“The Insulted Mid-Brain” – A Look Back at a Seminal Study

Recently Dr. Lucinda Bateman proposed that neuroinflammation in the middle part of the brain could explain many, if not all, of the symptoms found in Chronic Fatigue Syndrome. With that intriguing hypothesis in mind we take a look back at a fascinating MRI study by Dr. Leighton Barnden of the Department of Nuclear Medicine, The Queen Elizabeth Hospital, Adelaide, that came to a similar conclusion two years ago.

NMR Biomed. 2011 Dec;24(10):1302-12. doi: 10.1002/nbm.1692. Epub 2011 May 11.A brain MRI study of chronic fatigue syndrome: evidence of brainstem dysfunction and altered homeostasis.Barnden LR1, Crouch BKwiatek RBurnet RMernone AChryssidis SScroop GDel Fante P.
building foundation

Is the brain puzzle coming together?

This study examined MRI findings, symptom, depression, and anxiety scores and autonomic nervous system functioning via 24 hour blood pressure monitoring in 25 people with ME/CFS and 25 healthy controls.

Worries about the heterogeneous presentation in ME/CFS led Dr. Leighton Barnden to discard the normal ways of doing MRI studies. Barnden did do a straight MRI comparison of the brains of Chronic Fatigue Syndrome (ME/CFS) patients and healthy controls, but he also compared patterns of MRI results, autonomic functioning, and symptoms within each population. For example, if abnormal autonomic nervous system results in the ME/CFS group correlated with the abnormalities he found in his brain scans, Barnden would be able to zero in on areas of the brain that were of significance in ME/CFS.


Losses in Midbrain White Matter Associated with Worsened Symptoms

“These results are consistent with an insult to the midbrain at fatigue onset that affects multiple feedback control loops to suppress cerebral motor and cognitive activity and disrupt local CNS homeostasis, including resetting of some elements of the autonomic nervous system (ANS).”


Reduced white matter in the midbrain suggested demyelination was interrupting signals to the other parts of the brain

As Barnden expected, a straight comparison of MRI results revealed no significant differences between the two groups. When he performed a regression analysis of his MRI readings against the patient’s symptoms, however, issues in the midbrain popped out in the ME/CFS group. His analysis indicated that reduced white matter volume in the midbrain was highly associated with fatigue; i.e., the more fatigued a person was, the more likely they were to have reduced levels of white matter in their midbrains.  That suggested damage to myelinated cover of the nerves had occurred.

(It’s interesting, given the myelination problems in multiple sclerosis, that a small study recently found reductions in BDNF in both MS and Chronic Fatigue Syndrome.  Check out Knackered Nerves: Do Low BDNF Levels Spell Nerve Exhaustion in Chronic Fatigue Syndrome?)

Has communication broken down between different parts of the brain?

Has communication broken down between different parts of the brain?

The midbrain or mesencephalon is a portion of the brainstem associated with arousal (alertness), motor control, sleep/wake state, vision, hearing, and temperature regulation. It is located below the cerebral cortex and above the thalamus/hypothalamus – quite centrally located. The substantia nigra in the midbrain is closely associated with basal ganglia – an area of interest in ME/CFS. (A blog will appear shortly on basal ganglia dysfunction in Chronic Fatigue Syndrome. Miller’s findings suggest that reduced dopamine functioning in the substantia nigra leads to basal ganglia dysfunction in some people with ME/CFS.)

Calling the midbrain a conduit for information passing from the spine to the upper brain, the authors noted that it contains parts of the reticular activation system and centers of monoaminergic and cholinergic neurotransmission.

Grey and White Matter

Both grey and white matter were reduced in different parts of the brain in the people with ME/CFS.

spinal nerve

Grey and white matter in a spinal nerve.

Grey matter consists of neuronal cell bodies, glial cells, and capillaries. White matter is largely composed of the myelinated axons or limbs that stretch out from neuronal cell bodies and communicate the nervous system signals to the rest of the body. It’s composed of glial cells as well.  It’s the myelinated aspect of nerve axons that makes them whitish in color.

Think of grey matter as largely being the neuronal cell bodies and white matter as being their limbs. The nervous system signal is produced in the grey matter, and the white matter communicates the signal between different parts of the brain and the spinal nerves. Grey matter issues imply problems with nervous system signal processing and cognition (or a problem with the capillaries or the glial cells) while white matter problems imply problems communicating the signal and coordinating activity between parts of the brain.

Autonomic Nervous System Problems Associated with Losses in the Brainstem, Prefrontal Cortex and Hypothalamus   

Next Barnden regressed his fMRI findings against ‘hemodynamic scores’ produced by analyzing blood pressure and heart rate over a 24 hour period to determine if parts of the brain were associated with altered autonomic nervous system functioning.  ANS functioning was assessed while seated, while asleep, and all other times.

Barnden found alterations in 24-hour blood pressure and heart rates in ME/CFS patients compared with controls.  Those alterations were associated with reductions in grey matter in the brainstem as well as white matter in the prefrontal cortex and hypothalamus. It appeared that problems in these areas of the brain were causing autonomic nervous system problems in ME/CFS.

