Are there internal thought processes in the monkey?—Default brain activity in humans and nonhuman primates

Behavioural Brain Research 221 (2011) 295–303

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Review

Are there internal thought processes in the monkey?—Default brain activity in humans and nonhuman primates M. Watanabe ∗ Department of Psychology, Tokyo Metropolitan Institute for Neuroscience, 2-6 Musashidai, Fuchu, Tokyo, 183-8526, Japan

a r t i c l e

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Article history: Received 4 February 2011 Accepted 22 February 2011 Available online 11 March 2011 Keywords: Default mode of brain activity Monkey PET Rest Medial cortical areas Task-induced deactivation

a b s t r a c t Human neuroimaging studies have well demonstrated the presence of a “default system” in the brain, which shows a “default mode of brain activity”, i.e., greater activity during the resting state than during an attention-demanding cognitive task. The default system consists mainly of the medial prefrontal and medial parietal areas. It has been proposed that this default activity is concerned with internal thought processes. Here, I first describe activities observed in the human default system measured by several methods, in relation task performance, development, aging and psychiatric disorder. I will then introduce recent nonhuman primate studies that indicate correlated low-frequency spontaneous brain activity within the default system, high metabolic levels in these medial brain areas during rest and task-induced suppression of neuronal activity in the medial parietal area. Furthermore, I will present our data in which we found task-induced deactivation in the monkey default system, and will examine similarities and differences in default activity between the human and nonhuman primate. Finally, I will discuss the functional significance of the default system and consider the possibility of internal thought processes in the monkey. © 2011 Elsevier B.V. All rights reserved.

Contents 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Higher rCBF or metabolic activity during rest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Regions with task-induced deactivation revealed by PET and fMRI . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Regions with task-induced suppression of high-frequency EEG power . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Correlated low frequency spontaneous BOLD activity revealed by fMRI . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Developmental and age-related changes of default activity revealed by PET and fMRI . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Abnormality of the default system in psychiatric patients demonstrated by PET and fMRI . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Developmental disorder and default system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Functional significance of the default mode of brain activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Default mode of brain activity in the nonhuman primate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Task-induced deactivation in the monkey . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . rCBF in the resting monkey . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Differential task-induced deactivation depending on the difference in task and cognitive load in the human . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Are there internal thought processes in the monkey? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. Introduction Interest in resting brain activity has been increasing in recent human neuroimaging studies using positron emission tomogra-

∗ Corresponding author. Tel.: +81 42 325 3881x4308; fax: +81 42 321 8678. E-mail address: [email protected] 0166-4328/$ – see front matter © 2011 Elsevier B.V. All rights reserved. doi:10.1016/j.bbr.2011.02.032

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phy (PET) and functional magnetic resonance imaging (fMRI) [1]. Raichle has been a leading investigator in this area of research, and he used the phrase “default mode of brain activity” to designate the greater activity shown during the resting state than during an attention-demanding cognitive task [2]. This activity is observed in the “default system” or “default mode network” of the brain that mainly involves the medial prefrontal cortex (MPFC), anterior cingulated cortex (ACC), posterior cingulate cortex (PCC) including the retrosplenial cortex, precuneus and inferior parietal

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nal processes concerned with anticipatory programming of several alternative behaviors [4]. Technical advances in PET methodology have allowed examination of activities in whole brain areas during the resting period. Minoshima et al. [5] examined metabolic activity of the whole brain of both normal and early Alzheimer patients using 2-deoxy2 [18 F]fluoro-d-glucose ([18 F]FDG) as a ligand, which is known to accumulate and become trapped in neurons at a rate proportional to the glucose metabolic rate. They found higher metabolic activity during rest in the PCC in normal control subjects. Raichle et al. [2] used O15 -labeled radiopharmaceuticals as a ligand and showed higher rCBF in the medial cortical areas including MPFC and PCC/precuneus than in other areas. More recently, Rilling et al. [6] conducted a [18 F]FDG-PET study on both humans and chimpanzees. In the human resting brain, they found higher metabolic activity in the PCC/precuneus, MPFC, lateral prefrontal cortex (LPFC) and premotor areas. 3. Regions with task-induced deactivation revealed by PET and fMRI

Fig. 1. Regions with default mode of brain activity in humans. Medial and lateral indicate medial and lateral aspects of the human brain, respectively. Abbreviations, ACC: anterior cingulate cortex; IPL: inferior parietal lobule; PCC: posterior cingulate cortex; dMPFC: dorsal part of the medial prefrontal cortex; vMPFC: ventral part of the medial prefrontal cortex.

lobule (IPL) (Fig. 1). It has been proposed that this default (mode of brain) activity is concerned with internal thought rather than externally oriented processes [3]. In this review, I will first describe brain activities in the human default system examined using several different measures; (1) higher regional cerebral blood flow (rCBF) or higher metabolic activity during rest, (2) task-induced deactivation demonstrated by PET and fMRI, (3) task-induced suppression of high-frequency EEG power, (4) correlated spontaneous blood oxygen level dependent (BOLD) activity during rest. Then, I will describe developmental and age-related changes in the default mode of brain activity as well as abnormality of this activity in psychiatric patients and individuals with autism and attention deficit hyperactivity disorder (ADHD). Next, I will introduce nonhuman primate studies where resting brain activities were examined. I will also introduce our recent study in which we examined “task-induced deactivation” in the awake monkey using PET. Finally, I will discuss the functional significance of the default mode of brain activity referring to the resting brain activity observed in both human and nonhuman primates and consider the possibility of internal thought processes in the nonhuman primate. 2. Higher rCBF or metabolic activity during rest Since the beginning of human neuroimaging studies using radioactive ligand, it has been noticed that there are certain brain areas that show higher rCBF, compared with that in other areas, during the resting period. Ingvar reported that the rCBF measured with the intra-arterial 133 Xenon clearance technique was significantly (20–40%) higher in the frontal than in the postcentral, occipital and temporal regions, and called this higher frontal activity “hyperfrontal activity” [4]. He considered the high frontal activity in the resting conscious state that is unaccompanied by movements, speech or behavioral reactions, to be concerned with an anticipatory “simulation of behavior”, since the activity was low in the sensory-gnostic cortical areas, while there should be inter-

