《认知神经科学》课程教学资源（参考文献）[Buckner, R. L., Andrews-Hanna, J. R., & Schacter, D. L.（2008）]The brain's default network - Anatomy, function, and relevance to disease

The Brain's Default Network Anatomy,Function,and Relevance to Disease RANDY L.BUCKNER,JESSICA R.ANDREWS-HANNA, AND DANIEL L.SCHACTER -Department of Psycholog,Harvard University,Cambridge,Massachusetts,USA Center for Brain Science,Harvard University,Cambridge,Massachusetts,USA Athinoula A.Martinos Center for Biomedical Imaging.Massachusetts General Hospital Boston,Massachusetts,USA tment of Radiology,Harvard Medical School,Boston,Massachusetts,USA "Howard Hughes Medical Institute,Chevy Chase,Maryland 20815,USA Thirty years of brain imaging research has con ed to define the brain's default nety ed brain system i int modes of co ly defined b a pre y activ are ports the ginsight in fun r the futu ing t he I of oth omy The m dial te al lobe su inf tal s the ant me The two sub of the al obs L C igat inte twork for understanding mental disorders including autism,sc phrenia.and alzheimer's rdefauit mode default system;default netor MRI;PET;hippocampus;memoryi zophrenia;Alzheime A common observation in brain imaging research within the default network (Buckner Carroll 2007) is that a specific set of brain regionsreferred to as ations prompt one to ask such question ecngagrdtcndidala mmon?and what is the significanice of t al 2001 Raichle this network to adaptive function?The default net ing this phenomenon further reveals that other kinds of situations,beyond freethinking,engage the default net- non to c work.For example,remembering the past,envisioning be important to understanding discases of the mind (eg,Lustig et al.2003,Greicius et al.2004,Kennedy et a 2006.Bluhm et al.2007). Address for

The Brain’s Default Network Anatomy, Function, and Relevance to Disease RANDY L. BUCKNER, a,b,c,d,e JESSICA R. ANDREWS-HANNA, a,b,c AND DANIEL L. SCHACTERa aDepartment of Psychology, Harvard University, Cambridge, Massachusetts, USA bCenter for Brain Science, Harvard University, Cambridge, Massachusetts, USA c Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Boston, Massachusetts, USA dDepartment of Radiology, Harvard Medical School, Boston, Massachusetts, USA eHoward Hughes Medical Institute, Chevy Chase, Maryland 20815, USA Thirty years of brain imaging research has converged to define the brain’s default network—a novel and only recently appreciated brain system that participates in internal modes of cog￾nition. Here we synthesize past observations to provide strong evidence that the default net￾work is a specific, anatomically defined brain system preferentially active when individuals are not focused on the external environment. Analysis of connectional anatomy in the monkey sup￾ports the presence of an interconnected brain system. Providing insight into function, the default network is active when individuals are engaged in internally focused tasks including autobio￾graphical memory retrieval, envisioning the future, and conceiving the perspectives of oth￾ers. Probing the functional anatomy of the network in detail reveals that it is best understood as multiple interacting subsystems. The medial temporal lobe subsystem provides informa￾tion from prior experiences in the form of memories and associations that are the building blocks of mental simulation. The medial prefrontal subsystem facilitates the flexible use of this information during the construction of self-relevant mental simulations. These two sub￾systems converge on important nodes of integration including the posterior cingulate cortex. The implications of these functional and anatomical observations are discussed in relation to possible adaptive roles of the default network for using past experiences to plan for the fu￾ture, navigate social interactions, and maximize the utility of moments when we are not oth￾erwise engaged by the external world. We conclude by discussing the relevance of the default network for understanding mental disorders including autism, schizophrenia, and Alzheimer’s disease. Key words: default mode; default system; default network; fMRI; PET; hippocampus; memory; schizophrenia; Alzheimer Introduction A common observation in brain imaging research is that a specific set of brain regions—referred to as the default network—is engaged when individuals are left to think to themselves undisturbed (Shulman et al. 1997, Mazoyer et al. 2001, Raichle et al. 2001). Prob￾ing this phenomenon furtherreveals that other kinds of situations, beyond freethinking, engage the default net￾work. For example, remembering the past, envisioning Address for correspondence: Dr. Randy Buckner, Harvard University, William James Hall, 33 Kirkland Drive, Cambridge, MA 02148. rbuckner@wjh.harvard.edu future events, and considering the thoughts and per￾spectives of other people all activate multiple regions within the default network (Buckner & Carroll 2007). These observations prompt one to ask such questions as: What do these tasks and spontaneous cognition share in common? and what is the significance of this network to adaptive function? The default net￾work is also disrupted in autism, schizophrenia, and Alzheimer’s disease, further encouraging one to con￾sider how the functions of the default network might be important to understanding diseases of the mind (e.g., Lustig et al. 2003, Greicius et al. 2004, Kennedy et al. 2006, Bluhm et al. 2007). Motivated by these questions, we provide a com￾prehensive review and synthesis of findings about the Ann. N.Y. Acad. Sci. 1124: 1–38 (2008). !C 2008 New York Academy of Sciences. doi: 10.1196/annals.1440.011 1

