Predicting Modafinil-Treatment Response in Poststroke Fatigue Using Brain Morphometry and Functional Connectivity

Stroke. 2019 Mar;50(3):602-609. doi: 10.1161/STROKEAHA.118.023813.


Background and Purpose- Poststroke fatigue affects a large proportion of stroke survivors and is associated with a poor quality of life. In a recent trial, modafinil was shown to be an effective agent in reducing poststroke fatigue; however, not all patients reported a significant decrease in fatigue with therapy. We sought to investigate clinical and radiological predictors of fatigue reduction with modafinil therapy in a stroke survivor cohort. Methods- Twenty-six participants with severe fatigue (multidimensional fatigue inventory-20 ≥60) underwent magnetic resonance imaging at baseline and during the last week of a 6-week treatment period of 200 mg modafinil taken daily. Resting-state functional magnetic resonance imaging and high-resolution structural imaging data were obtained, and functional connectivity and regional brain volumes within the fronto-striato-thalamic network were obtained. Linear regression analysis was used to identify predictors of modafinil-induced fatigue reduction. Results- Multiple regression analysis showed that baseline multidimensional fatigue inventory-20 score (β=0.576, P=0.006) and functional connectivity between the dorsolateral prefrontal cortex and the caudate nucleus (β=-0.424, P=0.008) were significant predictors of modafinil-associated decreases in poststroke fatigue (adjusted r2=0.52, area under the receiver operator characteristic curve=0.939). Conclusions- Fronto-striato-thalamic functional connectivity predicted modafinil response for poststroke fatigue. Fatigue in other neurological disease has been attributed to altered function of the fronto-striato-thalamic network and may indicate that poststroke fatigue has a similar mechanism to other neurological injury related fatigue. Self-reported fatigue in patients with normal fronto-striato-thalamic functional connectivity may have a different mechanism and require alternate therapeutic approaches. Clinical Trial Registration- URL: . Unique identifier: ACTRN12615000350527.

Keywords: caudate nucleus; fatigue; magnetic resonance imaging; modafinil; quality of life.

Publication types

  • Clinical Trial, Phase II
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Brain / diagnostic imaging*
  • Caudate Nucleus / diagnostic imaging
  • Cohort Studies
  • Cross-Over Studies
  • Double-Blind Method
  • Fatigue / diagnostic imaging
  • Fatigue / drug therapy*
  • Fatigue / etiology*
  • Female
  • Forecasting
  • Humans
  • Magnetic Resonance Imaging
  • Male
  • Middle Aged
  • Modafinil / therapeutic use*
  • Neural Pathways / diagnostic imaging*
  • Prefrontal Cortex / diagnostic imaging
  • Quality of Life
  • Stroke / complications*
  • Stroke / diagnostic imaging
  • Thalamus / diagnostic imaging
  • Wakefulness-Promoting Agents / therapeutic use*


  • Wakefulness-Promoting Agents
  • Modafinil

Associated data

  • ANZCTR/ACTRN12615000350527