In most human neuroimaging studies, a subtractive methodology is commonly used, in which functional images acquired in a control state is subtracted from images acquired in a task state. The subtraction data are usually expressed as activations caused by the task requirement. Although reverse subtraction is rarely attempted, Raichle et al. [2] considered the importance of the “deactivations” obtained by the reverse subtraction, since deactivated areas are considered to play important roles in the control state. Shulman et al. [7] compared average brain activity at rest with average activity during a task by conducting meta-analysis on 132 human neuroimaging studies, and obtained a set of regions showing decreased activity during task performance. Such “task-induced deactivation” has been repeatedly confirmed by subsequent studies [8,9]. The fact that some brain regions were more active at rest than during task performance led to the hypothesis that the brain remained active in an organized fashion during the resting state, and the regions that routinely exhibit a decrease in activity during task performance became known as the ‘default (mode) network’ or ‘default system’ and were thought to mediate processes that are important for the resting state [10]. Importantly, rest-related activity increases are observed irrespective of whether the subject is resting in either visual fixation or with eyes closed. Furthermore, regardless of the task under investigation, the rest-related activity increase almost always includes the same default brain system [11]. 4. Regions with task-induced suppression of high-frequency EEG power It is not easy to examine EEG activity in the human default system since the default system consists mainly of medial cortical areas which are difficult to access using the surface EEG recording. However, there are a few rare studies in which EEG was recorded from the default system in epileptic patients in whom depth-EEG electrodes were implanted for pre-surgical examination of epileptic foci. Miller et al. [12] found diminished neural activity of high-frequency power (76–200 Hz) in the dorsal MPFC and precuneus while the subject was engaged in a task from restingstate levels. Jerbi et al. [13] also observed task-induced decrease of gamma (>50 Hz) power, which is known to be associated with attention demanding cognitive task performance, in the human PCC and MPFC. Interestingly, the high gamma suppression found in the default system co-occurred with task-related enhancement outside the default system. The authors suggested that gamma modulations represent an electrical correlate of BOLD signal modulations [13].

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5. Correlated low frequency spontaneous BOLD activity revealed by fMRI It has consistently been observed that regions with similar functionality tend to show a correlation in their spontaneous BOLD activity. For example, spontaneous BOLD fluctuations measured in the left somatomotor cortex are specifically correlated with spontaneous fluctuations in the right somatomotor cortex and with medial motor areas in the absence of overt motor behavior [14]. Correlations among spontaneous BOLD signal fluctuations have also been examined in the default system. To obtain correlations (connectivity analysis), there are two main techniques; i.e., seed-based and independent component analysis (ICP) techniques. In the seed-based technique, the signal is extracted from a specific region of interest (ROI), and a map is created by computing the correlation between this extracted signal and all other brain voxels, while the ICA technique considers all voxels at once and uses a mathematical algorithm to separate a dataset into distinct systems or networks that are correlated in their spontaneous fluctuations [15]. Correlations in spontaneous BOLD activity of very slow frequencies (around 0.1 Hz) are commonly observed across areas within the default system [16,17]. Furthermore, regions with apparently opposing functionality have been found to be negatively correlated or anti-correlated in their spontaneous activity. Thus, in relation to attention demanding cognitive task performance, regions with activity increases are anticorrelated with a set of regions showing activity decreases [16,18]. As described above, resting brain activity can be assessed by several measures. The important point that should be noted is that medial prefrontal and medial and lateral parietal areas that constitute the “core” default system are always included in all measures of (1) higher regional cerebral blood flow (rCBF) or higher metabolic activity, (2) task-induced suppression in BOLD activity and in high frequency EEG power, and (3) correlated low frequency spontaneous BOLD activity. However, it is also important to note that different measures demonstrate different default systems. While the connectivity analyses usually demonstrate hippocampal and anterior lateral temporal areas as components of the default system, these areas are usually not detected by rCBF/metabolic activity and taskinduced deactivation techniques [18]. Furthermore, it is important to remember that during the anesthetized condition, the task cannot be trained and thus no task-induced deactivation can be obtained whereas default activity can be demonstrated by correlated spontaneous low frequency BOLD activity [19,20]. In relation to rCBF and task-induced deactivation, Pfefferbaum et al. indicated that not only during rest but also during task performance, rCBF was higher in the posterior nodes of the default mode network (PCC/precuneus) than the cortical average across the whole brain [21]. They suggested that when an individual is in the default mode, PCC/precuneus are activated as indexed by high relative and absolute CBF, which is in turn reduced but still at higher levels than most other cortical regions during task performance.

6. Developmental and age-related changes of default activity revealed by PET and fMRI To clarify the functional significance of the default system, it is important to know its developmental and age-related changes. Development of the default system has been studied mostly by connectivity analysis. Fransson et al. [22] conducted seed-based connectivity analysis by scanning preterm infants, and found a primitive resting-state network that differs from the adult’s default network. Fair et al. [23] investigated functional connectivity in the

