Rev. Neurosci. 2014; 25(4): 469–479

Akira Ishii*, Masaaki Tanaka and Yasuyoshi Watanabe

Neural mechanisms of mental fatigue Abstract: Fatigue is defined as a decline in the ability and efficiency of mental and/or physical activities that is caused by excessive mental and/or physical activities. Fatigue can be classified as physical or mental. Mental fatigue manifests as potentially impaired cognitive function and is one of the most significant causes of accidents in modern society. Recently, it has been shown that the neural mechanisms of mental fatigue related to cognitive task performance are more complex than previously thought and that mental fatigue is not caused only by impaired activity in task-related brain regions. There is accumulating evidence supporting the existence of mental facilitation and inhibition systems. These systems are involved in the neural mechanisms of mental fatigue, modulating the activity of task-related brain regions to regulate cognitive task performance. In this review, we propose a new conceptual model: the dual regulation system of mental fatigue. This model contributes to our understanding of the neural mechanisms of mental fatigue and the regulatory mechanisms of cognitive task performance in the presence of mental fatigue. Keywords: cognitive function; dual regulation system; facilitation system; inhibition system; mental fatigue. DOI 10.1515/revneuro-2014-0028 Received April 14, 2014; accepted May 19, 2014; previously published online June 13, 2014

Introduction Fatigue can be defined as difficulty in initiating or sustaining voluntary activities (Chaudhuri and Behan, 2004). *Corresponding author: Akira Ishii, Department of Physiology, Osaka City University Graduate School of Medicine, 1-4-3 Asahimachi, Abeno-ku, Osaka 545-8585, Japan, e-mail: [email protected] Masaaki Tanaka: Department of Physiology, Osaka City University Graduate School of Medicine, 1-4-3 Asahimachi, Abeno-ku, Osaka 545-8585, Japan Yasuyoshi Watanabe: Department of Physiology, Osaka City University Graduate School of Medicine, 1-4-3 Asahimachi, Abenoku, Osaka 545-8585, Japan; and RIKEN Center for Life Science Technologies, 6-7-3 Minatojima-minamimachi, Chuo-ku, Hyogo 650-0047, Japan

Definitions of fatigue and fatigue sensation given by the Japanese Society of Fatigue Science are as follows: ‘Fatigue is defined as a decline in the ability and efficiency of mental and/or physical activities that is caused by excessive mental or physical activities or disease. Fatigue is often accompanied by a peculiar sense of discomfort, a desire to rest, and a decline in motivation, referred to as fatigue sensation’ (Kitani, 2011). Recently, behavioral, electrophysiological, and neuroimaging studies using functional magnetic resonance imaging (fMRI), positron emission tomography, and magnetoencephalography (MEG) have clarified some of the neural mechanisms underlying human physical fatigue as well as fatigue associated with human diseases and syndromes (Tanaka and Watanabe, 2012). When an individual performs a physical task and the active muscle fibers become fatigued, an increase in voluntary effort is required to increase the motor output from the primary motor cortex (M1) to compensate for the physical fatigue and maintain physical performance (­Gandevia et  al., 1996; Taylor et  al., 1996; Taylor and Gandevia, 2008). This occurs until the task requires a maximal voluntary effort. The system that increases the motor output from the M1 is known as the facilitation system and is composed of a re-entrant neural circuit that interconnects the limbic system, basal ganglia (BG), thalamus (TH), orbitofrontal cortex (OFC), dorsolateral prefrontal cortex (DLPFC), anterior cingulate cortex (ACC), premotor area (PM), supplementary motor area (SMA), and M1 (Dettmers et al., 1996; Chaudhuri and Behan, 2000, 2004; Johnston et  al., 2001; Liu et  al., 2003, 2007; Korotkov et  al., 2005; Post et al., 2009; Tanaka and Watanabe, 2012). A motivational input to this facilitation system enhances activity in the SMA and then M1, thereby increasing the motor output to the peripheral system (Tanaka and Watanabe, 2011). In contrast, sensory input from the peripheral system to M1 during physical fatigue decreases motor output (Jasmin et al., 2003; Ohara et al., 2005; Ruehle et al., 2006; Zhuo, 2008; Jouanin et al., 2009; Hilty et al., 2011; Tanaka et al., 2011). An inhibition system increases inhibitory input to M1 to limit the recruitment of motor units and/or slow the firing rate of active motor units in the M1 (Taylor and Gandevia, 2008). This inhibition system is composed of a neural pathway that interconnects the spinal cord, TH, secondary somatosensory cortex, insular cortex (IC), posterior cingulate cortex (PCC), ACC, PM, SMA, and M1

