Fatigue is a common symptom in multiple sclerosis (MS), with up to 90% of individuals with MS reporting fatigue (1). Moreover, more than half of individuals with MS report fatigue to be their worst symptom (2). For this reason, the topic of fatigue in MS has generated a great deal of research in the domains of neuropsychology, neuroscience, and pharmacology. Other clinical populations also report fatigue including: 80% of individuals with traumatic brain injury (TBI) (3), 56% of individuals with Parkinson’s Disease (PD) (4), 99% of cancer patients (5), 88% of individuals with human immunodeficiency virus (88%) (6), as well as individuals with chronic fatigue syndrome (CFS) who experience fatigue for more than 6 months for no known psychiatric or neurological reasons (7).

Fatigue is characterized by a lack of energy, feelings of exhaustion that are unaided by sleep, and the perception that one is unable to perform mental and physical activities (8). Although fatigue has been studied extensively, in part because it affects such a wide range of clinical populations, there has been no unifying framework within which to understand fatigue. In this review, we propose such a framework, with the aim of providing structure for this developing field of study.

We propose that fatigue arises due to a dopamine imbalance within the central nervous system (CNS). One of the ultimate goals of this review is to investigate the evidence that supports the dopamine imbalance hypothesis by examining studies showing structural and functional abnormalities in areas enervated by dopamine and clinical trials showing alleviation of fatigue after dopamine medication.

The current review examines the evidence in support of the dopamine imbalance hypothesis by focusing on central fatigue, which can be experienced as both physical and mental in nature. Further, the current review builds upon a previous framework of fatigue proposed by Chaudhuri and Behan (9), which suggests that central fatigue might arise due to the “failure of the non-motor functions of the basal ganglia” [(9), p. 40]. This hypothesis was developed based on evidence from both animal and clinical studies, which showed the effects of basal ganglia damage to be similar to the symptoms of central fatigue. The authors emphasized subcortical pallido–thalamo-cortical interactions and urged to clarify the influence of dopamine and serotonin on fatigue, since these neurotransmitters effect the activation of the pallido–thalamo-cortical loop. In the current review, we suggest a more precise mechanism based on recent studies that fatigue might develop as a result of a dopamine imbalance.

Dopamine is a modulatory neurotransmitter that is termed a catecholamine due to its chemical composition. Dopamine is the most common catecholamine in the CNS (10, 11) and is a precursor to the two other catecholamines, norepinephrine and epinephrine. In the CNS, dopamine is synthesized in two subcortical brain regions, specifically, the substantia nigra pars compact (SNc) and the ventral tegmental area (VTA) (10, 12–14). Dopaminergic neurons project from the SNc and VTA to various cortical areas and thus can be segregated onto several dopaminergic pathways: (1) the nigrostriatal pathway, which links the SNc with the striatum, and (2) the mesocorticolimbic pathway, which starts at the VTA and projects to the striatum, limbic areas, and the prefrontal cortex (PFC) (10, 13, 15, 16). Finally, dopamine from a third pathway is synthesized in the hypothalamus and projects to the pituitary gland, where it is involved in the inhibition of prolactin release, a hormone that is important in immune system regulation¹ (10) (Figure 1). Catecholamines also play an important role in the modulation of the immune system, with dopamine being synthesized and released by immune cells (17, 18).

Dopamine receptors (DRs) can be found in both the CNS and in the immune system. There are five types of DRs (D1, D2, D3, D4, and D5), subdivided into two groups: D1-like and D2-like. The D1 and D5 receptors belong to the D1-like group, while the rest of the DRs belong to the D2-like group of receptors (10, 13). These receptors have different distribution densities in the CNS, depending on the brain region. For example, more D1-like receptors are located in the PFC, while more D2-like receptors are found in the striatum. Therefore, different medications have a somewhat specific affinity for DRs and that way can have a greater effect on a specific brain region (e.g., a medication targeting D1 may have more influence on the PFC and its function than on the striatum) (19).

Dopamine has been known to play an important role in motor function. However, evidence from several past decades show that dopamine also plays a significant role in motivation and cognition. Specifically, dopamine has been shown to be involved in learning of action–outcome associations (20–22). In addition, dopamine has been shown to be involved in effortful behavior: the depletion of dopamine from the striatum or the administration of dopamine antagonists has been shown to result in the cessation of effortful reward-seeking behavior. That is, animals that learned to exert effort (e.g., climb a barrier or press a lever several times) for a larger food reward, start to prefer a smaller reward that can be obtained without effort exertion (23, 24). PFC dopamine has been shown to play an important role in working memory (25, 26). Further, increased amount of dopamine release in the striatum and the PFC has been shown to be associated with cognitive flexibility [see Ref. (27) for review].