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default system in children (7–9 years old) using the seed-based technique and found that the network is only sparsely connected. Using the ICA technique, Gao et al. [24] demonstrated that a primitive and incomplete default network is already present in 2-week olds, which is followed by an increase in the number of brain regions exhibiting connectivity, and showed that the default network including the MPFC, PCC and IPL areas becomes similar to that observed in adults by 2 years of age. According to the authors, PCC is central to the most and strongest connections of the default network, suggesting that this area may serve as the main “hub” of the default network. Supekar et al. [25] conducted not only functional but also structural connectivity analyses on the default network, and found that structural connectivity in children (7–9 years old) is not sufficiently developed despite adult-like levels of functional connectivity. The authors stressed that connectivity between the PCC and MPFC along the cingulum bundle is the most immature link in the default network in children. Thomason et al. [26] examined the default system of children (7–11-year-old) not only by connectivity analysis but also by the task-induced deactivation method. Children showed reliable reductions in BOLD response in the default system in response to increasing task demands or task difficulty as adults did. Interestingly, in children, task-induced deactivation was also observed in the somatosensory area and insular cortex, suggesting that the default system is not well differentiated. Connectivity analysis demonstrated resting-state functional connectivity across the default system similar to that in an adult, and there was good overlap between the area with task-induced deactivation and the areas with resting-state functional connectivity. As for age-related changes, Lustig et al. [27] showed that taskinduced deactivations observed in the MPFC were smaller in the elderly than in young adults despite the fact that greater task difficulty is usually associated with greater deactivation in young adults, and older people found the task more difficult than young adults did. Grady et al. [28] observed a linear decrease in memorytask induced deactivation with age in the default system, as well as decrease in activation in task-related areas (e.g., dorsolateral prefrontal cortex) with age. Damoiseaux et al. [29] found reduction in spontaneous low frequency BOLD activity in the default system, and showed that there was significant correlation between reduced spontaneous BOLD activity and less effective executive functioning/processing speed in the older group. It has also been shown that patients with Alzheimer disease (AD) demonstrate a specific anatomic pattern of reduced resting-state metabolism in the PCC relative to that in agematched healthy peers, and that this hypometabolism in the PCC progresses with the disease and correlates with mental status [5]. The default system of AD patients appears to be disrupted, since AD patients show reduced task-induced deactivation in the MPFC while showing task-induced activation, instead of deactivation in the PCC/Precuneus [27]. Furthermore, Greicius et al. [30] showed that the AD group demonstrates an age-related decrease in low frequency spontaneous BOLD activity in the default system, which activity may ultimately prove to be a sensitive and specific biomarker for incipient AD.

7. Abnormality of the default system in psychiatric patients demonstrated by PET and fMRI Task-induced deactivation in the default system has also been examined in schizophrenic patients, and the default system has often been reported to be overactive. For example, Harrison et al. [31] noted accentuated task-induced deactivation in the default system of schizophrenic patients. Garrity et al. [32] also showed that positive symptoms of the disease (hallucinations, delusions,

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and thought confusions) correlated with increased task-induced deactivation in the default system. On connectivity analysis, decreased functional connectivity was observed in schizophrenic patients during rest, not only in the default network, but also in the task-positive, executive network [33]. Furthermore, the extent of decrease in connectivity was found to be positively correlated with illness duration [34]. However, the results of studies examining default activity in schizophrenic patients are inconsistent. Thus, in contrast to the above results, Zhou et al. [35] reported increased connectivity in spontaneous BOLD signal within the default system in schizophrenic patients. Furthermore, Pomarol-Clotet et al. [36] showed that schizophrenic patients demonstrated not an increase but a decrease in task-induced deactivation in the default system. Abnormality of default activity is also observed in depressed patients, and the results are also inconsistent. However, it has often been demonstrated that in depressed patients, metabolism is decreased in the prefrontal cortex and increased in the subgenual ACC, a part of the default system, as compared to that in healthy adults [37,38]. Grimm et al. [39] indicated that depressive patients showed significantly reduced task-induced deactivation in several regions of the default system. Decreased deactivations were correlated with depression severity and feelings of hopelessness. It is suggested that the decreased task-induced deactivation found in this study may be caused by abnormally high resting-state neural activity rather than by a deficit in inducing deactivation in response to stimuli. Interestingly, it was found that resting-state cingulate functional connectivity with the default system was significantly greater in depressed subjects compared to that in the control group [40]. 8. Developmental disorder and default system Abnormality in the default mode of brain activity was also investigated in relation to developmental disorders, such as autism and ADHD. Kennedy et al. [41] found that the autism group failed to demonstrate a task-induced deactivation effect. Furthermore, there was a strong correlation between a clinical measure of social impairment and activity within the ventral MPFC, a part of the default system. The lack of deactivation in the autism group is suggested to indicate abnormality in internal thought processes at rest. Connectivity analysis also showed weaker resting state functional connectivity within the default system in autistic individuals [42]. Fassbender et al. [43] indicated that youths with ADHD showed a pattern of increasing deactivation similar to that in normal control in the MPFC as the task difficulty increased, but youth with ADHD showed significantly less deactivation than controls. Peterson et al. [44] showed that youths with ADHD were unable to suppress default-mode activity to the same degree as control subjects when off medication, whereas when on stimulant medication, they could suppress this activity to control group levels. On connectivity analyses, reduced functional connectivity was observed within the default system in the ADHD group [45,46]. 9. Functional significance of the default mode of brain activity Functional roles of the default system could be deduced from neuroimaging studies where relative activity increases in response to cognitive task manipulations can be obtained in the regions of the default system as well as from clinical studies on patients with disturbance of the region in the default system. Based on these studies, the default activity has been thought to be concerned with internal thought processes [3], such as the recall of autobiographical episodic memories [9], self-referential processing

[47], conceptual processing [8], spontaneous semantic processing [48], mind-wandering [49], and monitoring of the external environment, body image and emotional state [50]. According to Gusnard and Raichle [11], subdivisions of the default system appear to be related to specific functional roles (See Fig. 1). Thus, the functional significance of the posterior medial cortices (PCC, precuneus and retrosplenial) is concerned with emotional processing, orientation within, and interpretation of, the environment and episodic memory. Posterior lateral cortices are concerned with orienting individuals to salient novel or familiar stimuli, especially when they contain animate and socially relevant components. Ventral MPFC is concerned with a continuous process of online monitoring of associations between sensory information, responses and outcomes under changing circumstances. Dorsal MPFC is related to monitoring or reporting one’s own mental state, such as selfgenerated thoughts, intended speech and emotions, and attributing mental states to others (explicit representation of states of the self). Most of these functions are manifested during the awake conscious state and could be supported by linguistic abilities. To consider the functional significance of the default mode of brain activity, it would be interesting to determine whether default activity is similarly observed, or how it is modulated (when it is modulated), during sleep or anesthesia in humans. It would also be interesting to know whether similar default activity is observed in the nonhuman primate without linguistic ability. If the default mode of brain activity is observed in the nonhuman primate, it is possible that it is a manifestation of a more basic aspect of functional organization of the brain that may be conserved throughout animal evolution [51]. Greicius et al. [19] showed that although the default network still showed functional connectivity during light sedation (midazolam), there was significantly reduced functional connectivity. Horovitz et al. [52] found that although default network connectivity persisted during light sleep, the connectivity during light sleep decreased gradually as a person fell asleep, to the point of being virtually absent during the deepest stages of sleep. More specifically, only partial network involvement was observed; whereas correlations between the PCC and posterior parietal areas became stronger, the correlations between PCC and MPFC/ACC became nonsignificant. Gujar et al. [53] found that one night of sleep deprivation significantly disrupted task-related deactivation, resulting in a double dissociation within the anterior and posterior midline regions of the default network; i.e., significantly less deactivation in the ACC while there was significantly greater deactivation in the PCC/precuneus as compared with those in non sleep-deprived subjects. It should also be added that metabolic dysfunction of the default-mode brain regions, in particular the precuneus and MPFC is common in patients in a vegetative or minimally conscious state [54].

