Brain Research Reviews 43 (2003) 224 – 230 www.elsevier.com/locate/brainresrev

Review

A relation between rest and the self in the brain? Bruno Wicker a, Perrine Ruby b, Jean-Pierre Royet c, Pierre Fonlupt b,* a

Institut de Neurosciences Physiologiques et Cognitives, CNRS, 31 Chemin Joseph Aiguier, 13009 Marseille, France Processus Mentaux et Activation Ce´re´brale, INSERM-Unite´ 280, 151 Cours Albert Thomas, F69424 Lyon Cedex 03, France c Laboratoire de Neurosciences et Syste`mes Sensoriels, UMR CNRS 5020, 50 Avenue Tony Garnier, 69007 Lyon Cedex 07, France b

Accepted 5 August 2003

Abstract Neuroimaging techniques such as positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) are widely used to identify the cerebral correlates of cognitive tasks. The resting state presents the advantage to serve as a reference in all experiments but is also an ill-defined mental state because it may vary both from one subject to another and within the same subject. The most challenging question concerns the areas whose activity (revealed by PET or fMRI imaging) is greater in rest state than in an active condition. The present work reports the result of a meta-analysis including five previously published studies. The five different tasks involved are the following: attribution of intention, judgement of stimulus pleasantness, discrimination of spatial attributes, judgement of other peoples’ belief and perception of gaze. For each study, the general linear model was used to assess statistical difference and a contrast resting state minus other conditions was calculated. The intersection of the five contrasts was used to search for the variation jointly observed across the different experiments. This lead to a reduced number of clusters: one cluster in the lower/anterior part of the cingulate gyrus and four clusters located in the medial/ superior frontal gyrus, along the superior frontal sulcus. We discuss the location of these areas with respect to the location of activations induced by different tasks: externally focused attention, memory, general reasoning, theory of mind and self-referential tasks. We observed that medial prefrontal cortex exhibits a lower activity when the subject’s attention is focused towards the external world than when the subject has to additionally refer to some internal states. By contrast, this activity is greater during resting state than during both externally directed and internally directed attention. Thus, we hypothesize that during rest, the subject is in a state where he refers only to his own self. D 2003 Elsevier B.V. All rights reserved. Theme: Neural basis of behavior Topic: Cognition Keywords: Resting state; Self; Neuroimaging; Prefrontal cortex

Contents 1. 2. 3. 4.

Search for the self in neuroimaging . . . . . . . . . . . . . . . . . . . . . . The resting state in neuroimaging . . . . . . . . . . . . . . . . . . . . . . . Brain areas exhibiting a greatest activity during resting state: a meta-analysis Materials and methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1. Subjects. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2. Data acquisition . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.3. Experimental conditions . . . . . . . . . . . . . . . . . . . . . . . . 4.4. Data analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.4.1. Image pre-processing . . . . . . . . . . . . . . . . . . . . . 4.4.2. Conjunction analysis . . . . . . . . . . . . . . . . . . . . .

* Corresponding author. Tel.: +33-6-60-54-68-29; fax: +33-4-72-68-19-02. E-mail address: [email protected] (P. Fonlupt). 0165-0173/$ - see front matter D 2003 Elsevier B.V. All rights reserved. doi:10.1016/j.brainresrev.2003.08.003

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5. Results of the meta-analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6. Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Conscious rest has been widely used as a baseline condition in positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) neuroimaging experiments. However, a number of recent neuroimaging studies have suggested that the activity of some brain structures can be greater during rest than during active cognitive tasks [18,21,29]. One can ask for the significance of such enhanced activity by searching cognitive processes that produce activation of the same brain regions. Using results from the literature and a metaanalysis involving five PET experiments which paradigm included a resting state condition, we compared the brain areas which are more active both during resting state and during given cognitive tasks. A good agreement is noticed between the locations of brain areas exhibiting high activity during resting state and when subjects perform self-referential tasks.