Unlike the two major neurotransmitters, glutamate and gamma aminobutyric acid, which have excitatory and inhibitory properties, respectively, dopamine is a neuromodulator. Studies in animals and humans show that the influence of dopamine on cognition follows an inverted “U” shape function (13, 25), with too much or too little dopamine administration leading to impaired cognitive performance. Fatigue might be subject to a similar mechanism. In the case of working memory, Gibbs and D’Esposito (63) found that healthy participants who were given a dopamine agonist (i.e., bromocriptine) showed an increase in working memory capacity (63). Harel et al. (64) showed a similar effect in individuals with MS. The authors conducted a DBRC study with 26 MS patients. Patients were classified as working memory impaired according to baseline performance on a complex task that involves working memory, processing speed, and attention. Compared to the placebo control group, follow-up task performance in the treatment group significantly improved after a single dose of methylphenidate (10 mg) taken 1 h before task follow-up (64). According to the dopamine imbalance hypothesis, administration of a dopamine agonist, such as the methylphenidate, should have lead to an increase in dopamine levels in the brain and a negative correlation between fatigue and performance; unfortunately, Harel et al. (64) did not report fatigue measures such as the FSS and the MFIS, or on-task fatigue.

Neuroimaging studies on working memory show that performance improvement in individuals with low working memory capacity is accompanied by increased connectivity between mesocorticolimbic structures increases after dopamine agonist administration (43). Vytlacil et al. (65) also showed a correlation between increased connectivity of the striatum and the midbrain nuclei (VTA and SN) and working memory performance after bromocriptine administration in individuals with low working memory capacity; an opposite pattern of results was observed in individuals with high working memory capacity. Similarly to what has been observed in the working memory literature, fatigue has been shown to be associated with reduced connectivity between mesocorticolimbic structures (39, 40). However, the effect of dopamine on mesocorticolimbic activation and connectivity in individuals with fatigue has not yet been investigated.

According to the gating hypothesis, dopamine might modulate cognition due to its interaction with other neurotransmitters in the PFC. When there is too much dopamine, the “gate” for excitatory inputs from glutamate neurons to post-synaptic PFC cells shuts down, while too little dopamine allows interference between different inputs (13, 19, 25). Similar to the gating hypothesis relating dopamine levels to cognition, the dopamine imbalance hypothesis proposes that fatigue might occur when there is too much or too little dopamine. Several studies show that while fatigue decreases with dopaminergic medication, the effect might be dose-dependent. Johansson et al. (42) observed a decrease in fatigue while participants were on a low dose of methylphenidate (5 mg), with an even greater decrease in fatigue observed when participants were on a higher dose of methylphenidate (20 mg). Similar results were obtained in hospice patients (66). Advanced cancer patients who reported high baseline fatigue, had greater fatigue reduction after 20 mg of methylphenidate (67, 68). Another DBRC trial with 109 human immunodeficiency virus participants showed methylphenidate titration to be effective in reducing fatigue. However, while some patients took the maximum dose of the medication to achieve fatigue reduction (up to 60 mg per day), other patients were able to achieve fatigue reduction with a lower dose (69).

Taken together, these studies highlight the modulatory effect of dopamine on cognition and fatigue. However, there is no evidence showing an increase in fatigue when there is too much dopamine in the CNS. Therefore, it remains to be tested if and at what dose dopamine medication ceases to be helpful in reducing fatigue. Given that dopamine is a neuromodulator that has been shown to have a variable effect on cognition (i.e., too low or too high levels of dopamine do not improve cognitive functioning), it is likely that it has a similar effect on fatigue. That is, fatigue might result from too much or too little dopamine in the brain.