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470      A. Ishii et al.: Neural mechanisms of mental fatigue (Tanaka and Watanabe, 2012). Hence, the motor output from the M1 is regulated primarily by the balance between the facilitation and inhibition systems (Tanaka and ­Watanabe, 2012). In human diseases or syndromes such as multiple sclerosis and chronic fatigue syndrome (CFS), there have been several studies that have shown dysfunction and/or abnormal activation patterns in these brain regions included in the facilitation and inhibition systems (Roelcke et al., 1997; Caseras et al., 2006; Tanaka et al., 2006; Cook et al., 2007; DeLuca et  al., 2008; Tanaka and Watanabe, 2010, 2012). Dysfunction of the facilitation system and enhancement of the inhibition system both result in difficulties driving the facilitation system. Voluntary effort enhances the facilitation and inhibition systems, but the enhanced inhibition system causes further difficulties in driving the facilitation system (Filippi et  al., 2002; de Lange et  al., 2004; Lange et al., 2005; White et al., 2009). This process induces dysfunction of the facilitation system and activation of the inhibition system through central sensitization or classic conditioning of the inhibition system, which we describe later, and causes severe fatigue in these diseases and syndromes (Tanaka and Watanabe, 2010). Although the neural mechanisms underlying physical fatigue and fatigue associated with diseases or syndromes are understood to some extent, knowledge about the neural mechanisms underlying mental fatigue is more limited. In this review, we describe the neural mechanisms underlying mental fatigue that have been identified using behavioral, electrophysiological, and neuroimaging techniques.

Cognitive function The relation between mental fatigue and cognitive function is not well understood. However, declines in executive functions such as executive attention (van der Linden et  al., 2003b; Holtzer et  al., 2011), sustained attention (Dorrian et al., 2007; Langner et al., 2010; Lim et al., 2010), goal-directed attention (Boksem et al., 2005), alternating attention (van der Linden et  al., 2003a), divided attention (van der Linden and Eling, 2006), response inhibition (Kato et  al., 2009), planning (Lorist et  al., 2000; Lorist, 2008), and novelty processing (Massar et  al., 2010) are a common feature of mental fatigue. Among the various components of executive function, selective attention, particularly conflict-controlling selective attention (response inhibition), is highly vulnerable to mental fatigue (Tanaka et al., 2012). Conflict-controlling selective

attention was evaluated using reaction time and error rate of Stroop-like trials in a traffic-light task and was impaired after performance of a fatigue-inducing mental task, even though cognitive task performance related to executive functions such as alternating attention, divided attention, sustained attention, and working memory was not altered (Tanaka et al., 2012). During Stroop-like trials in the traffic-light task, the color and word aspects of the task activate the associated responses, resulting in conflict between the activated responses and an increase in reaction time and error rate (Tanaka et al., 2012). It has been proposed that this conflict activates a conflict monitor in the ACC that engages the control function of the DLPFC and that this engagement of the DLPFC increases attention on subsequent trials, resulting in improved performance (Smith and Jonides, 1999; Carter and van Veen, 2007). The gray matter volume in the DLPFC was decreased in CFS patients compared with that in healthy controls, and the decrease in the gray matter volume was reversed after the cognitive behavioral therapy, which improved the health status and cognitive performance of the CFS patients (Okada et al., 2004; de Lange et al., 2008). In patients with fibromyalgia, decreased gray matter volume in the ACC was observed, and the level of microstructural change in the ACC assessed by fractional anisotropy was positively associated with the level of fatigue (Lutz et al., 2008). In addition, a decrease in the density of serotonin transporter assessed by positron emission tomography in CFS patients has been reported (Yamamoto et al., 2004). Thus, the ACC and DLPFC are the brain regions associated with fatigue in fatigue-related diseases and syndromes such as fibromyalgia and CFS. Taking these findings into consideration, mental fatigue might cause deterioration of cognitive function through impairments in these brain regions (i.e., the ACC and DLPFC), in particular the response inhibition components of executive function.