1. Search for the self in neuroimaging Defining the concept of self, in general, remains a challenging problem because no universal definition can be proposed. From an experimental point of view, we have to define the self in a more restrictive sense. Churchland [7] proposed that ‘‘The self thus turns out to be identifiable not with a nonphysical soul, but rather with a set of representational capacities of the physical brain’’. This justifies the definition and use of experimental paradigms dedicated to the search for brain correlates of mental processes involving the self. However, in the past 10 years, only a relatively limited number of neuroimaging studies (PET or fMRI) have searched for a brain correlate of self-referential processing. These few reports can be classified according to the nature of the cognitive function included in the experimental design: Emotion: The earliest neuroimaging study which explicitly distinguishes between externally and internally directed tasks was performed by Reiman et al. [37]. The aim of this experiment was to identify the brain correlates of externally versus internally generated emotion. Very comparable paradigms were recently used in other reports [21,27]. Introspective ability: Three recent studies were designed to explore the brain correlates of tasks requiring knowledge of, and reflection on the subjects’ own abilities, traits and attitudes [23,25,45]. Autobiographical memory: Autobiographical memory (also subsumed under episodic memory) is supposed to

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deal with individual. A mnemonic superiority resulting from material relating to the self is widely recognized (see Ref. [42] for review). Brain correlates specific to autobiographical memory have been studied both for encoding [8] and retrieval [12]. Face recognition: The perception of one’s own face compared to perception of another’s unknown face [24,26]. Independent thought: MacGuire et al. [28] have developed a paradigm allowing the detection of brain correlates of the frequency of independent thoughts’ occurring while subject concurrently performed different sets of cognitive tasks [28]. Each of these neuroimaging studies has revealed different networks of brain areas which activity was greater during self-referential processes as compared to externally directed processes. If one accepts the idea that a specific network of brain areas is dedicated to the representation of the self, this network should include the areas common to all the networks found in all the experiments described above. It appears that only one region meets this criteria: the medio-dorsal frontal cortex bilaterally (MDFC). This region includes Brodmann areas 8 –10 and can be extended to the anterior cingulate gyrus (Fig. 2).

2. The resting state in neuroimaging In most brain imaging studies, using positron emission tomography (PET) or functional magnetic resonance imaging (fMRI), specific activity is completed as the result of subtraction between activities obtained during two different tasks. Generally, the brain activity during a control task, considered as a baseline, is subtracted from the brain activity related to a given cognitive task. Results of such a comparison depend heavily on the choice of an appropriate control state. The choice of a wise control task is relatively easy when the experiment is designed to study the activity in primary sensory areas (e.g., the effect of two distinct visual stimuli on primary visual areas). However, the choice is made more difficult for high-level cognitive tasks implying integrative areas (e.g., the effect of deductive reasoning on prefrontal cortex). This problem has been emphasised in two recent publications [20,41]. Conscious rest has been widely used as a control/baseline condition. Most often, rest state is defined as a state that differs from the active state both in terms of condition (open/closed eyes, absence/presence of a stimulus input) and in terms of instructions given to the subject. Instruc-

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tions probably define more accurately (e.g., ‘‘do not take care of the perceptual input from the world’’) a rest state than the stimulus per se. A rest state can therefore be used in a wide variety of experiments. However, it is an illdefined mental state because it may vary both from one subject to another and within the same subject. A challenging question concerns areas whose activity has been reported to be higher during the resting state compared to an active condition. Shulman et al. [40] performed a metaanalysis including nine neuroimaging experiments where passive visual perception (considered as a resting state) was compared to detailed processing of a visual image. A greater rCBF increase was reported in the parietal, precuneus and prefrontal cortex in the case of passive viewing. More recently, Mazoyer et al. [29] performed a new meta-analysis with experiments including protocols using both auditory and visual inputs. Results were consistent with the study by Shulman et al. [40], except for a prevalence of activity in the left hemisphere. A recent publication reported protocol specifically devoted to the comparison of brain activity during resting state and goal-directed state [2].