Activating System in the Brain was Hit

With the strongest correlations showing up in the reticular activativation system (RAS) the authors drew special attention to it. The RAS is responsible for maintaining cerebral cortex activation. It also transfers messages between the central and peripheral autonomic nervous system neurons.

tired woman

The reticular activating system may not be activating much in ME/CFS

With the reticular activating system presumably not activating the cerebral cortex properly or relaying all the autonomic nervous system messages from the brain to the body, the stage  appeared to be set perhaps for the ‘slowed brain’ that the Zinns spoke of at the Stanford Symposium as well as the autonomic  issues present in ME/CFS.

Highly significant reductions in brainstem white matter over time also suggested that the longer a person had been ill with ME/CFS the more declines in brainstem white matter occurred.

Brain Blood Flow Problems

Brainstem grey matter reductions, on the other hand, were associated with altered pulse pressure in the ME/CFS patients. The authors proposed this correlation suggested problems with cerebrovascular autoregulation (i.e., regulating blood vessel flows in the brain) were present in ME/CFS.

Specifically they noted their findings suggested that problems controlling capillary hydrostatic pressure in the brain were present. Cerebrovascular autoregulation is primarily a function of the arterioles that control the rate of blood flow into the capillaries. Arteriole activity is regulated both locally (myogenic reflex) and centrally via the brainstem as well as via astrocytes.

The authors suggested problems with astrocytes – a form of glial cell – in the brainstem were probably responsible for the problems with brain blood vessel flows.

Glial Cells Take Center Stage

Their findings suggested, then, that problems with glial cells – in particular astrocytes – either localized in the brain stem or possibly widespread throughout the brain were causing both the white matter shrinkage and the autonomic nervous system problems found.


An astrocyte – the kind of glial cell the authors think may be playing a role in ME/CFS

Glial cells provide both scaffolding and protection for the neurons. Through the production of a wide array of pro-inflammatory factors, glial cells also direct much of the immune response in the brain. Over-active glial cells are believed to be major drivers of central sensitization. Glial cell activation may be behind the widespread neuroinflammation found in the Japanese ME/CFS study.

Prefrontal Cortex

One of the odder findings concerned increased heart rates when asleep. This finding, which has been validated in several studies, appears to reflect increased sympathetic nervous system activation in ME/CFS. The study found that increased heart rates when asleep were associated with reduced prefrontal cortex volumes in ME/CFS patients and increased prefrontal cortex volumes in healthy controls. The authors noted that the prefrontal cortex communicates with various regions of the brain (anterior cingulate, dorsolateral cortex) involved in the autonomic nervous system, and then pinpointed perhaps the locus of ANS problems in ME/CFS – the hypothalamus.


The hypothalamus, which sits right below the midbrain, has long been suspected as the cause of the HPA axis issues in ME/CFS, but the hypothalamus also plays a key role in autonomic nervous system regulation. White matter volume alterations in the hypothalamus were associated with sleep heart rate differences in ME/CFS. Those alterations suggested the messages from the hypothalamus to the rest of the brain and the body were perhaps not getting  through.

Lying at the center of all the brain structures involved in autonomic regulation, the hypothalamus also communicates with autonomic nerves in the body via the reticular activating formation in the brainstem – the very locus of the midbrain problems the authors found.  The hypothalamus also modulates and is modulated by the immune system.  As with the midbrain, the authors believe glial cell issues are behind the white matter changes detected in the hypothalamus.

The authors stated that a second study looking more deeply into the autonomic nervous system and the brain was forthcoming, but it’s now several years later and no studies have been published.


“These findings therefore support our original hypothesis of involvement of the midbrain, prefrontal WM and/or supraspinal autonomic control regions in CFS, and indicate that CFS is associated with biological changes affecting fundamental and evolutionarily primitive structures of the CNS.”

Suggesting these findings provide a ‘unifying’ observation, the authors proposed that demyelination in the midbrain that impairs communication and coordination with the rest of brain may explain many of the symptoms found in Chronic Fatigue Syndrome, including those associated with the autonomic nervous system dysfunction.

Is white matter damage in the primitive areas of the brain causing ME/CFS?  More studies are needed...

Is white matter damage in the primitive areas of the brain causing many symptoms in ME/CFS? More studies are needed…

They also found evidence that grey matter issues in the brainstem were associated with impaired blood flow regulation in the brain. The hypothalamus and reticular activating system received special mention.

Glial cell problems – already of great interest in ME/CFS – were front and center, with the authors proposing glial cells were behind both the white matter and grey matter problems found. The authors noted that glial cell problems may be more widespread in the brain.

It will be intriguing to see if these findings correlate with the Zinns’ findings of a ‘slowed brain’  and their proposal that a limbic encephalitis is present in ME/CFS.  The Zinns highlighted problems in similar parts of the brain: the brainstem, the limbic  system, and the prefrontal cortex. Their suggestion that a pattern of ‘global hypoactivation’ could fit with the Barnden findings of damage to the reticular activating  system.

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