Facilitation system The facilitation system of mental fatigue (i.e., the mental facilitation system) has been described in behavioral, electrophysiological, and neuroimaging studies of fatigue-inducing submaximal mental tasks, as described below. There have been some reports suggesting that task performance is not altered during fatigue-inducing mental task trials (Desmond and Hancock, 2001; Matthews and Desmond, 2002), even though cognitive performance was potentially affected. While the reaction time and accuracy

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of two-back test trials did not change over time during a fatigue-inducing two-back test session of 30-min duration (Mizuno and Watanabe, 2007; Tanaka et  al., 2009, 2012; Shigihara et  al., 2013b), task performance on the advanced trail making test (ATMT) (Kajimoto, 2007) was impaired after the two-back test session of 30-min duration (Tanaka et al., 2009; Shigihara et al., 2013b). In the ATMT, circles numbered from 1 to 25 are randomly located on the display of a personal computer, and participants are required to use a computer mouse to click the center of the circles in sequence, starting with circle number 1. The number of errors on the ATMT and the subjective level of mental fatigue assessed using a visual analogue scale (Lee et  al., 1991) were higher after the fatigue-inducing two-back test session than those before. These findings demonstrate that the participants were mentally fatigued after the two-back test session and suggest that two-back test performance was maintained by a compensatory mechanism, i.e., the mental facilitation system (Shigihara et al., 2013b). Variability of electrocardiography R-R wave intervals can be used to evaluate the activity of the sympathetic nervous system (Pagani et al., 1997). Low-frequency (LF) and high-frequency (HF) components are calculated by frequency domain analysis of the R-R wave intervals. The HF is vagally mediated (Akselrod et  al., 1981; Pomeranz et  al., 1985; Malliani et  al., 1991) and the LF originates from a variety of sympathetic and vagal mechanisms (Akselrod et  al., 1981; Appel et  al., 1989). The frequency domain analysis of the R-R wave intervals indicates that the sympathetic nervous system is active during a fatigueinducing two-back test session (Tanaka et  al., 2009). Increased motivation or mental effort has been associated with increased activation of the sympathetic nervous system (Mezzacappa et  al., 1998; Johnson et  al., 2006); therefore, the increase in sympathetic nervous system activity during the two-back test session may reflect an increase in the contribution of motivation or mental effort to the maintenance of cognitive task performance in the presence of mental fatigue. For example, an increased level of motivation resulted in an improvement of cognitive task performance during a fatigue-inducing mental task (Boksem et al., 2006). Oscillatory brain rhythms are considered to originate from synchronous synaptic activities of a large number of neurons (Brookes et  al., 2011). Synchronization of neural networks may reflect integration of information processing, and multiple, broadly distributed, and continuously interacting dynamic neural networks are achievable through the synchronization of oscillations at particular time-frequency bands (Varela et al., 2001). Such

synchronization processes can be evaluated using MEG time-frequency analyses. Alpha-band (8–13 Hz) power in the frontal cortex was lower after the fatigue-inducing two-back test session than that before the two-back test session, and the level of decrease in the alpha-band power was positively associated with the task performance of the two-back task trials (Shigihara et al., 2013a). Large-scale rhythmic oscillations in brain activity at alpha-band frequencies are generated by interactions between thalamocortical neurons and GABAergic (γ-aminobutyric acid cells) in the thalamic reticular nucleus (Lopes da Silva, 1991; Rinzel et  al., 1998). Therefore, suppressed spontaneous alpha-band power, i.e., desynchronization due to intrinsic events, in the frontal cortex caused by mental fatigue suggests an overactivation of the thalamic-frontal circuit. Considering that the task performance was maintained during the fatigue-inducing two-back test trials, this thalamic-frontal circuit related to motivation or mental effort is a candidate neural substrate for the mental facilitation system (Shigihara et al., 2013a). The results of studies using event-related potentials indicate that evaluation of predicted rewards and potential risks of actions is central to mental fatigue, and the evaluation system was considered to consist of a neural circuit that interconnects the limbic system, BG, TH, OFC, DLPFC, and ACC (Boksem and Tops, 2008). In addition, resting regional cerebral blood flow assessed using fMRI in the TH and frontal cortex was positively associated with cognitive task performance during mental fatigue (Lim et  al., 2010). Finally, it has been proposed that fatigue in neurological disorders occurs due to a failure to integrate motivational input and that dopaminergic drive to the striatal-thalamic-frontal circuit plays a central role in this failure (Chaudhuri and Behan, 2000; Lorist et al., 2009; Dobryakova et al., 2013). Hence, the mental facilitation system may be a neural circuit that interconnects the limbic system, BG, TH, and frontal cortex, and an increase in motivational input to this facilitation system, mainly through increased dopaminergic drive (Lorist et al., 2005, 2009), may activate the system and compensate for the effects of mental fatigue. Activation of the mental facilitation system and the associated improvements in cognitive task performance required to maintain task performance in the presence of fatigue may be favorable. Conversely, excessive activation of the mental facilitation system may cause dysfunction of this system to induce further mental fatigue. Dysfunction of the mental facilitation system causes difficulties driving the system. Therefore, while mental effort or motivation enhances the mental facilitation system, further enhancement of this system can cause further difficulty driving