10. Default mode of brain activity in the nonhuman primate Similar to research into the human default system, the default activity has been investigated by using several measures in the nonhuman primate; (1) metabolic activity, (2) correlation in lowfrequency spontaneous BOLD activity, and (3) electrical activity. The first PET study on the default system of the nonhuman primate was conducted in the chimpanzee [6]. Chimpanzees first received a dose of [18 F]FDG and rested quietly in their home cage during 75 min of [18 F]FDG uptake period. Then, they were anesthetized and underwent a PET scan to image the distribution of [18 F]FDG in the brain (It was thought that [18 F]FDG uptake was complete before sedation). It was demonstrated that the highest level of metabolic activity (5% most active voxels during

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rest) occurred in both the (dorsal and ventral) medial and lateral prefrontal areas and medial and lateral parietal areas [6]. A single photon emission computed tomography (SPECT) study on rhesus monkeys, which was not directly concerned with examining the default activity, suggested that there is relatively higher metabolism in the PFC than in the other cortical areas in the resting monkey [55]. To date, correlation in low-frequency BOLD spontaneous activity has not been examined in the awake state in the nonhuman primate. In the anesthetized monkey, low-frequency, spontaneous BOLD activity showed a correlation between MPFC and PCC/precuneus [20]. Furthermore, significant anticorrelation was observed between the default system and lateral prefrontalintraparietal executive system. In a study in which neuronal activity was recorded from awake monkeys, task-induced suppression of neuronal activity was found in the PCC [56]. It was found that firing rates in the PCC were reliably suppressed during task performance and returned to a higher baseline during resting periods. Interestingly, higher firing rates were also observed during the resting period when monkeys were instructed to be temporarily liberated from exteroceptive vigilance (by the cue indicating that the next trial would not begin for 4 s). They found that higher firing (reflecting deeper resting activity) during the pre-trial period in the PCC predicted errors and slow behavioral responses. Although experimental studies conducted to date have demonstrated specific resting activity in nonhuman primates, there has not been any PET or fMRI study in the nonhuman primate demonstrating the default system that shows task-induced deactivation. As I described before, areas with task-induced deactivation are similar but often differ from areas with the highest level of metabolic activity or from areas with correlated low frequency spontaneous BOLD activity during rest. Thus, it is not clear whether regions showing the highest level of metabolic activity during rest, or regions with correlated spontaneous low frequency BOLD activity within the medial brain areas in nonhuman primates correspond to regions showing task-induced deactivation.

11. Task-induced deactivation in the monkey In order to demonstrate task-induced deactivation in the monkey brain, we conducted a PET study on awake, unanesthetized monkeys that sat on a primate chair [57]. We measured the changes in regional cerebral blood flow (rCBF) using [15 O]H2 O PET. We compared the resting (sitting quietly on a monkey chair without task performance) brain activity with that during a working memory (WM) task. We also examined regions that showed the highest level of blood flow during rest, and compared these regions with those regions showing task-induced deactivation. Fig. 2 indicates areas of the monkey brain that were more active during rest than during spatial WM task. LPFC, MPFC, ACC, OFC, and PCC/precuneus areas were more active during rest than during a spatial WM task in all three monkeys examined. The reverse subtraction of (spatial WM related activity minus resting activity) identified regions that were more active during the spatial WM task. During the task, monkeys looked at the CRT display, moved their right hand, and licked the tube to obtain the liquid reward. In all monkeys, higher activities were observed in the sensory-motor, ventral premotor and visual areas. Besides the spatial WM task, we also trained monkeys on spatial control (no WM requirement), nonspatial WM and nonspatial control (no WM requirement) tasks [58]. Not only during the nonspatial WM task, but also during the spatial and nonspatial controls tasks, we observed task-induced deactivation in areas similar to those induced by spatial WM task. In our study, the magnitude of

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the task-induced deactivation did not differ depending on the task condition since there was no significant difference in the number of voxels showing task-induced deactivation between the four kinds of rest-related activity for all monkeys. On conjunction analysis, we obtained subtraction images of (resting activity minus all kinds of task-related activity) for each monkey. As found on individual analyses, activities during rest were higher in LPFC, MPFC, ACC, OFC and PCC/precuneus for all three monkeys. Furthermore, the IPL and visual association areas were also more active during rest in all monkeys. In the multi-subject analysis, we obtained the average location of spatial and nonspatial task-induced deactivations by averaging data of different monkeys. Average locations of both spatial and nonspatial task-induced deactivations obtained by multi-subject analysis, were similar to the regions that were more active during rest compared to the spatial or nonspatial WM task in each monkey, except that the PCC/precuneus area did not show significant deactivation. Additional deactivations were also observed in the IPL, visual association and motor areas. 12. rCBF in the resting monkey To examine the regions that showed the highest levels of rCBF during rest, we first identified the top 5% most active voxels in the whole brain (Fig. 3A) for each monkey. In all monkeys, the highest level of activity was observed in the dorsal striatum. In contrast to the chimpanzee study on resting metabolism [6], the MPFC and PCC/precuneus were not sufficiently active to meet 5% or even 10% threshold levels. When we employed a more liberal threshold and highlighted the top 20% most active voxels for each monkey, in addition to the striatum, all monkeys demonstrated higher-level rCBF in the medial brain areas that showed task-induced deactivation (i.e., the ACC, PCC/precuneus, MPFC; Fig. 3B). However, there was no high-level rCBF observed in the OFC in any of the monkeys. While a previous study indicated the highest metabolic activity in the default system in the resting chimpanzee [6], we found the highest rCBF in the dorsal striatum in the resting monkey. Chimpanzees in the previous study remained in the home cage during the [18 F]FDG uptake period. In contrast, the monkeys in our study were sitting in the primate chair in an upright posture. The high rCBF in the dorsal striatum during rest in the present study could be caused by the requirement that the animal sit upright on the primate chair with the head rigidly restrained. In all monkeys, there were significant differences between regions showing task-induced deactivation and regions showing the highest level of rCBF during rest. For example, the ventromedial PFC, which consists of the anterior parts of the ventral MPFC and OFC, showed clear task-induced deactivation, while there was no high-level rCBF observed in this brain area during rest in any monkey. 13. Differential task-induced deactivation depending on the difference in task and cognitive load in the human Here, I reconsider the characteristics of the human default brain activity in order to consider the functional significance of the monkey default system. During the auditory discrimination task, McKiernan and colleagues showed that task-induced deactivations increased as task-processing demands increased [48]. Moreover, the same group showed that the frequency of so-called “task unrelated thoughts” co-varied with the magnitude of task-induced deactivation in the default system [59]. Thus, it is assumed that default activity is an inverse function of cognitive demand, where higher demands reduce activity in the default regions because the mental resources used for various internal processes are sus-