3. Brain areas exhibiting a greatest activity during resting state: a meta-analysis The present paper reports on the result of a meta-analysis including five previously published neuroimaging studies. In all studies, tasks engaged subjects in complex, elaborated cognitive processes. Tasks included the following: attribution of intention, judgement of stimulus pleasantness, discrimination of spatial attributes, judgement of other peoples’ belief and passive perception of other’s gaze behaviour [3,11,38,39,44].

4.3. Experimental conditions Experimental conditions will be only briefly described here. For detailed description, see original reports (references in Table 1). Experiment 1: Subjects performed a matching test requiring the discrimination of simultaneously presented objects based on one of their spatial properties. Experiment 2: Subjects were presented with three pictures of comic strips and had to make a choice about the most appropriate fourth picture. The choice was based on attribution of intention or physical logic. Experiment 3: Subjects (medical students) were presented with sentences stating medical assertions. They had to judge the truthfulness of the statement from their own point of view or from the point of view of a ‘‘lay’’ person. Experiment 4: Subjects had to rate the pleasantness of olfactory, visual or auditory stimuli. Experiment 5: Subjects were presented with video sequences of faces featuring, respectively, switch from averted gaze to eye contact, averted gazes, or eyes closed (no gaze condition). In all experiments, subjects were told to relax and to think of nothing in particular during the rest condition. 4.4. Data analysis The data were analysed with the SPM99 software (www.fil.ion.ucl.ac.uk) and with some additional software implemented with Matlab. 4.4.1. Image pre-processing An intrasubject registration was performed in order to correct for motion between scans within a subject’s PET session. Image sets for each subject were spatially normalized to the Montreal Neurological Institute (MNI) template and were then 3D smoothed with a 12-mm Gaussian filter.

4. Materials and methods 4.1. Subjects All subjects gave their written informed consent and were paid for their participation. Experiments were conducted in accordance with the Declaration of Helsinski.

4.4.2. Conjunction analysis The resting state condition was compared to the other conditions using a multigroup conjunction analysis as implemented in SPM99. We also performed a random effect analysis within each experiment that leads to one contrast ‘‘resting state versus alternative condition’’ per experiment. The intersection of these five contrasts allows the determi-

4.2. Data acquisition PET scans were performed with subjects lying supine. Head position was maintained by the use of an individually moiled foam headrest. PET scans were obtained using a Siemens CTI HR+ tomograph. The system allows 63 continuous transaxial slices with an axial resolution of 4.1 mm and a transverse resolution of 4.4 mm. Data were collected during a 60-s period starting approximately 20 s after the injection of a H215O (9 mCi per injection) which served as CBF tracer.

Table 1 Description of the TEP experiments included in the meta-analysis References

No. of subjects

Nature of task

(1) (2) (3) (4) (5)

7 8 10 7 10

matching objects according to spatial attributes attribution of intention judgement of other peoples’ belief judgement of the stimulus pleasantness perception of gaze

[11] [3] [39] [38] [44]

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Table 2 Location of rCBF increases during resting state as compared to the other tasks in each of the five studies included in the meta-analysis Location

R/L

BA

Anterior cingulate Anterior cingulate Middle frontal Middle frontal Superior frontal Middle frontal

R R L R R L

32 32 10 10 8, 9 8, 9

x

y 4 2 24 32 22 28

z

44 32 46 50 36 24

2 10 14 4 34 42

T

Z equivalent

p-corrected

Extent

t min

2.63 2.66 2.03 3.48 2.39 2.81

6.92 7.02 5.74 >10 6.47 7.33

< 0.001 < 0.001 0.001 < 0.001 < 0.001 < 0.001

15 19 25 165 18 105

2.02 1.90 2.49 2.65 1.82 3.09

BA: Brodmann’s areas. x, y, z are given in the coordinates relative to the template from the MNI. T, Z, p-corrected are calculated using multigroup conjunction analysis from SPM99 software. Extents are given in voxels (2  2  2 mm). t min is the minimum of the five t-contrasts (resting state minus conditions) obtained for the different studies.

nation of the minimum t value obtained through the five experiments.