2 Annals of the New York Academy of Science brain's default network.This review covers both ba sic science and clinical observations,with its content organized across five sections.We begin with a brief nalysis of the anatomy rn the role of the default rk in task settings(section IV).While recognizing alterna- tive possibilities,we hypothesize that the fundamental an 1 isto faciltate GuREl.Aheotinegeotfregonalcerebralblbod ents before they ha The final s gevidence that relates the default network to cognitive disorders,including ged over e the possibility that activity in the default network aug gvar'sonian ments a metabol cascade that is conducive to the development of Alzheimer's disease (section V). 7ATg7gh98gmesdcuadinthieiewege I.A Brief History mcta the brain's defaul suggests th e rest state conta when individuals solve externally administered math problems. brain activity in humans during undire ted menta The Swedish brain physiologist David Ingvar was states.Even though no early studies were explicitly de- the first to aggregate imaging findings from rest task signed to explore such unconstrained states,relevant tes and note the importance ot data were nonetheless acquired because of the com- 1974, rest o CBE I nd hi s observed that frontal activity reached high levels during rest states(FIG.1).To explain this une most goal-direeted tasks.In almost all cascs.the lo pected phenomenon,Ingvar proposed that the "h ration of activity during the control states occurred as perfrontal"pattern of activity corresponded"to und an afterthought- -as part of reviews and meta-analyses tancous,con 3101 performed subsequent to the original reports,which a one un fr urbe focused on the goal-directed task 1031 Early Observations his work established that the brain is not idle when lef A clue that brain activity persists during undirected undirected.Rather,brain activity persists in the ab sence of external task direction.Second,Ingvar's ob wa 19 vations suggested that increased activity during res /1055 sed the ket-Schmidt nitr Schmidt 1948)to ask whether cerebral metabolism The Era of Task-Induced Deactivation changes globally when one goes from a quiet rest state Ingvar's ideas about resting brain activity remained largely unexplored for the next decade until positron on tomography (PE 1) ds for ain imag ing gained promi had finer resolution an

2 Annals of the New York Academy of Sciences brain’s default network. This review covers both ba￾sic science and clinical observations, with its content organized across five sections. We begin with a brief history of our understanding of the default network (section I). Next, a detailed analysis of the anatomy of the default network is provided including evidence from humans and monkeys (section II). The follow￾ing sections concern the role of the default network in spontaneous cognition, as commonly occurs in passive task settings(section III), aswell asitsfunctionsin active task settings (section IV). While recognizing alterna￾tive possibilities, we hypothesize that the fundamental function of the default network is to facilitate flexi￾ble self-relevant mental explorations—simulations— that provide a means to anticipate and evaluate up￾coming events before they happen. The final section of the review discusses emerging evidence that relates the default network to cognitive disorders, including the possibility that activity in the default network aug￾ments a metabolic cascade that is conducive to the development of Alzheimer’s disease (section V). I. A Brief History The discovery of the brain’s default network was entirely accidental. Evidence for the default network began accumulating when researchers first measured brain activity in humans during undirected mental states. Even though no early studies were explicitly de￾signed to explore such unconstrained states, relevant data were nonetheless acquired because of the com￾mon practice of using rest or other types of passive conditions as an experimental control. These stud￾ies revealed that activity in specific brain regions in￾creased during passive control states as compared to most goal-directed tasks. In almost all cases, the explo￾ration of activity during the control states occurred as an afterthought—as part of reviews and meta-analyses performed subsequent to the original reports, which focused on the goal-directed tasks. Early Observations A clue that brain activity persists during undirected mentation emerged from early studies of cerebral metabolism. It was already known by the late 19th century that mental activity modulated local blood flow(James 1890). Louis Sokoloff and colleagues(1955) used the Kety-Schmidt nitrous oxide technique (Kety & Schmidt 1948) to ask whether cerebral metabolism changes globally when one goes from a quiet rest state to performing a challenging arithmetic problem—a task that demands focused cognitive effort. To their surprise, metabolism remained constant. While not FIGURE 1. An early image of regional cerebral blood flow (rCBF) at rest made by David Ingvar and colleagues using the nitrous oxide technique. The image shows data av￾eraged over eight individuals to reveal a “hyperfrontal” ac￾tivity pattern that Ingvar proposed reflected “spontaneous, conscious mentation” (Ingvar 1979). Ingvar’s ideas antici￾pate many of the themes discussed in this review (see Ingvar 1974, 1979, 1985). their initial conclusion, the unchanged global rate of metabolism suggests that the rest state contains persistent brain activity that is as vigorous as that when individuals solve externally administered math problems. The Swedish brain physiologist David Ingvar was the first to aggregate imaging findings from rest task states and note the importance of consistent, region￾ally specific activity patterns(Ingvar 1974, 1979, 1985). Using the xenon 133 inhalation technique to measure regional cerebral blood flow (rCBF), Ingvar and his colleagues observed that frontal activity reached high levels during rest states (FIG. 1). To explain this unex￾pected phenomenon, Ingvar proposed that the “hy￾perfrontal” pattern of activity corresponded “to undi￾rected, spontaneous, conscious mentation, the ‘brain work,’whichwe carry outwhen left alone undisturbed” (Ingvar 1974). Two lasting insights emerged from Ing￾var’s work. First, echoing ideas of Hans Berger (1931), his work established that the brain is not idle when left undirected. Rather, brain activity persists in the ab￾sence of external task direction. Second, Ingvar’s ob￾servations suggested that increased activity during rest is localized to specific brain regions that prominently include prefrontal cortex. The Era of Task-Induced Deactivation Ingvar’s ideas about resting brain activity remained largely unexplored for the next decade until positron emission tomography (PET) methods for brain imag￾ing gained prominence. PET had finer resolution and