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472      A. Ishii et al.: Neural mechanisms of mental fatigue this system (Filippi et  al., 2002; de Lange et  al., 2004; Lange et al., 2005; DeLuca et al., 2008; White et al., 2009). This may induce further mental fatigue, and repeated or prolonged activation of the facilitation system may cause chronic or accumulated mental fatigue (Tanaka and Watanabe, 2010). Understanding the mechanisms that contribute to dysfunction of the facilitation system is central to understanding mental fatigue. Impaired energy metabolism and oxidative damage may contribute to a functional decline in this system. The relation between mental fatigue and impaired brain energy metabolism (decreased phosphocreatine level) has been studied using 31P-magnetic resonance spectroscopy (Kato et  al., 1999). Oral supplementation of D-ribose, a sugar moiety of adenosine triphosphate (Pauly and Pepine, 2000), and oral supplementation of melon juice concentrate (Extramel), which is rich in superoxide dismutase (Decorde et  al., 2010), attenuated impaired cognitive function caused by mental fatigue (Milesi et  al., 2009). However, evidence supporting a relation between impaired energy metabolism and oxidative damage and dysfunction of the facilitation system is limited, and the contribution of impaired energy metabolism and oxidative damage to functional decline of the facilitation system during mental fatigue remains to be clarified.

Inhibition system The inhibition system of mental fatigue (i.e., the mental inhibition system) has been described in behavioral and neuroimaging studies. It has been consistently reported that although both high- and low-demand mental task trials induce mental fatigue, deterioration of the cognitive performance caused by the high-demand task trials is smaller than that caused by the low-demand task trials (van der Linden et  al., 2003a; Nakagawa et  al., 2013). This may be caused not only by activation of the mental facilitation system during high-demand, fatigue-inducing mental tasks (as described in the Facilitation system section) but also by activation of the mental inhibition system during low-demand mental tasks. Activation of the inhibition system during low-demand mental tasks was suggested by a behavioral study that assessed alterations in cognitive task performance and sleepiness during highand low-demand mental tasks (Shigihara et al., 2013b). In this study, 30-min zero- and two-back tests were used as fatigue-inducing mental tasks. Although the task performance of the two-back test trials did not change over time