0.05 (uncorrected). This showed that in all five experiments rCBF was significantly higher in the resting state than in the active condition.

5. Results of the meta-analysis 6. Discussion Results are reported in Table 2 and Fig. 1. Conjunction analysis of the PET data revealed multiple foci of significant rCBF increases during resting state compared to the others tasks. Two maxima were revealed bilaterally along the superior frontal sulcus. The first one is located ventrally in the anterior part of the superior frontal sulcus (BA 10) whereas the second focus is more dorsal (BA 8/9). Another rCBF increase is observed in the anterior cingulate gyrus. As conjunction analysis could be not conservative enough, we decided to perform further analysis. A tcontrast (resting state minus other tasks) was calculated within each of the 5 experiments using a random effect model. For all clusters reported in Table 2, the minimum tvalue (defined as the lowest t-value obtained for the five different experiments) corresponded to a risk lower than

The present paper reports the results of a meta-analysis including five previously published studies where subjects were engaged in elaborated processes such as attribution of intention, judgement of stimulus pleasantness, discrimination of spatial attributes, judgement of other peoples’ belief and passive perception of other’s gaze behaviour [3,11,38,39,44]. The meta-analysis reveals a network of brain areas that exhibited a greater activity during a conscious resting state than during active tasks. The highlighted network is restricted to prefrontal and anterior cingulate cortices. These results contrast with those of two previous meta-analysis that revealed, in addition to similar foci in the prefrontal cortex, some other areas exhibiting a greater activity when comparing resting state or passive viewing to active tasks [29,40]. These areas

Fig. 1. Location of the areas where rCBF is greater when resting state was compared to others conditions. Figure shows the voxels where a significant ( p < 0.05) increase was detected in each of the five experiments. The voxels were superimposed on the MRI template from the MNI. Left panel: coronal and axial section; right panel: front view of the pseudo-3D render.

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included angular gyrus, anterior cingulate cortex and precuneus. A first obvious explanation of this difference could be that our analysis was more conservative because of the method and significance threshold we used. However, it seems unlikely because we used the same method as in Mazoyer et al. [29], which is less conservative than the method used in Shulman et al. [40]. Moreover, as prefrontal cortex were not the region of the greatest activity in the previous meta-analysis, a more conservative analysis should have excluded activity of these areas in our study. A more likely hypothesis is that active tasks included in the present meta-analysis involved cognitive

processes of different nature from those included in Mazoyer et al.[29] or Shulman et al. [40]. Our analysis revealed foci located in the dorso-medial prefrontal cortex, along the superior frontal sulcus. In line with this result, the two meta-analysis described above [29,40] and a detailed review [20] also pointed out the MDFC as the seat of greater activity when comparing rest to the other tasks. As a degree of anatomo-functional specificity has been suggested within the prefrontal cortex [30], we compared the location of the region whose activity appeared greater during resting state with the locations of regions activated during others tasks known to involve

Fig. 2. Location of the activation derived from literature compared to the foci revealed by the meta-analysis. The red lines surround the areas whose voxels exhibit a greater activity during resting state than during the tasks used in the five studies included in our meta-analysis [3,11,38,39,44]. Each colored dot corresponds to the location of the activations described in the literature. The dots indicate the location of the voxel exhibiting the greatest significance. Color of the representative point is given according the nature of the task and the references of publications are as follows: Theory of mind: Castelli et al. [5]; Fletcher et al. [13]; Gallagher et al. [14]; Goel et al. [15]; Keenan et al. [24]; MacGuire et al. [28]; Nichelli et al. [31]; Vogelay et al. [43]. Memory: Burgess et al. [4]; Donaldson et al. [9]; Prabhakaran et al. [35]. Attention: Banich et al. [1]; Dove et al. [10]; Gruber et al. [19]; Pochon et al. [34]; Rees et al. [36]. Reasoning: Christoff et al. [6]; Goel et al. [16]; Houde´ et al. [22]; Partiot et al. [32]; Paulus et al. [33]. Increase during rest: Binder et al. [2]; Mazoyer et al. [29]; Shulman et al. [40]. Self-referential mental activity: Churchland [7]; Craik et al. [8]; Fink et al. [12]; Gusnard et al. [21]; Johnson et al. [23]; Keenan et al. [24]; Kelley et al. [25]; Kircher et al. [26]; MacGuire et al. [28]; Reiman et al. [37]; Zysset et al. [45].

