Cognitive fatigue is one of the most pervasive yet least understood symptoms in persons with multiple sclerosis (PwMS). The current neuroimaging study examined whether an effort-reward imbalance, a framework based in cognitive neuroscience, could explain cognitive fatigue. The effort-reward framework posits that cognitive fatigue results from a mismatch between effort and reward processing. As such, we hypothesized that increased activation of frontal regions that mediate effort processes, and decreased activation of striatal regions that mediate reward processes, would be associated with cognitive fatigue.

Twenty PwMS and 20 cognitively healthy controls (HC) underwent fMRI during a computerized switching task with independent high- and low-demand (effort) and reward conditions. Fatigue was assessed using the Visual Analog Scale of Fatigue (VAS-F) before the start of the task and after each condition. Mixed effects models were used to estimate the association between effort, reward, VAS-F, and functional activity in frontal (dorsolateral prefrontal cortex, DLPFC; orbitofrontal cortex, OFC; ventromedial prefrontal cortex, vmPFC; and dorsal anterior cingulate cortex, dACC) and striatal (dACC and nucleus accumbens, NAcc) regions previously implicated in cognitive fatigue.

We found that PwMS reported higher VAS-F scores than their HC counterparts (p=.01). Results indicated that during the task, PwMS showed significantly higher right-DLPFC (p<.05), lower left-vmPFC (p=.01), and lower bilateral dACC (p<.05) activation than the HC group. During the reward presentation, PwMS showed significantly higher left-dACC deactivation (p<.01) and bilateral-NAcc activation (p<.01) than the HC group. We did not observe a relationship between VAS-F and DLPFC, OFC, vmPFC, or NAcc activation. However, we found that in PwMS, right-dACC activation during the high-demand condition was associated with lower VAS-F scores (=-.33, 95% CI: -.65- -.01, p<.05).

The current study identified the dACC as a potential key region underlying cognitive fatigue. As expected, PwMS showed increased DLPFC activation to meet task demands, consistent with the high-effort portion of the effort-reward imbalance framework. However, PwMS also showed increased NAcc activation, suggesting intact reward processing. Notably, the dACC, which is associated with evaluating the value of exerting effort, is often activated with DLPFC during effortful tasks. In the current study, dACC activation in PwMS was significantly lower across both task demands and reward conditions. Therefore, our findings suggest that while PwMS recruit frontal and striatal regions appropriately to process effort and reward, their ability to identify the utility of effortful action driven by the dACC (i.e., “is it worth it?”) may be compromised. In conclusion, this is the first functional neuroimaging study, to our knowledge, to show the dACC and thereby, the expected value of control, is directly related to self-reported cognitive fatigue and may be central to the effort-reward imbalance framework and understanding cognitive fatigue in PwMS.