Dr. Barnden of the National Centre for NeuroImmnology and Emerging Diseases (NCNED) in Griffith University, Australia has been doing some fascinating brain imaging work in chronic fatigue syndrome (ME/CFS). Over the past six years Barnden has been publishing results from a multifaceted brain imaging study, which analyzed magnetic resonance imaging results in two ways.

ME/CFS produces a plethora of possible central nervous system (fatigue, pain, movement, gait, stimulus problems, etc.) and autonomic nervous system symptoms (fatigue, pain, sleep, gut issues, cognition. Barnden’s unique contribution has been to tie both together by identifying parts of the brain that may be causing the autonomic nervous system problems.

2011 Study

A brain MRI study of chronic fatigue syndrome:evidence of brainstem dysfunction and altered homeostasis Leighton R. Barndena,b*, Benjamin Croucha, Richard Kwiatekc, Richard Burnetd, Anacleto Mernonea, Steve Chryssidise, Garry Scroopf and Peter Del Fanteg. NMR in Biomedicine, 11 May 2011: DOI: 10.1002/nbm.1692

The Gist

  • Increased gray matter loss associated with fatigue duration suggested that gray matter loss may be proceeding more rapidly in ME/CFS over time. (As we age we all lose gray matter.)
  • Reduced white matter levels in the midbrain suggested it may be involved in the autonomic nervous system problems found in ME/CFS
  • Other clusters in the hypothalamus and brainstem suggested that the central autonomic network has been damaged in ME/CFS
  • The damage appears to occur in the signaling pathways that connect the network
  • The low stressors employed in the study (sitting up) suggest Barnden has identified core issues in ME/CFS.
  • The NIH Intramural study should be able to greatly expand on Barnden’s findings

Barnden put 50 ME/CFS patients and healthy controls into an MRI and had them wear a monitor of blood pressure and heart rate for two days. Then he determined if the blood pressure and heart rate abnormalities he found were associated with changes in functioning of the brainstem area.

All the ANS measurements were done while the patients were lying flat or sitting up – as close to resting as possible. Plus none of the ME/CFS patients met the criteria for postural orthostatic tachycardia syndrome (POTS) – so they didn’t exhibit the major autonomic nervous system problems that those patients have.

The lack of stressors made this study all the more interesting. Many studies use physical stressors to push patients’ systems into an altered state where it’s easier to find abnormalities, but these studies purposefully removed these stressors and individuals (POTS patients) who were likely to exhibit autonomic nervous system issues.

white matter brain me/cfs

Barnden found that white matter loss in the midbrain may be affecting the autonomic nervous system

No differences in the total brain volume of the grey or white matter in ME/CFS were found but greater drops in grey matter over time in the ME/CFS group suggested they might be aging more rapidly. (We all lose brain matter as we age).

Changes in total brain volume were not, however, associated with the severity of fatigue or other symptoms. A regression analysis, did find a significant reduction in white matter volume in the midbrain that was associated with fatigue duration. The longer a chronic fatigue syndrome (ME/CFS) patient had been fatigued, the worse their midbrain white matter loss was.

Low activity levels could cause this, but if so one would expect to see fatigue severity affecting the findings because increasing fatigue severity should result in reduced activity and therefore, according to the inactivity hypothesis, reduce brain volume. Fatigue severity did not, however,  affect brain white matter volume.

The midbrain, not surprisingly given its location in the middle of the brain, sits in the midst of a vast communications network that is constantly zinging signals from one part of the brain to another. We know now that even simple actions require different parts of the brain working together.  Midbrain damage, for instance, can affect the functioning of the “central autonomic network” made up of the hypothalamus, brainstem and other areas.

RAS brain

Reductions in reticular activation system white matter were associated with ANS abnormalities

The study suggested that altered blood pressure-pulse readings were, in fact, associated with a cluster in a part of the mid-brain that regulates the reticular activation system (RAS). The RAS regulates cerebral cortex activity and is a conduit through which autonomic nervous system signals from the brain to the body pass. That suggests that the white matter loss Barnden found could be contributing to autonomic nervous system problems and/or  – because the RAS regulates cerebral cortex excitation – could impair motor and cognitive activities: i.e. movement and thinking.

