The Neurobiology of Pathological Fatigue: New Models, New Questions

Abstract

The last decade has seen the emergence of new theoretical frameworks to explain pathological fatigue, a much neglected, yet highly significant symptom across a wide range of diseases. While the new models of fatigue provide new hypotheses to test, they also raise a number of questions. The primary purpose of this essay is to examine the predictions of three recently proposed models of fatigue, the overlap and differences between them, and the evidence from diseases that may lend support to the models of fatigue. I also present expansions for the sensory attenuation model of fatigue. Further questions examined here are the following: What are the neural substrates of fatigue? How can sensory attenuation, which underpins agency also explain fatigue? Are fatigue and agency related?

Fatigue in perinatal stroke is associated with resting-state functional connectivity

“…Although the proprioceptive and interoceptive predictive processing accounts of fatigue are often contrasted 14,15 , it is more likely that fatigue can arise from ongoing and unreconcilable proprioceptive and interoceptive prediction errors, which both signal challenges to allostatic control 17 . Since fatigue is believed to be the affective response signalling ongoing unresolvable prediction errors and thus failure to exert allostatic control, these results support the predictive processing accounts of fatigue 14,15 . At present, there is considerable uncertainty about how predictive processing networks function and much more evidence of the strength and direction of relationships is required before this suggestion can be genuinely considered.…”

“…In a preliminary analysis of this data 35 , we performed both ROI-to-ROI and seed to voxel analysis in eight predetermined ROI's within the sensorimotor network. However, based on feedback to this preprinted analysis, and subsequent experimental and theoretical advances in the study of fatigue 15,21,22 , we decided to adopt a data-driven analysis plan to reduce possible bias in seed selection. Individuals with perinatal stroke often have widespread morphological and functional differences in brain structure and development ( 46 for a review).…”

“…The interoceptive predictive processing account identi es several regions in the brain that may compose a 'fatigue network,' including the anterior insula, the anterior cingulate cortex and frontal/prefrontal areas 12 . The exteroceptive and proprioceptive predictive coding account of fatigue predicts that in addition to the insula, networks comprised of sensorimotor, visual, and attentional hubs also contribute to fatigue 15 . There is emerging evidence from resting-state functional magnetic resonance imaging studies that connectivity between these areas is associated with fatigue perception [20][21][22] .…”

“…This ongoing discrepancy between predicted and actual body state is consciously perceived as the feeling of fatigue, which acts as a signal for allostatic behavioral adjustment: rest. Two predictive coding accounts of fatigue have been proposed; the rst suggests that fatigue arises from a failure to attenuate from proprioceptive or exteroceptive sensory prediction errors, speci cally during motor actions 15 . An opposing account posits that fatigue arises through the metacognitive awareness of an ongoing discrepancy between predicted and actual interoceptive information, processed in an interoceptive predictive processing network 12 .…”

“…An opposing account posits that fatigue arises through the metacognitive awareness of an ongoing discrepancy between predicted and actual interoceptive information, processed in an interoceptive predictive processing network 12 . These two accounts are often presented as disparate, assigning fatigue to either interoceptive or exteroceptive and proprioceptive predictive processing (see Kuppuswamy 2021;Manjaly et al 2019 for reviews). However, these systems likely interact to predict proprioceptive and interoceptive signals in the pursuit of goal-states 16 and thus are both likely to contribute to the perception of fatigue 17 .…”