Based in large part on the evidence from the MS animal model, experimental autoimmune encephalomyelitis (EAE), MS is considered to be an autoimmune disorder of the CNS. To a large extent, the immune system depends on the functioning of the leukocytes or white blood cells. T cells are a type of white blood cell that produce an immune response, i.e., they are activated when the body needs to fight an infection. In autoimmune diseases, including MS, T cells proliferate and attack healthy cells (18), passing though the blood–brain barrier into the CNS. It has been shown that proliferating CD4⁺ cells (a type of T cells) express the D3 receptor that contributes to the destruction of dopamine neurons in the SN and generate interferon-γ, a compound that proliferates inflammation and prevents dopamine synthesis (11, 18, 70, 71). This potentially can result in decreased dopamine levels. Indeed, animal studies showed that CNS dopamine depletion by means of administration of the neurotoxin that kills dopamine cells in the SN leads to EAE exacerbation, while daily administration of a dopamine agonist, bromocriptine that has an affinity for D2 DRs (of which the striatum has a high concentration), has been shown to have beneficial effects on EAE. Treatment with bromocriptine has been shown to result in reduced severity and duration of relapses in rats with acute EAE. It also leads to the suppression of prolactin, a pituitary hormone that is inhibited by dopamine synthesized in the hypothalamus (see above) (10, 11, 17, 72). Though highly speculative, this line of reasoning suggests that fatigue might occur due to the dopamine imbalance that starts in the immune system, subsequently affecting the CNS.

IFNβ is an immunomodulatory drug approved for treatment in relapsing remitting MS. It is the first line of treatment and has been shown to prevent relapses. There are two types of IFNβ: IFNβ-1a and IFNβ-1b (73). Even though the precise mechanism of action of the IFNβ is not completely understood, it is thought that IFNβ prevents relapses and slows disability progression through retarding inflammatory processes, such as T-cell proliferation and passing of the CD4⁺ T cells through the blood–brain barrier. More importantly, recent findings also show that IFNβ treatment leads to increased production of dopamine (58, 73–75).

Given that IFNβ increases dopamine synthesis, while dopaminergic medications help increase levels of dopamine in the brain, it is possible that individuals with MS on the IFNβ treatment might benefit more from the dopaminergic fatigue treatment or even have lower levels of fatigue than individuals with MS on a different treatment. To our knowledge, there is only one study that looked at fatigue in relapsing remitting MS with IFNβ treatment (76). Melanson et al. (76) in a non-randomized open-label study showed that fatigue decreases in patients on IFNβ treatment.

In this review, we propose that fatigue arises due to an imbalance of dopamine, a modulatory neurotransmitter, in the CNS and the immune system. Based on the evidence cited above and building upon a previous framework on fatigue (9), we propose that fatigue depends on the base levels of dopamine in the CNS. Neuroimaging studies in clinical populations with fatigue repeatedly show structural and functional impairments in regions heavily innervated by dopaminergic neurons, namely the striatum and the PFC (See Supplementary Table 1 for the list of studies). While these brain structures underlie a wide range of processes, converging evidence suggests that an imbalance in dopamine plays a key role in fatigue. Indeed, dopaminergic medication that increases dopamine levels in the brain has been shown to increase the functioning and connectivity between these regions in healthy individuals and to decrease fatigue in clinical populations (See Supplementary Table 2 for the list of studies). Thus, the dopamine imbalance hypothesis provides a unifying framework for the study of fatigue.

Given this framework, future research should be geared toward testing specific aspects of the hypothesis. While studies in cognition show that dopamine has a modulatory influence on cognitive performance, clinical trials in fatigue so far only show that dopaminergic medication decreases fatigue. Since fatigue and cognitive functions such as working memory and attention rely on a similar neural network, it is likely that dopamine has a modulatory effect on fatigue as well. Future neuroimaging and pharmacological research is needed to directly test whether this is the case. Thus, an important question is, does fatigue increase as dopamine levels increase above optimal levels? Another question that should be investigated is whether dopamine agonist administration decreases on-task or “state” fatigue in conjunction with performance improvement. This will help in linking objective measures of performance, which have been shown to be affected by dopamine, with subjective on-task fatigue ratings. Pharmacological studies should evaluate the effect of a dopaminergic medication not only in comparison to a placebo but also in comparison with non-dopaminergic medications, to show whether fatigue is differentially affected by a dopaminergic medication versus, for example, serotonergic medication.

Neuroimaging studies should focus on manipulating mesocorticolimbic network activity in controlled experimental settings. This would allow researchers to observe network functioning in fatigued individuals and to answer specific questions about the time course of network activation in a controlled environment. Investigating the time course of network activation during task performance would reveal whether it correlates with on-task fatigue. It is also worth looking at whether the increased connectivity observed after dopamine medication, which has been shown to lead to an increase in working memory performance, is associated with fatigue reduction. Answering these questions will provide valuable evidence about the underlying mechanisms of fatigue, and will ultimately allow us to develop targeted treatments for fatigue.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

The Supplementary Material for this article can be found online at http://www.frontiersin.org/Journal/10.3389/fneur.2015.00052/abstract