Chronic fatigue is experienced through the brain

An important study just published in PLOS One reveals a primary mechanism by which the fatigue of chronic fatigue syndrome (CFS) is experienced in the brain, and that this is associated with immune inflammatory activation. The authors state:

"Reduced basal ganglia function has been associated with fatigue in neurologic disorders, as well as in patients exposed to chronic immune stimulation. Patients with chronic fatigue syndrome (CFS) have been shown to exhibit symptoms suggestive of decreased basal ganglia function including psychomotor slowing, which in turn was correlated with fatigue. In addition, CFS patients have been found to exhibit increased markers of immune activation."

Moreover...

"The basal ganglia play a fundamental role in the regulation of motor activity and motivation and have been implicated as a major brain system associated with fatigue...In CFS patients, neurocognitive testing has also revealed specific impairments compatible with basal ganglia dysfunction, including motor slowing that correlated with severity of fatigue..."

Regarding immune activation and autoimmune inflammatory phenomena:

"Of note, increased peripheral blood markers of inflammation have been reported in CFS subjects, and chronic fatigue is often the outcome of a number of viral infections. Interestingly, administration of inflammatory stimuli has been shown to alter basal ganglia function in association with fatigue. Indeed, using functional magnetic resonance imaging (fMRI), chronic administration of the anti-viral and inflammatory cytokine interferon alpha was shown to reduce the neural response of the basal ganglia (ventral striatum) to a hedonic reward task, and changes in neural activity were in turn highly correlated with symptoms of fatigue. Similar results have been found after acute administration of endotoxin to healthy volunteers where the basal ganglia response to hedonic reward was found to be reduced. Taken together, these data suggest that inflammatory stimuli including viruses, cytokines and cytokine inducers can cause fatigue through alterations in basal ganglia function."

To investigate decreased basal ganglia function in CFS the authors used functional magnetic resonance imaging to examine neural activation in the basal ganglia to a reward task (monetary gambling) in 59 male and female subjects, 18 of whom were diagnosed with CFS. Their fMRI data for each subject on reward activation in elements of the basal ganglia including the caudate nucleus, putamen, and globus pallidus. There was indeed a strong correlation between fatigue and reduced basal ganglia activation:

"Compared to non-fatigued controls, patients with CFS exhibited significantly decreased activation in the right caudate and right globus pallidus. Decreased activation in the right globus pallidus was significantly correlated with increased mental fatigue, general fatigue and reduced activity as measured by the Multidimensional Fatigue Inventory. No such relationships were found in control subjects. These data suggest that symptoms of fatigue in CFS subjects were associated with reduced responsivity of the basal ganglia, possibly involving the disruption of projections from the globus pallidus to thalamic and cortical networks."

Their comments highlight the need to consider changes in the brain as the basis of chronic fatigue in a variety of disorders:

"CFS subjects exhibited reduced neural activation to a reward task in caudate and globus pallidus, which in turn was correlated with symptoms of fatigue. These data suggest that basal ganglia circuits, especially those involving the globus pallidus, are associated with the expression of fatigue in CFS subjects. In addition, the data suggest that the neurocircuitry of fatigue in CFS patients may share a similar basis in the basal ganglia as is observed in other neurologic disorders and cases of basal ganglia lesions, as well as in the context of immune activation."

These insights are relevant also in clinical investigations of ADHD:

"Small hemispheric asymmetries in morphometric measures of the basal ganglia have been previously reported in healthy subjects, as well as in patients with attention deficit disorder (ADHD), where a dysfunction of a right-sided striatal-prefrontal circuit has been proposed to underlie the attentional deficits."

Of premiere importance in this new age of autoimmunity is the effect of inflammation on the brain in chronic fatigue:

"One mechanism that may contribute to alterations in function and neurotransmission in the basal ganglia in CFS is inflammation. CFS patients have been shown to exhibit a number of immune alterations including the presence of increased inflammatory markers in the peripheral blood and increased production of inflammatory cytokines in ex vivo preparations of peripheral blood mononuclear cells. As noted above, a number of inflammatory stimuli including the inflammatory cytokine, interferon alpha and cytokine inducers such as endotoxin and typhoid vaccination have been shown to alter basal ganglia function while also leading to symptoms of fatigue including psychomotor slowing and reduced motivation, both fundamental behavioral processes regulated by basal ganglia structures. Recent work in humans and non-human primates suggests that some of the effects of inflammatory stimuli, in particular interferon alpha, are mediated by effects on basal ganglia dopamine."

As clinicians expert in case management of autoimmunity know well, viral and other infections can trigger autoimmune expression:

"Of note, interferon alpha is a cytokine well known to be released during viral infections, and increased levels of central nervous system interferon alpha have been associated with behavioral deficits in animal models of human immunodeficiency virus (HIV) and HIV patients. Thus, the activation of inflammatory pathways by viruses or other pathogens – as well as in a variety of conditions known to be associated with increased inflammation, including obesity and psychosocial stress – may represent one mechanism of altered basal ganglia function leading to symptoms of fatigue in patients with CFS."

The authors summarize their findings by concluding:

"CFS subjects free of psychotropic medications and without significant psychiatric disease were found to exhibit reduced activation of basal ganglia structures that correlated with symptoms of fatigue. The findings are consistent with diseases known to affect the basal ganglia and are consistent with basal ganglia changes seen after administration of a variety of stimuli that induce an inflammatory response."

Clinical bottom line: Practitioners engaged in case management of chronic fatigue should carefully consider assessment of brain function and neuroinflammation, including anti-brain antibodies, in their analysis of underlying causes.