in the high-demand two-back test session, reaction time and sleepiness increased over time in the low-demand zero-back test session. Since zero-back test was boring (Shigihara et  al., 2013b), one possible explanation is that there was insufficient application of mental effort to perform the zero-back test, and the other possible explanation is that the boredom activated the inhibitory system during zero-back test session. Since boredom can increase sleepiness level (Mavjee and Horne, 1994) and sleepiness can be considered to be a request for rest in order to recover from fatigue (Kumar, 2008), the low-demand zeroback task seemed to have activated the mental inhibition system rather than deactivated the mental facilitation system (Shigihara et al., 2013b); in fact, since there were no differences in the level of motivation between the zeroand two-back tests (Shigihara et  al., 2013b), decreased application of the mental effort in the zero-back test was not the case. Activation of the mental inhibition system during low-demand mental tasks has also been suggested by an MEG study with time-frequency analyses (Shigihara et  al., 2013a). In this study, beta-band power in the left precentral gyrus increased after the zero-back test session but not after the two-back test session, and the increase in beta-band power in the zero-back test session was negatively associated with the correction rate and positively associated with reaction time. A decrease in the amplitude of oscillatory beta-band power in the precentral gyrus reflects increased activity of M1 (Murthy and Fetz, 1996; Baker et  al., 1997; Jensen et  al., 2005; Yamawaki et  al., 2008; Hall et  al., 2011); therefore, it has been suggested that activity in the precentral gyrus is suppressed by the mental inhibition system. As the zero-back test does not require activation of the mental facilitation system, these observations can be interpreted as indicating activation of the mental inhibition system during low-demand mental tasks. Enhanced activation of the mental inhibition system has been demonstrated in patients with CFS (Tanaka et al., 2006), who often experience cognitive impairments (Fukuda et  al., 1994). During fatigue-inducing visual search trials, neural activity assessed by blood-oxygenlevel-dependent response in task-related (i.e., visual cortex) and task-unrelated (i.e., auditory cortex) brain regions decreased over time in CFS patients, but only neural activity in task-related brain regions decreased over time in healthy control participants, suggesting that there is enhanced activation of the mental inhibition system in CFS patients. Several studies have shown that the mental inhibition system can suppress not only cognitive task performance but also physical task performance (Marcora et al., 2009;

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Pageaux et  al., 2013). In these studies, mental fatigue enhanced the perception of effort and impaired physical performance during exercise trials, even though cardio­ respiratory and muscular variables were not affected by mental fatigue. These observations imply that the mental inhibition system shares common neural substrates with the physical inhibition system. The physical inhibition system is thought to involve the IC and the PCC. An fMRI study reported increased activation of the IC during submaximal physical task (i.e., a muscle fatiguing exercise of right finger flexors at 70% of individual’s maximal voluntary contraction) in the case of subsequent task failure (Hilty et  al., 2011), and an MEG study reported fatiguerelated location shifts of equivalent current dipoles toward the medial IC and PCC during submaximal physical tasks (Jouanin et al., 2009). Thus, the IC and PCC may be involved in the mental inhibition system. Fatigue sensation plays an important role as a biological alarm signal under conditions of fatigue and urges us to take a rest to avoid upsetting homeostasis and to allow recovery from fatigue. It can be postulated that the neural mechanisms of fatigue sensation caused by mental fatigue are closely related to the mental inhibition system (Boksem and Tops, 2008). In fact, several studies have reported that the neural substrates of fatigue sensation involve the IC and PCC, i.e., brain regions that are thought to be involved in the mental inhibition system. Activation of the IC was positively related to the level of fatigue sensation induced by the typhoid vaccination (Harrison et al., 2009) and was related to the evaluation of mental effort (Otto et al., 2013). During high-demand, mental-fatigue-inducing tasks, the increase in blood-oxygen-level-dependent fMRI signal in the PCC was positively associated with the level of fatigue sensation assessed using a visual analogue scale and the Profile of Mood States questionnaire (Cook et  al., 2007). Furthermore, it has been reported that the PCC is involved in self-evaluation of the level of physical (Ishii et  al., 2014b) and mental (Ishii et al., 2014a) fatigue. Involvement of the IC and PCC in the neural mechanisms of fatigue sensation has also been suggested in a study that focused on the neural substrates activated by viewing others expressing fatigue (Ishii et  al., 2012). In this study, MEG activations were observed in the PCC when participants were viewing pictures of people with fatigued expressions, and MEG activations in the IC were also observed in some participants. The IC is involved in monitoring the state of the body, i.e., sensing the physiological condition of the entire body (Craig, 2002, 2009), and the PCC is involved in selfreflection or self-monitoring (Denton et al., 1999; Johnson et al., 2002; Kircher et al., 2002; Vogt and Laureys, 2005; Vogt et al., 2006); therefore, it is plausible that these two