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prefrontal cortex. Indeed, a wide variety of studies engaging subjects in tasks such as selective attention, working memory, rule- and goal-directed behaviour have reported an activation of this part of the prefrontal cortex. Fig. 2 shows the location of foci of rCBF increases reported in these different studies. Only the voxel corresponding to the maximum significance is given because the locations of all the voxels that constitute the activated area are not available in the publications. When comparing these locations with the clusters obtained in our meta-analysis, one has to consider that the corresponding activated areas should be substantially larger than this unique dot representing the voxel at maximum. We distinguished four kinds of cognitive processes: externally focused attention, memory, general reasoning, theory of mind and self-referential tasks. Some points must be highlighted: – dorsal prefrontal clusters linked to attentional tasks are located more laterally (BA 46, yellow in Fig. 2) than our rest-related cluster. These tasks included preparation of forthcoming actions, task switching, mental calculation, self-recognition and visual attention [1,10,19,34] which consequently suggests that this part of the prefrontal cortex might exert a top-down control on more primary areas [36]. – by contrast, the clusters described in our analysis appear at a location similar to clusters of activations related to tasks such as general reasoning (purple in Fig. 2: inductive reasoning, decision making in presence of uncertainty, and relational integration [6,16,22,32,33]); tasks related to memory (blue in Fig. 2: working memory [35] or recognition memory [4,9]); tasks related to theory of mind (orange in Fig. 2: judgment about another’s knowledge about the function of objects, understanding of scripts and stories with an intentional content, movement interpretation, or retrieval of the spatial context of lifelike events [5,13 – 15,17,31,43]. – it is worth noting here that all these experimental paradigms have a common characteristic. Indeed, in all studies, tasks of interest have been compared to a control task where subjects had to direct their attention towards an external stimulus, i.e., fixate on a fixation cross or perform a very basic task like perceiving and recognising a color, or a movement, which does not need the use of memory, knowledge or personal judgement. Thus, previous data on the function of this prefrontal region point to its role in internally versus externally directed processes. – this last point is confirmed by activation of the MDFC obtained by contrasting the activity during self-referential task and externally directed task (green in Fig. 2). This includes tasks related to emotion, autobiographical memory, introspective ability or face recognition. Tasks in the studies included in our meta-analysis can be considered as tasks where subjects had to direct their attention towards external stimuli. By contrast, the rest state

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can therefore be considered as a task where subjects had to direct their attention towards internal processes. This is especially true as instructions during rest conditions were often defined like ‘‘do not take care of the perceptual input from the world’’. This observation leads us to propose that the MDFC is involved when subjects are engaged in tasks that refer to internal triggered processes versus tasks that refer to external percepts (self-directed attention versus externally directed attention). In line with this proposition, most of the tasks used in the studies included in the metaanalysis (theory of mind, emotion, perspective taking) necessitate the use of internal information/knowledge about the subject’s self. It is therefore most likely that activity in the MDFC should be seen as decreasing as a function of the degree of attention that the subject has to pay to the external world. MDFC exhibits increased activity in externally directed attention compared to internally directed attention, and also exhibits increased activity in resting state compared to both externally directed and internally directed attention. Thus, we hypothesize that resting state can be considered as an ultimate state of inspection of the self. This observation will have an impact on the interpretation of neuroimaging data from the literature. With no doubt, significant rCBF increase in the MDFC revealed by the contrast between tasks involving elaborated cognitive functions and tasks involving attention to external stimuli will now have to be considered under a different point of view, i.e., not as an increase of activity but as a lower decrease from a default state activity of the brain.

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