The white matter of the brain is made of blood vessels, fluid, and glial cells and nerve axons – everything but the actual nerve bodies.  Further analyses suggested reduced numbers of glial cells were the most likely cause of the white matter loss found.Since glial cells when functioning properly are protective, a reduction could impair the brain’s ability to fight off pathogens.

2015 Study

Autonomic correlations with MRI are abnormal in the brainstem vasomotor centre in Chronic Fatigue Syndrome Leighton R. Barndena,b,⁎, Richard Kwiatekc, Benjamin Croucha, Richard Burnet d, Peter Del Fantee. NeuroImage: Clinical 11 (2016) 530–537

Barnden expanded on the brain’s connection to the autonomic nervous system problems he found in ME/CFS in his 2012 study. In this study he again compared the MRIs of the two groups and then did regression analyses using the MRI findings and the autonomic nervous system readings.

Apparently because Barnden assessed parts of the brain that regulate “steady state” blood pressure, he did not include stressors such as standing, walking or exercising which other studies have used to pop the brain or the ANS into a dysregulated state

Even at rest, heart rates were increased and pulse pressure was reduced in the ME/CFS patients. Anxiety and depression were negatively correlated with pulse pressure when patients were standing; otherwise no correlations were found.

Barnden assessed anxiety and depression because of concerns that they could affect blood pressure and heart rate. (In the original study he found evidence of mild anxiety and depression.) Adjusting for anxiety and depression did affect which clusters in the brain showed up in the study but did not affect the number of clusters that showed up.

One of the potentially malfunctioning clusters in the brainstem that popped out in the ME/CFS patients is designed to inhibit heart rate. Other clusters in the midbrain and hypothalamus that increase heart rate could be contributing to the increased heart rates found during sleep. Another cluster associated with the default mode network may also be affecting sleep. Several others found in the prefrontal areas regulate blood pressure and heart rate responses to stress.

vasomotor center

The vasomotor center deep in the brainstem was similarly affected

The vasomotor center of the brainstem was particularly affected. Sitting in the center of autonomic nervous system activity, the vasomotor center communicates with sensors that regulate steady state blood pressure and heart rate. The hypothalamus and areas in the midbrain, in turn, regulate the vasomotor center. The fact that each of these areas of the brain have popped up in Barnden’s studies suggests that much of the central autonomic nervous system network in the brain may be affected in chronic fatigue syndrome (ME/CFS).

When the Barnden group simply compared the MRIs of the patients and the healthy controls without assessing autonomic nervous system functioning, however, they found no significant differences at all. This suggested that signaling between these autonomic nervous system nuclei is the problem, not the autonomic nervous system nuclei themselves. Something appears to be interfering with the proper flow of autonomic signals between these different parts of the brain.

This finding is not out of sorts with other findings in the past. While alterations in brain volume have been found in ME/CFS, signaling and connectivity issues may be more of a problem.

Barnden’s 2011 and 2016 study results were thankfully consistent with each other. Both implicate the midbrain and/or the brainstem in the autonomic nervous system problems in ME/CFS.

Barnden’s studies have been notable for their lack of stressors used. Exercise or other stressors are often used to enhance findings in ME/CFS. The fact that none were needed to flush out Barnden’s findings was significant. Barnden’s ability to connect brain issues with autonomic nervous system problems that emerged when ME/CFS patients were doing nothing more than sitting up suggested the study identified core problems in ME/CFS.

All this came using limited autonomic nervous system readings (pulse pressure and heart rate). One wonders what would have emerged if Barnden had been able to do more extensive autonomic nervous testing.

Hopefully an expanded study is underway in Australia. At the very least it appears to be underway in the U.S. in the NIH’s larger (80 person) intramural study which Nath reported will be employing top autonomic nervous system experts and doing multiple brain imaging tests. Since Barnden was able to get results with his autonomic nervous system testing regimen, hopefully the NIH with its more refined testing procedures and larger study size will be able to find much more.

The NIH Intramural study, like everything else it seems at the NIH, is going slowly. Nath reported in the Feb. 1 telebriefing that six healthy controls have gone through the study thus far – two of which they had to kick out after brain imaging abnormalities showed up. ME/CFS patients, thankfully, are apparently not in short supply. Nath reported that they’ve screened many of them and they’ll start, one at a time, going through the week-long study in March. It’s going to take more time than we wish but it’s a powerful study and could tell us much.



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