Buckner et al.:The Brain's Default Network uctures tha (Raichle 1987) ed tha cluded ma sk and co ed to iso.By the mid-vdomgin nonmemory control.In addition.to better understand were completed that examined perception,language, the cognitive processes associated with the rest state attention,and memory.Sca ns of rest-state brain ac they informally asked their participants to subjectively tivity were often acquired across these studies for a describe their mental experiences and re ongiated from this work tha what a the tim in fact at nd c onsists of a mixt The term "deactivation"was used because analyses of freely wandering past recollection,future plans,and and image visualization were referenced to the target, other personal thoughts and experiences."Second,the experimental task.Within this nomenclature,region more active in the target condi ton (c.g..rca onsas well a a distin post g d"n ation nia h stcm at isc nsistently activated in humans durin csent and often the most robust efTect in many carly ndirected mental states Broad awareness of the common regions that be interest emerged was activity reductions in unattended come active during passive task states emerged with of its a pair of meta-analyses that pooled extensive data to 1994.Buc (e.g 19 unction 1g0 sis oftask-induced de active as to explicitly determine if there were com on hrain re pared to passive task conditions.There was no initial rions active during undirected (passive)mental states They pooled data from 132 normal adults for which an r et al.19 part was cor ctc.)coul lirectly compar I to a pa pres he sa e state for an autobic phical men ctal.2001) ted data a ory task Andreasen and colleagues (1995)expl mal adults that included both visually and aurally cued the possibility that spontancous cognition makes an active tasks as compared to passive rest conditions important contribution to rest states.Much like other These two analyses revealed a remarkably consis studies at the time,the researchers included a rest con tent set of brain regions that were more actrve during n to their target co con ditio h rimental targct of the stud ns)The sults of the Shulman t al (1997)me ternally directed cognition much like the ntaneous analysis are shown in This image displays cognition that occurs during"rest"states.For this rea the full cortical extent of the brain's default network son.Andreasen and colleagues explored both the rest The broad generality of the rest activity pattern across any diverse studies reinforced the intriguing pos ty that a c this idea.ag the tes.Mo ed by ct2001) tor in the b thought by asking pants to describe their musings following the scanned y rest periods.Paralleling the informal observations by