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Fig. 2. Regions with higher activity during rest than during the spatial WM task. Subtraction images are shown separately for each monkey. Upper left (a), lower left (b) and right panels (c, d and e) indicate transverse, sagittal and coronal brain sections of each monkey, respectively. Vertical line b in the upper left panel indicates the L–R line corresponding to the sagittal section pictured in the lower left panel (b). Horizontal line a in panel (b) indicates the top-bottom line corresponding to the transverse section pictured in panel (a). Lines c, d and e in panels (a) and (b) indicate the A–P line corresponding to the coronal sections pictured in the right panels (c, d and e) (from Ref. [57] with permission)

pended to accommodate task-related processing [2,11,47,59]. It is also indicated that not only task-induced deactivations but also intrinsic, spontaneous brain activity in the default system is modulated by cognitive load. Thus, the mean power density of intrinsic low-frequency (0.01–0.1 Hz) BOLD signal is significantly decreased during the WM task compared to that at rest in the default system [60]. It is also indicated that the spontaneous intrinsic activity in the default system is not extinguished but rather attenuated during performance of the WM task and that the intrinsic, spontaneous signal fluctuations in the default system persist and are reorganized in response to changes in the external work load [60]. Default activity appears to differ depending on the type of task. Tomasi et al. [61] examined task-induced deactivation during attention task and WM task, and found stronger deactivation in the default system during the WM than during the attention task. Mayer et al. [62] also examined task-induced deactivation during attention task and WM task, and found task general deactivation in the core default system (PCC and insular cortex in their study) as well as differential deactivation in the other non-core default system. Quite recently, it was indicated that the default system, especially in the left brain, is less deactivated when the task involves semantic memory processing, suggesting that the default system is concerned with the internal mentation process that involves declarative memory function [63]. Interestingly, some parts of the default system show taskinduced “activation” when specific cognitive operations are needed. Zysset et al. [64] demonstrated activity increase, not decrease in MPFC and precuneus during two tasks, episodic retrieval and self-referential processing, compared to that during the passive fixation baseline. Furthermore, they showed a functional dissociation between the activations in the MPFC and precuneus with the former being more concerned with selfreferential processes while the latter being more associated with episodic retrieval processes. Knauff et al. [65] also showed, not taskinduced deactivation, but differential increase in precuneus activity depending on differences in reasoning tasks. These findings indicate that, some regions of the default system not only show task-induced ‘deactivation’ with differing magnitudes depending on the task, but also task-induced ‘activation’ in relation to specific task requirements, such as episodic retrieval or self-referential processing.

14. Are there internal thought processes in the monkey? Human default activity has been observed predominantly in medial parts of the brain (the anterior medial prefrontal and posterior medial parietal areas) [2]. Similar to the human default system, all monkeys showed higher rest-related activity in the medial prefrontal and medial parietal areas. Although the functional roles of the medial brain areas may differ between monkeys and humans, there are some functional similarities between the medial brain areas in humans [50] and those in monkeys; it has been shown in the monkey that the MPFC is involved in monitoring behavioral outcomes, especially in social contexts [66] and PCC is concerned with outcome evaluation and subsequent behavioral modification [67]. Considering that the human default system is related to internal thought processes [3], the findings of the present study demonstrating that default activity also occurs in the medial brain areas of the monkey suggest that there might be internal thought processes in the monkey. The IPL area, which is part of the human default system [7], involves angular and supramarginal gyri that are concerned with linguistic processing and may support internal thought. In the present study, task-induced deactivation in IPL was not observed in individual analyses, but was observed when across-task conjunction analyses and multi-subject analyses were conducted. Thus, the IPL also appears to constitute the default system in the monkey, but the roles of this area in the default system may not be as critical as those in humans. It is notable that we observed consistently higher rest-related activity in the lateral and orbital PFC as well as the medial brain areas in the monkey. The monkey LPFC is thought to be concerned with higher executive control [68]. It thus appears that resting cognition involves greater executive control than task performance. However, it is suggested that LPFC may show task-induced deactivation when the task is easy, but may not show deactivation when the task demands a higher cognitive load [3]. Thus, task-induced deactivations observed in LPFC may be caused, not because resting cognition involves greater executive control, but because the task situation did not demand much executive control. Recently, simultaneous deactivation of both the default and executive systems were observed in relation to mind-wandering in human neuroimaging studies [69]. Thus, in addition to default system activation, mind-wandering was associated with execu-

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Fig. 3. Regions with high levels of rCBF. Regions with rCBF levels in the top 5% (A) and top 20% (B) are illustrated separately for each monkey. Panels in the upper left (a), lower left (b), and right (c, d and e) indicate transverse, sagittal and coronal brain sections of each monkey, respectively. Other conventions are the same as in Fig. 2 (from Ref. [57] with permission)

tive network (mainly LPFC) recruitment. The observed parallel recruitment of executive and default network regions suggests that mind-wandering may evoke a unique mental state that allows otherwise opposing networks to work in cooperation [69]. Thus, it is also possible that resting activity observed in the LPFC as well as medial cortical areas in monkeys may be associated with a kind of mind-wandering process in the monkey.

