The GIST is at the bottom right

Small research teams can make a big difference. One wonders where we would be without Leighton Barnden and the National Centre for Neuroimmunology and Emerging Diseases (NCNED) team at Griffith University. The fact that the brainstem has become a major area of interest is largely due to Barnden and the NCNED team.

Barnden has been attracted to the “subcortical” parts of the brain (below the cerebral cortex) which affect basic things like movement, sensory signal processing, alertness, sleep, emotions, breathing, blood pressure, the heart rate, etc. Get these things wrong and you have the potential for widespread problems.

While some structural problems (reduced white matter, brainstem volume) have been found, the evidence thus far suggests that altered connections between the different brain regions are the central issue in ME/CFS and fibromyalgia. Something is off in the information highways that make the brain function smoothly. It’s as if you plugged Los Angeles in, and Google Maps kept directing you to San Diego.

Altered connections are the least-worst-case scenario regarding the brain, as repairing structural problems in the brain is very difficult, while altering the connectivity between regions of the brain can, at times, be done.

The strange connections DeLange in 2003 found suggested that the parts of the brain involved in “motor planning” or movement weren’t connecting properly. Miller found something similar when he probed the connections to the basal ganglia. With eleven studies popping up, by far the most impacted area, though, appears to be connections with the default mode and intrinsic networks.

The Study

The Australian researchers used an ultra-high field 7 Tesla MRI to assess the connections (blood oxygen levels) between 27 areas of interest in these regions of the brain as 31 ME/CFS and 15 healthy controls engaged in the Stroop cognitive task, in the “Subcortical and default mode network connectivity is impaired in myalgic encephalomyelitis/chronic fatigue syndrome” study.

With the brainstem and the cerebellum being particularly involved in cognitive impairment, motor dysfunction, and the sleep-wake cycle, the authors probed the connectivity (activity) between: (a) the salience network (SA) and default mode network (DMN); and (b) the cerebellar vermis and brainstem regions.

The Two Regions

The Default Mode Network (DMN) – Because the DMN allows thoughts to bubble up, it can promote creativity. On the other hand, because it excels at introspection, it does not allow you to be present in the here and now. When you think about your past or the future, wonder how you are doing, what’s happening to you, etc., (notice the reference to yourself), the default mode network (DMN) is in play.

Since the DMN is self-referential, if you want to get something done, you need to turn it off, and that’s what the salience network does. When it’s time to buckle down and carry out a task, the salience network turns off the default mode network, stops the distractions, and effectively engages us in the task at hand.

The cerebellar vermis – The cerebellar vermis regulates the autonomic nervous system (heart rate, breathing, arousal) via the brainstem. It is also involved in coordination, gait, and movement, and connects with the emotionally charged limbic system.

Results

Movement problems – Reduced connectivity (read activity) between a part of the cerebellum and the brainstem suggests that the signals that help one move easily, track things with our eyes, stand correctly, and engage in skilled movements are not getting through as they should.

Frontal Brain Problems – Stronger connectivity between the pontine nuclei and clusters of cortical voxels in the frontal pole and superior frontal gyrus suggests that frontal regions of the brain have been damaged.

This is not new. Other ME/CFS and FM studies have found that the frontal cortex (particularly the dorsolateral prefrontal cortex (DLPFC) and anterior cingulate cortex (ACC)) have been impacted. These parts of the brains keep us on task, prevent distractions, integrate sensory signals, regulate movement, and keep the emotionally charged limbic system under control.

This finding suggests that in ME/CFS, the brain has attempted to compensate for the frontal cortex failure by asking the pontine nuclei—a relay center that transmits information between the frontal regions of the brain and the cerebellum—to boost the signal to help people with ME/CFS complete tasks. The authors proposed that a kind of “hyper-stimulation” (hyper-effort?) had occurred.

Problems with Alertness, Sleep, and More – More fun showed up when reduced connectivity to several areas of the cerebellum suggested that the reticular activation system (the RAS), which keeps us alert, regulates sleep-wake cycles and controls attention and the autonomic nervous system—all obvious problem areas in ME/CFS—had been inhibited.

DMN Problems Affect Basic Baseline Functioning – The authors noted that the DMN’s connections across the brain make it “one of the primary intrinsic networks of the brain essentially responsible for the brain’s baseline functions.”

As noted earlier, the default mode network (DMN) has shown up again and again in functional connectivity studies in ME/CFS. Instead of being inhibited, though, the DMN showed stronger connectivity (activity) in the ME/CFS patients than in the healthy controls.

Overactivity of the DMN can have some real consequences: mind wandering makes it more difficult to engage in tasks (again), increased focus on one’s self can lead to cycles of rumination, increased recall of past events and more difficulty disengaging from negative thoughts has obvious consequences and—given a potential connection with the amygdala in ME/CFS—increased emotional responses to those negative thoughts may be present. Oh yes, high DMN activity is also a recipe for brain or fibro fog.

