFS. Two small, but successful and very promising brain studies – this one and the Watanabe neuroinflammation study – have prompted larger validation studies. We also await the results of the large and promising Zinn brain study from Stanford.
- See Neuroinflammation: Putting the ‘itis’ back into Myalgic Encephalomyelitis – Back to the Future For Chronic Fatigue Syndrome?
- Check out more on Stanford’s Chronic Fatigue Syndrome program – Comprehensive, Rigorous and Deep” – Is Stanford Going to Solve Chronic Fatigue Syndrome?