In human neuroimaging study, it is indicated that (1) increasing the difficulty and attentional demand of the task results in fewer stimulus-independent thoughts, and (2) the more stimulus independent thoughts that occur during a task session, the more the activity of the default system and the worse the subject’s performance [60]. Indeed, it is interesting to note that higher firing during the pre-trial period in the monkey PCC predicted errors and slow

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behavioral responses, suggesting that the higher the resting activity, the greater the magnitude of task-unrelated thoughts also in the monkey [56]. The OFC is known to be concerned with processing reward information. During the experiment, the monkeys were fluid-restricted and therefore must have been eager to perform the tasks in order to obtain their reward. Thus, the monkey’s desire for a liquid reward might have been very strong during rest. On the other hand, the resting condition may have been frustrating to the monkey since it was not allowed to perform the task to obtain the reward. Considering that OFC is related to processing both appetitive and aversive stimuli [70], the resting activity observed in OFC in the present study, which does not constitute the human default system, may have been concerned with internal thought processes, which may have involved more motivational and emotional contents, such as reward expectancy and frustration. Rilling et al. [6] suggested that the resting state of chimpanzees involves emotionally laden episodic memory retrieval and some level of mental self-projection. The IPL area constitutes the default system in humans and may support internal thought processes by its language-related activity. It is speculated that resting activity observed in this brain area in the chimpanzee, but only weakly observed in the monkey, may be related to much higher cognitive, possibly pre-linguistic, operations conducted in this brain area in the chimpanzee but not in the monkey. While some researchers have argued that monkeys may not have a theory of mind [71], there are data indicating that the monkey has a degree of social intelligence, as exemplified by their capacity for deceptive behavior [72], altruistic behavior [73] and fairness judgments [74]. Furthermore, a recent study suggested that monkeys demonstrate Theory of Mind abilities when tested in more ecologically relevant situations [75]. Considering that monkeys live within a complex social structure, and thus, are required to process self and others in the context of society, it is not implausible to consider that internal thought processes exist not only in chimpanzees but also in monkeys. Acknowledgements The author expresses his thanks to H. Onoe, K. Hikosaka, K. Tsutsui and H. Tsukada for collaboration in conducting the PET studies presented in this paper. This study was supported by a Grant-in-Aid for Scientific Research on Priority Areas (Integrative Brain Research) from the Ministry of Education, Culture, Sports, Science and Technology of Japan (No. 17022050), and by a Grantin-Aid for Target-Orientated Research and Development in Brain Science from the Japan Science and Technology Corporation (No. 13073-2125). References [1] Uddin LQ, Menon V. Introduction to special topic—resting-state brain activity: implications for systems neuroscience. Front Syst Neurosci 2010;4:37. [2] Raichle ME, MacLeod AM, Snyder AZ, Powers WJ, Gusnard DA, Shulman GL. A default mode of brain function. Proc Natl Acad Sci USA 2001;98:676–82. [3] Christoff K, Ream JM, Gabrieli JD. Neural basis of spontaneous thought processes. Cortex 2004;40:623–30. [4] Ingvar DH. “Hyperfrontal” distribution of the cerebral grey matter flow in resting wakefulness; on the functional anatomy of the conscious state. Acta Neurol Scand 1979;60:12–25. [5] Minoshima S, Giordani B, Berent S, Frey KA, Foster NL, Kuhl DE. Metabolic reduction in the posterior cingulate cortex in very early Alzheimer’s disease. Ann Neurol 1997;42:85–94. [6] Rilling JK, Barks SK, Parr LA, Preuss TM, Faber TL, Pagnoni G, et al. A comparison of resting-state brain activity in humans and chimpanzees. Proc Natl Acad Sci USA 2007;104:17146–51. [7] Shulman GL, Fiez J, Corbetta M, Buckner R, Miezin FM, Raichle ME, et al. Common blood flow changes across visual task: II Decreases in cerebral cortex. J Cogn Neurosci 1997;9:648–63.

