In this second of three blogs on the work the ‘Dubbo’ group in Australia is doing we look at a controversial and rather difficult topic called interoception. Interoception deals with our awareness of our bodies internal state.
The field of interoception began to take off when it was found that small nerve fibers that feed sensory information from all over the body (on CO2 and oxygen levels, electrolyte salt levels, muscle metabolic by-products, pain, touch, etc.) converge in the dorsal horn of spinal cord.
From there the information loops into a main integration site in the brainstem which automatically maintains our breathing, metabolism, energy uptake and electrolyte balance. From the brainstem it move up into the anterior cingulate, insula and thalamus in the brain which, in turn, reach down and regulate activity in the brainstem. (A lesion in these areas will throw off regulation of breathing, cardiovascular functioning, etc.)
We should note that the interoceptive process is tightly tied to the autonomic nervous system. Those nerve fibers merge with the nerves leading from the vagus nerve to convey information first to autonomic nervous system centers that regulate homeostasis, and then to organs in the brain.
Once those signals get to the higher brain regions the brain is believed to form a picture of the physiological status of the body. If that picture indicates something is off in the bodies homeostasis the brain tweaks the autonomic nervous system and produces the emotions and behaviors needed to bring the body back into balance. The insula is essentially a place where a problem in the body shows up as an alarm in our consciousness. These Australian researchers believe the insula is where the alarm has gone off in ME/CFS.
This study examined whether an infectious event caused people who’d come down chronic fatigue syndrome (post-infective fatigue syndrome) to develop a) an overcharged autonomic nervous system and b) and an increased sensitivity to their body sensations – something they called ‘physiological hypervigilance’. They also examined autonomic nervous system variables during a cognitive test.
They determined the level of interoception present by measuring the participants awareness of their heartbeat and the point at which pressure on their skin induced pain. Heartbeat awareness has been used as an index of interoceptive sensitivity for years. Various measures of symptom, functionality, psychological distress and disability were also taken.
Hight Levels of Interoception Hurt….But Are Not Tied to Mood
They found that the patients who were more aware of their heartbeat and more sensitive to pain tended to be more fatigued, have more mental and physical symptoms and be less functional.
No association between personality traits and interoceptive sensitivity was found. The correlation of psychological distress scores, disability and negative affectivity with increased sensitivity to pain but not to heartbeat discrimination suggested that pain was more of a cause of psychological distress and disability than an increased awareness of body sensations.
Cytokine Imbalance – The Gateway to Interoceptive Issues?
These findings strengthen the evidence of a pivotal role of a balanced cytokine response in dealing with acute infections
Why would people with ME/CFS be more aware of their body sensations? The participants in this study came down with ME/CFS after an infection and these authors proposed that something early in the infection had caused an unending upregulation of what they called the ‘neurovisceral regulatory circuits’.
Several years ago these researchers found that severe symptoms and high levels of cytokines early in the acute stages of infection set the stage for ME/CFS. Severe symptoms early in the infection, in particular, played an extraordinarily strong role in determining who came down with chronic fatigue syndrome afterwards; people with severe symptoms were 200 x’s more likely to come down with ME/CFS than people with less severe symptoms.
The evidence therefore strongly suggests that events occurring early during the acute infection and linked to illness severity and the intensity of the inﬂammatory response are critical to understanding the development of PIFS.
The cytokine levels suggested an unbalanced immune system early in the infection played a key role in who came down with chronic fatigue syndrome. Since they were unable to find evidence of increased cytokine or pathogen levels later in the they suggested that the die is cast, so to speak, very early in the illness- at least for pathogen triggered ME/CFS patients.
Next they looked to see if a genetic basis for an unbalanced immune response was present. They knew that slightly altered forms of genes (called polymorphisms) have been associated with greater susceptibility to or worsened outcomes of several infections including Epstein-Barr virus, tuberculosis, sepsis, malaria, etc. but no one had looked at ME/CFS.
They found that these unsuspecting, soon to be chronically ill patients indeed carried altered forms of two immune genes for IFN-y and IL-10 genes that could set the stage for an unusually strong, unbalanced immune response
Their IFN-y gene suggested that when met with an infection, they would pump out high levels of IFN-y- a pattern that’s associated with more severe cases of tuberculosis and may play a key role in infectious mononucleosis – a common way to get ME/CFS.
Couple that with a tendency to produce less IL-10, a proinflammatory cytokine inhibitor, and you may have set the stage for an overheated immune response to infection that fried some important ‘neurovisceral circuits’. Individuals with these polymorphisms were eight times more likely to come down with ME/CFS than those who didn’t have them.