One can see that the way the DMN functions to allow thoughts to bubble up – which can be a creative process – could turn harmful in anyone who’s experienced traumatic events, such as in ME/CFS, fibromyalgia or long COVID when the thoughts that bubble up are going to be mostly negative.

Increased Pain – Positive correlations between several parts of the salience network (anterior cingulate cortex (ACC), insula and vermis VIIIb, and left supramarginal gyrus (SMG) and vermis VIIIb) provided a potential reason for the increased “self-focus” found—increased detection of stimuli and levels of pain—forcing one’s attention onto those. Both the insula and anterior cingulate have been associated with fatigue and pain in ME/CFS and fibromyalgia.

While not everyone with ME/CFS is in pain, many are – and everyone with fibromyalgia is. If ME/CFS/FM is, as Dr. Clauw has proposed, at least in part a “sensory disease,” one can see all these issues – the difficulty being on task, the possibly increased rumination, the negative thoughts – might naturally emanate from the difficulty of trying clawing through a maze of sensory stimuli. With the body’s alert systems on full blast, a degree of “self-focus” is probably an appropriate, if not helpful in the long run, response.

Rumination has not been assessed much in ME/CFS or fibromyalgia, but the inability to do gainful work (or sometimes almost any work), the hit to finances, the loss of friends, the inability to do the thing that used to bring joy – all provide ample room for rumination.

Implications for Energy Production

The default mode network’s increased connections with the amygdala and hypothalamus in ME/CFS suggest a state of chronic stress has dysregulated both of the stress responses: the hypothalamic-pituitary-adrenal (HPA) axis and autonomic nervous system activity. The energy-intensive nature of an autonomic nervous system in “fight/flight” mode puts extra strain put on one’s energy resources and the mitochondria – potentially leading to the state of immune cell exhaustion we’ve seen in these diseases.

Getting stuck in “DMN mode” (wandering thoughts, self-focused thoughts, negative thoughts) has major implications for energy. Trying to do a task while one’s mind wanders uses more energy. If it’s a physical task (remember the motor planning issue), moving smoothly and efficiently becomes impossible; with a mental task, one has to keep jerking oneself back to the task—a costly and PEM-inducing enterprise as the brain has to keep shifting resources back and forth.

We recently saw evidence of increased oxygen and glucose consumption in the brains of ME/CFS patients, and two large studies are underway to assess this.

Negative emotions are also associated with increased levels of pro-inflammatory cytokines (e.g., IL-6, TNF-α, CRP), which can potentially slow the immune response, throw the gut microbiome off, accelerate cellular aging, and impact the cardiovascular system and metabolism.

Dopamine Connection 

Because dopamine suppresses the DMN, the low dopamine levels that may be present in these diseases may play a role in DMN activation seen. One hypothesis proposes that low dopamine levels play a crucial role in fatiguing neurological diseases such as multiple sclerosis, ME/CFS, and traumatic brain injury.

Dopamine provides the motivation and, therefore, the energy needed to engage in and carry out tasks. Since dopamine is the “reward” neurotransmitter, the “low rewards” associated with tasks in people with low dopamine levels could make it difficult to break out of a DMN chokehold. By assessing our energy state, it helps us choose what tasks to carry out. Low dopamine levels result in tasks being associated with low rewards which translates into difficulty carrying out tasks.

Stimulants like modafinil, Adderal, and Ritalin can be tricky to use, but they can increase dopamine levels and have been used successfully in some people with ME/CFS/FM.

Treatment Suggestions

Treatment is not mentioned in the paper. Unfortunately, there don’t appear to be any easy answers to the increased default mode network activity present in ME/CFS. Neurostimulation (transcranial direct current stimulation, transcranial magnetic stimulation), stimulants, mitochondrial support might help, but all the other recommendations I found involved mind/body techniques.

Neuroplasticity practices, including mindfulness and meditation practices, challenging negative thoughts and replacing them, purposely bringing focused attention to bear (one person found focusing on the minutiae around her helped), repeatedly returning oneself to the present moment, loving-kindness meditations, breathing techniques to rebalance the autonomic nervous system (4-7-8 Breathing: Inhale for 4 seconds, hold for 7, and exhale for 8; Box Breathing (4-4-4-4): Inhale, hold, exhale, and pause—each for 4 seconds. Alternate Nostril Breathing), relaxation exercises, brain training apps, good sleep practices, and gratitude journaling (increases dopamine production), were suggested.

Conclusion

Difficulties with movement, cognitive and physical exhaustion, mind wandering, difficulty keeping focus and completing tasks, negative thoughts, and increased pain levels – they are nothing new. It’s good to see these issues show up in brain imaging studies. It may be possible for some people with these diseases to turn the DMN down a bit and get some relief.

 

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