[8] Binder JR, Frost JA, Hammeke TA, Bellgowan PSF, Rao SM, Cox RW. Conceptual processing during the conscious resting state: a functional MRI study. J Cogn Neurosci 1999;11:80–93. [9] Mazoyer B, Zago L, Mellet E, Bricogne S, Etard O, Houde O, et al. Cortical networks for working memory and executive functions sustain the conscious resting state in man. Brain Res Bull 2001;54:287–98. [10] Fox MD, Raichle ME. Spontaneous fluctuations in brain activity observed with functional magnetic resonance imaging. Nat Rev Neurosci 2007;8: 700–11. [11] Gusnard DA, Raichle ME. Searching for a baseline: functional imaging and the resting human brain. Nat Rev Neurosci 2001;2:685–94. [12] Miller KJ, Weaver KE, Ojemann JG. Direct electrophysiological measurement of human default network areas. Proc Natl Acad Sci USA 2009;106:12174–7. [13] Jerbi K, Vidal JR, Ossandon T, Dalal SS, Jung J, Hoffmann D, et al. Exploring the electrophysiological correlates of the default-mode network with intracerebral EEG. Front Syst Neurosci 2010;4:27. [14] Biswal B, Yetkin FZ, Haughton VM, Hyde JS. Functional connectivity in the motor cortex of resting human brain using echoplanar MRI. Magn Reson Med 1995;34:537–41. [15] Fox MD, Greicius M. Clinical applications of resting state functional connectivity. Front Syst Neurosci 2010;4:19. [16] Fox MD, Snyder AZ, Vincent JL, Corbetta M, Van Essen DC, Raichle ME. The human brain is intrinsically organized into dynamic, anticorrelated functional networks. Proc Natl Acad Sci USA 2005;102:9673–8. [17] Fransson P. Spontaneous low-frequency BOLD signal fluctuations: an fMRI investigation of the resting-state default mode of brain function hypothesis. Hum Brain Mapp 2005;26:15–29. [18] Buckner RL, Andrews-Hanna JR, Schacter DL. The brain’s default network: anatomy, function, and relevance to disease. Ann N Y Acad Sci 2008;1124: 1–38. [19] Greicius MD, Kiviniemi V, Tervonen O, Vainionpaa V, Alahuhta S, Reiss AL, et al. Persistent default-mode network connectivity during light sedation. Hum Brain Mapp 2008;29:839–47. [20] Vincent JL, Patel GH, Fox MD, Snyder AZ, Baker JT, Van Essen DC, et al. Intrinsic functional architecture in the anaesthetized monkey brain. Nature 2007;447:83–6. [21] Pfefferbaum A, Chanraud S, Pitel AL, Müller-Oehring E, Shankaranarayanan A, Alsop DC, et al. Cerebral blood flow in posterior cortical nodes of the default mode network decreases with task engagement but remains higher than in most brain regions. Cereb Cortex 2011;21:233–44. [22] Fransson P, Skiold B, Horsch S, Nordell A, Blennow M, Lagercrantz H, et al. Resting-state networks in the infant brain. Proc Natl Acad Sci USA 2007;104:15531–6. [23] Fair DA, Cohen AL, Dosenbach NU, Church JA, Miezin FM, Barch DM, et al. The maturing architecture of the brain’s default network. Proc Natl Acad Sci USA 2008;105:4028–32. [24] Gao W, Zhu H, Giovanello KS, Smith JK, Shen D, Gilmore JH, et al. Evidence on the emergence of the brain’s default network from 2-week-old to 2-year-old healthy pediatric subjects. Proc Natl Acad Sci USA 2009;106:6790–5. [25] Supekar K, Uddin LQ, Prater K, Amin H, Greicius MD, Menon V. Development of functional and structural connectivity within the default mode network in young children. Neuroimage 2010;52:290–301. [26] Thomason ME, Chang CE, Glover GH, Gabrieli JD, Grecius MD, Gotlib IH. Default mode function and task-induced deactivation have overlapping brain substrates in children. Neuroimage 2008;41:1493–503. [27] Lustig C, Snyder AZ, Bhakta M, O’Brien KC, McAvoy M, Raichle ME, et al. Functional deactivations: change with age and dementia of the Alzheimer type. Proc Natl Acad Sci USA 2003;100:14504–9. [28] Grady CL, Springer MV, Hongwanishkul D, McIntosh AR, Winocur G. Agerelated changes in brain activity across the adult lifespan. J Cogn Neurosci 2006;18:227–41. [29] Damoiseaux JS, Beckmann CF, Arigita EJ, Barkhof F, Scheltens P, Stam CJ, et al. Reduced resting-state brain activity in the “default network” in normal aging. Cereb Cortex 2008;18:1856–64. [30] Greicius MD, Srivastava G, Reiss AL, Menon V. Default-mode network activity distinguishes Alzheimer’s disease from healthy aging: evidence from functional MRI. Proc Natl Acad Sci USA 2004;101:4637–42. [31] Harrison BJ, Yucel M, Pujol J, Pantelis C. Task-induced deactivation of midline cortical regions in schizophrenia assessed with fMRI. Schizophr Res 2007;91:82–6. [32] Garrity AG, Pearlson GD, McKiernan K, Lloyd D, Kiehl KA, Calhoun VD. Aberrant “default mode” functional connectivity in schizophrenia. Am J Psychiatry 2007;164:450–7. [33] Liang M, Zhou Y, Jiang T, Liu Z, Tian L, Liu H, et al. Widespread functional disconnectivity in schizophrenia with resting-state functional magnetic resonance imaging. Neuroreport 2006;17:209–13. [34] Liu Y, Liang M, Zhou Y, He Y, Hao Y, Song M, et al. Disrupted small-world networks in schizophrenia. Brain 2008;131:945–61. [35] Zhou Y, Liang M, Tian L, Wang K, Hao Y, Liu H, et al. Functional disintegration in paranoid schizophrenia using resting-state fMRI. Schizophr Res 2007;97:194–205. [36] Pomarol-Clotet E, Salvador R, Sarro S, Gomar J, Vila F, Martinez A, et al. Failure to deactivate in the prefrontal cortex in schizophrenia: dysfunction of the default mode network? Psychol Med 2008;38:1185–93. [37] Mayberg H. Depression. II: Localization of pathophysiology. Am J Psychiatry 2002;159:1979.

