Background/Purpose: Chronic pain patients report increased levels of fatigue; however, very little is known about the underlying mechanisms of this symptom. Previous work by our group found that chronic pain patients diagnosed with fibromyalgia (FM) have elevated levels of intrinsic connectivity between the insula and the Default Mode Network (DMN) [1], a network thought to be engaged in self-referential thinking.  Moreover reductions in DMN to insula connectivity were associated with concomitant reductions in clinical pain [2]. In this exploratory analysis, we investigate the relationship between longitudinal changes in fatigue levels and variation in DMN connectivity, while controlling for pain and depression.

Methods: 17 FM patients underwent resting state fMRI at baseline and at 4 weeks following non-pharmacological intervention. Within-subject resting fMRI data analysis was performed using FSL dual-regression Independent Component Analysis as reported previously [1, 2]. Group level multiple linear regression was done with FSL using change in resting DMN connectivity from baseline to post therapy versus change in fatigue scores, correcting for age and pain or depression. Clinical fatigue, pain, and depressive symptoms were assessed with Multidimensional Fatigue Inventory, the Short Form of the McGill pain questionnaire, and the Center for Epidemiologic Studies Depression questionnaires respectively.

Results: Following therapy there was a trend for reduced fatigue levels (difference mean = -1.37; SD = -0.09 ± 2.84; p=0.06). No significant correlation was seen between change in fatigue and pain scores (p=0.92), but a trend towards positive correlation between change in fatigue and depression (p=0.07). FM patients demonstrated significant (p<0.05 corrected) positive correlations between changes in resting DMN connectivity to multiple brain regions and changes in self reported fatigue, even after adjusting for pain and depression.  These regions included the bilateral superior frontal gyrus (pain corrected r=0.79 and depression corrected r=0.80), insula (pain corrected r=0.50 and depression corrected r=0.62), and thalamus (pain corrected r=0.63 and depression corrected r=0.72).

Conclusion: This study suggests that connectivity of multiple brain regions to the DMN is associated with subjective reports of fatigue. While the insula and thalamus are known to be involved in pain processing and modulation, the superior frontal gyrus is more typically involved in cognitive function. We speculate that enhanced connectivity of this structure to the DMN could signify altered cognitive function specifically during periods of elevated fatigue.

Reference:

1. Napadow V, Lacount L, Park K, As-Sanie S, Clauw DJ, Harris RE. Intrinsic brain connectivity in fibromyalgia is associated with chronic pain intensity. Arthritis Rheum 2010; 62(8):2545-2555.
2. Napadow V, Kim J, Clauw DJ, Harris RE. Decreased intrinsic brain connectivity is associated with reduced clinical pain in fibromyalgia. Arthritis Rheum 2012.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/frontal-brain-connectivity-to-the-default-mode-network-is-associated-with-subjective-fatigue-irrespective-of-pain-and-depression/