Cell cultures indicated the cells of these individuals were pouring out the pro-inflammatory cytokines IL-1B, TNF-a, IL-6 as well. Each of these proinflammatory cytokines has been associated with ME/CFS at one time or the other. They have been associated with pain hypersensitivity (IL-1B) and fever and inflammation (TNF-a, IL-6).
Pathway to the Brain
We suspect that in individuals with a prolonged postinfective illness, a prominent cytokine response in the acute phase causes sensitization in these CNS pathways
From the beginning of the Dubbo studies, the lead researcher, Dr. Andrew Lloyd pointed to the brain. In the gene polymorphism paper the Dubbo researchers pointed to the remarkable fact that a single exposure to bacterial (LPS) triggered TNF-a in the brain can send the immune cells in the brain – the microglia – into a tizzy for up to a year.
They’re not alone in thinking that immune activation can tweak with the way the brain views the body. Vaccinations have been associated with activation of the brain regions believed involved in interoception. Indeed, ‘ interoceptionists’ count the symptoms that show up during an infection (‘sickness behavior’) as an interoceptive process.
It is plausible that in vulnerable individuals a severe immunological stressor leads to sensitization in interoceptive pathways which manifests as physiological hyper-vigilance resulting in the symptom complex characteristic of post-infectious fatigue.
An Autonomic Hypervigilance
Since they published this paper this group has documented autonomic dysfunction in their post-infective ME/CFS patients. Autonomic abnormalities have been associated with trouble ‘learning’ in both ME/CFS and FM patients. The Vollmer-Conna/Lloyd group found that the heart rates of healthy controls dropped during a cognitive test, but that the heart rates of post-infective fatigue patients actually continued to increase. This pointed to an autonomic hypervigilance that fit very well, the authors believed, with the pattern of increased interoception in this study.
The authors suggested that these sensitized circuits had lead ME/CFS patients to ‘an internal focus of attention on the(ir) disease state” which could lead to the interpretation of any physiological disturbance as being ‘pathological’. In fact, they suggested that enormous fatigue many people with ME/CFS feel after exertion could derive from this process.
The authors went a long way when they suggested that post-exertional malaise might be due to an internal focus of attention on one’s ‘disease state’. That surprised me given theirs and others findings of autonomic problems. They did note that the autonomic hypervigilance they and others have found in ME/CFS fit with their interoception theory. Indeed, a recent study suggested that the same parasympathetic withdrawal/sympathetic dominance found in ME/CFS/FM is associated with high levels of interoception.
To conclude that post-exertional malaise is simply the result of a heightened awareness of ones internal state, however, is to ignore evidence that something physiologically often goes awry in ME/CFS/FM during exertion. As evidence of muscle and ANS problems accumulates in both ME/CFS and FM a brain focused, top-down interpretation of the increased pain/fatigue found in both is losing some of the traction it’s had. (Look forward to a fascinating blog on this issue in FM coming up :)).
There’s no reason both body and brain problems aren’t both occurring. For me, I’m content to consider the possibility that something heightened my sensitivity to body sensations; I have too many of those to ignore that possibility, and other research suggests that the proposed seat of interoception, the insula, is activated in ME/CFS and FM. I’m also very comfortable with Gupta’s idea that ‘watching my body’, ie attention to my body symptoms is not a good idea.
(The insula is involved in more than body awareness, though. Another study suggested the insula played a key role in the hearts response to stress. Another that it helped produced the same kind of parasympathetic downturn/sympathetic upturn in tinnitus that’s seen in ME/CFS.)
It’s still somewhat incredible to me and my exertionally challenged state, though, how little impact the Pacific Foundations (now Workwell Foundation) exercise studies have had on the prevailing interpretations of this disorder. Yes, exercise is commonly used in research studies, and yes, some studies have validated their finding but Workwell’s central finding that a unique metabolic problem is present a significant number of ME/CFS patients has never assumed a fundamental position in this field.
It’ll be fascinating to see the results of Klimas’ teams study indicating that autonomic nervous system problems kick off an immune cascade that ultimately results in PEM and the Lights continuing research suggesting that sensory data from over-active sensory receptors is slamming the central nervous system. (The Vollmer-Conna/Lloyd group has been unable to validate their findings but more is on the way from them.)
- Nervous System Abnormalities Tied to Cognitive Problems in Chronic Fatigue Syndrome – Part I of the Australian Research Series
- Next up we’ll see the Australian team integrate their autonomic nervous system findings into their brain research to come up with a new model of ME/CFS.
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