M. Watanabe / Behavioural Brain Research 221 (2011) 295–303 [38] Mayberg HS. Modulating dysfunctional limbic-cortical circuits in depression: towards development of brain-based algorithms for diagnosis and optimised treatment. Br Med Bull 2003;65:193–207. [39] Grimm S, Boesiger P, Beck J, Schuepbach D, Bermpohl F, Walter M, et al. Altered negative BOLD responses in the default-mode network during emotion processing in depressed subjects. Neuropsychopharmacology 2009;34: 932–43. [40] Greicius MD, Flores BH, Menon V, Glover GH, Solvason HB, Kenna H, et al. Resting-state functional connectivity in major depression: abnormally increased contributions from subgenual cingulate cortex and thalamus. Biol Psychiatry 2007;62:429–37. [41] Kennedy DP, Redcay E, Courchesne E. Failing to deactivate: resting functional abnormalities in autism. Proc Natl Acad Sci USA 2006;103:8275–80. [42] Cherkassky VL, Kana RK, Keller TA, Just MA. Functional connectivity in a baseline resting-state network in autism. Neuroreport 2006;17:1687–90. [43] Fassbender C, Zhang H, Buzy WM, Cortes CR, Mizuiri D, Beckett L, et al. A lack of default network suppression is linked to increased distractibility in ADHD. Brain Res 2009;1273:114–28. [44] Peterson BS, Potenza MN, Wang Z, Zhu H, Martin A, Marsh R, et al. An FMRI study of the effects of psychostimulants on default-mode processing during Stroop task performance in youths with ADHD. Am J Psychiatry 2009;166: 1286–94. [45] Castellanos FX, Margulies DS, Kelly C, Uddin LQ, Ghaffari M, Kirsch A, et al. Cingulate-precuneus interactions: a new locus of dysfunction in adult attention-deficit/hyperactivity disorder. Biol Psychiatry 2008;63:332–7. [46] Uddin LQ, Kelly AMC, Biswal BB, Margulies DS, Shehzad Z, Shaw D, et al. Network homogeneity reveals decreased integrity of defaultmode network in ADHD. J Neurosci Methods 2008;169:249–54. [47] Kelley WM, Macrae CN, Wyland CL, Caglar S, Inati S, Heatherton TF. Finding the self? An event-related fMRI study. J Cogn Neurosci 2002;14:785–94. [48] McKiernan KA, Kaufman JN, Kucera-Thompson J, Binder JR. A parametric manipulation of factors affecting task-induced deactivation in functional neuroimaging. J Cogn Neurosci 2003;15:394–408. [49] Mason MF, Norton MI, Van Horn JD, Wegner DM, Grafton ST, Macrae CN. Wandering minds: the default network and stimulus independent thought. Science 2007;315:393–5. [50] Gusnard DA, Akbudak E, Shulman GL, Raichle ME. Medial prefrontal cortex and self-referential mental activity: relation to a default mode of brain function. Proc Natl Acad Sci USA 2001;98:4259–64. [51] Welberg L. Unconscious activity in the monkey brain. Nat Rev Neurosci 2007;8:407. [52] Horovitz SG, Braun AR, Carr WS, Picchioni D, Balkin TJ, Fukunaga M, et al. Decoupling of the brain’s default mode network during deep sleep. Proc Natl Acad Sci USA 2009;106:11376–81. [53] Gujar N, Yoo SS, Hu P, Walker MP. The unrested resting brain: sleep deprivation alters activity within the default-mode network. J Cogn Neurosci 2010;22:1637–48. [54] Laureys S. The neural correlates of (un)awereness: lessions from the vegetative state. Trend Cog Sci 2005;9:556–9. [55] Machado CJ, Snyder AZ, Cherry SR, Lavenex P, Amaral DG. Effects of neonatal amygdala or hippocampus lesions on resting brain metabolism in the macaque monkey: a microPET imaging study. Neuroimage 2008;39:832–46.

303

[56] Hayden BY, Smith DV, Platt ML. Electrophysiological correlates of defaultmode processing in macaque posterior cingulate cortex. Proc Natl Acad Sci USA 2009;106:5948–53. [57] Kojima T, Onoe H, Hikosaka K, Tsutsui K, Tsukada H, Watanabe M. Default mode of brain activity demonstrated by positron emission tomography imaging in awake monkeys: higher rest-related than working memory-related activity in medial cortical areas. J Neurosci 2009;29:14463–71. [58] Kojima T, Onoe H, Hikosaka K, Tsutsui K, Tsukada H, Watanabe M. Domainrelated differentiation of working memory in the Japanese macaque (Macaca fuscata) frontal cortex: a positron emission tomography study. Eur J Neurosci 2007;25:2523–35. [59] McKiernan KA, D’Angelo BR, Kaufman JN, Binder JR. Interrupting the “stream of consciousness”: an fMRI investigation. Neuroimage 2006;29:1185–91. [60] Fransson P. How default is the default mode of brain function? Further evidence from intrinsic BOLD signal fluctuations. Neuropsychologia 2006;44:2836–45. [61] Tomasi D, Ernst T, Caparelli EC, Chang L. Common deactivation patterns during working memory and visual attention tasks: an intra-subject fMRI study at 4 Tesla. Hum Brain Mapp 2006;27:694–705. [62] Mayer JS, Roebroeck A, Maurer K, Linden DE. Specialization in the default mode: task-induced brain deactivations dissociate between visual working memory and attention. Hum Brain Mapp 2010;31:126–39. [63] Miranka W, Kay J, Thomas D, Andrea F, Roland W, Helge H. Semantic memory involvement in the default mode network: A functional neuroimaging study using independent component analysis. Neuroimage 2011;54:3057–66. [64] Zysset S, Huber O, Ferstl E, von Cramon DY. The anterior frontomedian cortex and evaluative judgment: an fMRI study. Neuroimage 2002;15:983–91. [65] Knauff M, Fangmeier T, Ruff CC, Johnson-Laird PN. Reasoning, models, and images: behavioral measures and cortical activity. J Cogn Neurosci 2003;15:559–73. [66] Rushworth MF, Buckley MJ, Behrens TE, Walton ME, Bannerman DM. Functional organization of the medial frontal cortex. Curr Opin Neurobiol 2007;17:220–7. [67] Hayden BY, Nair AC, McCoy AN, Platt ML. Posterior cingulate cortex mediates outcome-contingent allocation of behavior. Neuron 2008;60:19–25. [68] Miller EK, Cohen JD. An integrative theory of prefrontal cortex function. Annu Rev Neurosci 2001;24:167–202. [69] Christoff K, Gordon AM, Smallwood J, Smith R, Schooler JW. Experience sampling during fMRI reveals default network and executive system contributions to mind wandering. Proc Natl Acad Sci USA 2009;106:8719–24. [70] Thorpe SJ, Rolls ET, Maddison S. The orbitofrontal cortex: neuronal activity in the behaving monkey. Exp Brain Res 1983;49:93–115. [71] Povinelli DJ, Parks KA, Novak MA. Do rhesus monkeys (Macaca mulatta) attribute knowledge and ignorance to others? J Comp Psychol 1991;105:318–25. [72] Hauser MD. Minding the behaviour of deception. In: Whiten A, Byrne RW, editors. Machiavellian Intelligence II: Extensions and Evaluations. Cambridge: Cambridge UP; 1997. p. 112–45. [73] Burkart JM, Fehr E, Efferson C, van Schaik CP. Other-regarding preferences in a non-human primate: common marmosets provision food altruistically. Proc Natl Acad Sci USA 2007;104:19762–6. [74] Brosnan SF, De Waal FB. Monkeys reject unequal pay. Nature 2003;425:297–9. [75] Flombaum JI, Santos LR. Rhesus monkeys attribute perceptions to others. Curr Biol 2005;15:447–52.