brain regions are related to both fatigue sensation and the mental inhibition system. It has been hypothesized that repeated and prolonged mental workload causes overactivation of the mental inhibition system through central sensitization and/or classic conditioning (Tanaka and Watanabe, 2010). Overactivation of the mental inhibition system can cause chronic or accumulated mental fatigue. Central sensitization and classic conditioning of the inhibition system were first demonstrated in an animal model of fatigue (Katafuchi, 2004). Empirical support that classic conditioning of the physical inhibition system can occur in humans and that activation of the PCC is related to classic conditioning of the inhibition system was recently provided by an MEG study (Tanaka et al., 2013). It has also been shown that classic conditioning of the mental inhibition system can occur in humans (Ishii et  al., 2013). In this study, metronome sounds and two-back test trials were used as conditioned and unconditioned stimuli, respectively, to cause mental fatigue sensation. MEG measurement was performed for 6 min before the conditioning session while participants listened to the metronome sounds. Thereafter, two-back test trials were performed for 60 min as a conditioning session. In the conditioning session, metronome sounds were started 30 min after the start of the two-back task to ensure that fatigue sensation had been caused when the sounds were started. The next day, MEG measurement while listening to the metronome was repeated. The mental fatigue sensation caused by listening to the metronome after the conditioning session was higher than before the conditioning session. During the second MEG session, activations in the IC were observed and activations in the PCC were also observed in some participants. These results indicate that overactivation of the mental inhibition system due to classic conditioning can take place in humans and that the IC and PCC are involved in classic conditioning of the mental inhibition system (Ishii et al., 2013). In an animal model, central sensitization and classic conditioning of fatigue were completely blocked by a 5-hydroxytryptamine (5-HT; serotonin) 1A receptor agonist (Katafuchi, 2004). This suggests that decreased 5-HT 1A activity may be involved in central sensitization and classic conditioning of the mental inhibition system. In fact, a reduction of 5-HT1A binding in the IC has been reported in patients with CFS (Cleare et  al., 2005). However, further study is needed to clarify the molecular mechanisms of central sensitization and classic conditioning of the mental inhibition system. As described above, the IC and PCC are the candidate brain regions that are related to the mental inhibition

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474      A. Ishii et al.: Neural mechanisms of mental fatigue system. However, the IC and/or PCC may inhibit task performance through other brain regions such as the frontal area rather than the IC and/or PCC directly suppressing task performance. In fact, the DLPFC has been postulated to be a brain region that determines cognitive performance, which receives input from both the facilitation and inhibition systems (Tanaka et al., 2014).

Dual regulation system On the basis of these observations, we propose a new conceptual model of mental fatigue related to cognitive task performance: the dual regulation system. In this model, mental workload activates the mental facilitation system to maintain cognitive task performance in the presence of mental fatigue (Figure 1). The thalamic-frontal loop that interconnects the limbic system, BG, TH, and frontal cortex constitutes the mental facilitation system, and an increase in motivational input to this system increases its activation. However, mental workload also activates the mental inhibition system to impair cognitive task performance (Figure 2). The IC and PCC are involved in the mental inhibition system. Acute mental workload activates the mental facilitation and inhibition systems: As

Figure 1 Mental facilitation system. Mental workload activates a mental facilitation system that maintains cognitive task performance in the presence of mental fatigue. The mental facilitation system is composed of a thalamic-frontal loop that interconnects the limbic system, BG, TH, and frontal cortex, and activity in this system is increased by motivational input.

Figure 2 Mental inhibition system. Mental workload activates a mental inhibition system that impairs cognitive task performance. The mental inhibition system is composed of the IC and PCC.

a result, acute mental fatigue is caused. Activation of the mental facilitation system maintains or improves cognitive task performance, whereas activation of the mental inhibition system impairs cognitive task performance. The balance between the activation of the two systems determines whether performance of the cognitive task is impaired (as in the zero-back task trials), maintained, or improved (as in the two-back task trials). Cognitive task performance is therefore regulated by these two systems, i.e., the dual regulation system. In a situation in which mental workload is high enough to cause impairments in cognitive task performance, increased motivational input further activates the mental facilitation system to maintain cognitive task performance and the mental inhibition system to avoid disrupting homeostasis, to request for rest, and to recover from mental fatigue. Repeated and prolonged mental workload causes dysfunction of the facilitation system due to impaired energy metabolism or oxidative damage and overactivation of the inhibition system through central sensitization or classic conditioning. These alterations in the dual regulation system result in severely reduced cognitive task performance, i.e., chronic mental fatigue (Figure 3). Importantly, the dual regulation system proposes that there may be at least three types of acute mental fatigue: that caused by insufficient activation of the mental facilitation system, that caused by enhancement of the mental inhibition system, and that caused by a combination of these systems. Similarly, there may be three types of chronic mental fatigue: that caused by dysfunction of the mental facilitation system, that caused by central sensitization or classic conditioning of the mental inhibition system, and that caused by a combination of these systems. Of course, environmental factors, such as unpleasant ambient temperature and lack of sleep, may affect cognitive functions through impairment of the facilitation and/or inhibition systems

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Figure 3 Dual regulation system. Acute mental workload activates the mental facilitation and inhibition systems to cause acute mental fatigue. The activated mental facilitation system maintains or improves cognitive task performance, whereas the activated mental inhibition system impairs cognitive task performance. Cognitive task performance is regulated by these two systems, i.e., the dual regulation system. Repeated and prolonged mental workload causes dysfunction of the facilitation system due to impaired energy metabolism or oxidative damage and overactivation of the inhibition system through central sensitization or classic conditioning. These alterations in the dual regulation system result in severely reduced cognitive task performance, i.e., chronic mental fatigue.

and may therefore cause mental fatigue. We would like to emphasize that although overactivation and dysfunction of the mental facilitation system have been considered a primary cause of mental fatigue, overactivation and central sensitization or classic conditioning of the mental inhibition system are also important contributing factors to mental fatigue.

Conclusion and future studies In this review, we have summarized and integrated the behavioral, electrophysiological, and neuroimaging findings related to the neural mechanisms of mental fatigue related to cognitive task performance and proposed a new conceptual model that illustrates the regulatory mechanism of cognitive task performance. This model increases our understanding of the neural mechanisms of mental fatigue. Taking both the mental facilitation and mental inhibition systems into account, it is possible to understand the results of most previous studies of mental fatigue, even though the studies focus on different aspects of mental fatigue and employ different study designs. We emphasize the importance of the concept that enhancement and central sensitization or classic conditioning of the mental inhibition system are also deeply related

to the neural mechanisms of mental fatigue, which has rarely been discussed before (Boksem and Tops, 2008). The proposed dual regulation system contributes to our understanding of the pathophysiology of mental fatigue. However, knowledge about mental facilitation and inhibition systems is still limited, and further studies are necessary to confirm this conceptual model. In this review, we focused mainly on the existence of the mental facilitation and inhibition systems and the regulatory mechanisms of cognitive task performance related to the neural mechanisms of mental fatigue. There are several other components of mental fatigue, such as the perception of mental fatigue sensation (St Clair Gibson et al., 2003) and decision making in the presence of mental fatigue (Lorist et al., 2000; Lorist, 2008); however, knowledge of these aspects of mental fatigue is limited. In the future, we aim to conduct multifaceted studies and construct a comprehensive view of the neural mechanisms of mental fatigue and the strategies employed to overcome mental fatigue. Acknowledgments: This work was supported, in part, by a Grant-in-Aid for Scientific Research B (KAKENHI: 23300241) and a Grant-in-Aid for Young Scientists (B) (KAKENHI: 23700804, 25750351) from the Ministry of Education, Culture, Sports, Science, and Technology (MEXT)

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476      A. Ishii et al.: Neural mechanisms of mental fatigue of Japan and by grants from the Japanese Ministry of Health, Labor, and Welfare. We thank Forte Science Communication for editorial help with the manuscript.

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Akira Ishii is an Assistant Professor, Department of Physiology, Osaka City University Graduate School of Medicine, Osaka, Japan. He is also a medical doctor. In 2010, he took a medical doctorate (PhD) at Osaka City University Graduate School of Medicine. His specialty is Fatigue Science and Functional Neuroimaging.

Yasuyoshi Watanabe is a Director, Center for Life Science Technologies, RIKEN and a Professor, Department of Physiology, Osaka City University Graduate School of Medicine. He is also a medical doctor. In 1981, he took a medical doctorate (PhD) at Kyoto University. His specialty is Fatigue Science and Molecular Neuroimaging.

Masaaki Tanaka is an Assistant Professor, Department of Physiology, Osaka City University Graduate School of Medicine, Osaka, Japan. He is also a medical doctor. In 2003, he took a medical doctorate (PhD) at Osaka City University Graduate School of Medicine. His specialty is Fatigue Science and Functional Neuroimaging.

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