Buckner et al.: The Brain’s Default Network 3 sensitivity to deep-brain structures than earlier meth￾ods and, owing to the development of isotopes with short half-lives (Raichle 1987), typical PET studies in￾cluded many task and control conditions for compar￾ison. By the mid-1990s several dozen imaging studies were completed that examined perception, language, attention, and memory. Scans of rest-state brain ac￾tivitya were often acquired across these studies for a control comparison, and researchers began routinely noticing brain regions more active in the passive con￾trol conditions than the active target tasks—what at the time was referred to as “deactivation.” The term “deactivation” was used because analyses and image visualization were referenced to the target, experimental task. Within this nomenclature, regions relatively more active in the target condition (e.g., read￾ing, classifying pictures) compared to the control task (e.g., passive fixation, rest) were labeled “activations”; regions less active in the target condition than the con￾trol were labeled “deactivations.” Deactivations were present and often the most robust effect in many early PET studies. One form of deactivation for which early interest emerged was activity reductions in unattended sensory modalities because of its theoretical relevance to mechanisms of attention (e.g., Haxby et al. 1994, Kawashima et al. 1994, Buckner et al. 1996). A second form of commonly observed deactivationwas along the frontal and posterior midline during active, as com￾pared to passive, task conditions. There was no initial explanation for these mysterious midline deactivations (e.g., Ghatan et al. 1995, Baker et al. 1996). A particularly informative early study was con￾ducted while exploring brain regions supporting episodic memory. Confronted with the difficult issue of defining a baseline state for an autobiographical mem￾ory task, Andreasen and colleagues (1995) explored the possibility that spontaneous cognition makes an important contribution to rest states. Much like other studies at the time, the researchers included a rest con￾dition as a baseline for comparison to their target con￾ditions. However, unlike other contemporary studies, they hypothesized that autobiographical memory (the experimental target of the study) inherently involves in￾ternally directed cognition, much like the spontaneous cognition that occurs during “rest” states. For this rea￾son, Andreasen and colleagues explored both the rest aPET and functional MRI (fMRI) both measure neural activity indi￾rectly through local vascular (blood flow) changes that accompany neu￾ronal activity. PET is sensitive to changes in blood flow directly (Raichle 1987). fMRI is sensitive to changes in oxygen concentration in the blood which tracks blood flow (Heeger and Ress 2002). For simplicity, we refer to these methods as measuring brain activity in this review. and memory tasks referenced to a third control con￾dition that involved neither rest nor episodic memory. Their results showed that similar brain regions were engaged during rest and memory as compared to the nonmemory control. In addition, to better understand the cognitive processes associated with the rest state, they informally asked their participants to subjectively describe their mental experiences. Two insights originated from this work that fore￾shadow much of the present review’s content. First, Andreasen et al. (1995) noted that the resting state “is in fact quite vigorous and consists of a mixture of freely wandering past recollection, future plans, and other personal thoughts and experiences.” Second, the analysis of brain activity during the rest state revealed prefrontal midline regions as well as a distinct poste￾rior pattern that included the posterior cingulate and retrosplenial cortex. As later studies would confirm, these regions are central components of the core brain system that is consistently activated in humans during undirected mental states. Broad awareness of the common regions that be￾come active during passive task states emerged with a pair of meta-analyses that pooled extensive data to reveal the functional anatomy of unconstrained cogni￾tion. In the first study, Shulman and colleagues (1997) conducted meta-analysis of task-induced deactivations to explicitly determine if there were common brain re￾gions active during undirected (passive) mental states. They pooled data from 132 normal adults for which an active task (word reading, active stimulus classification, etc.) could be directly compared to a passive task that presented the same visual words or pictures but con￾tained no directed task goals. Using a similar approach, Mazoyer et al. (2001) aggregated data across 63 nor￾mal adults that included both visually and aurally cued active tasks as compared to passive rest conditions. These two analyses revealed a remarkably consis￾tent set of brain regions that were more active during passive task conditions than during numerous goal￾directed task conditions (spanning both verbal and nonverbal domains and visual and auditory condi￾tions). The results of the Shulman et al. (1997) meta￾analysis are shown in FIGURE 2. This image displays the full cortical extent of the brain’s default network. The broad generality of the rest activity pattern across so many diverse studies reinforced the intriguing pos￾sibility that a common set of cognitive processes was used spontaneously during the passive-task states. Mo￾tivated by this idea, Mazoyer et al. (2001) explored the content of spontaneous thought by asking partici￾pants to describe their musings following the scanned rest periods. Paralleling the informal observations by

Annals of the New York Academy of Sciences conditions were simply too unconstrained to be useful as control states.Richard Frackowiak summarized this widely held concern:"To call a'free-wheeling'state, or even a state where you are hxating on a cross and is to my mind quite wrongr and Fletcher 2007.Buckner Vincent 2007.Raichle Snyder 2007).As a result of this uneasiness in inter preting passive task conditions,beyond the few earlier studies mentioned,there was a general trend not to thoroughly report or discuss the meaning of rest state tically ard et al.2001) Their papers directly considered the empirical and theoretical implications of defining baseline states and what the specific pattern of activity in the default net- work might represent.Several lasting consequences on dE. FIGURE 2.The brain's default network was originally default network from other forr cluding attenuation of activity in unattended sensory The areas).Second,they compiled a considerable array of egions lin ork and what thei alzed in Buckner e al)mges show the st a n.A key ir ulation-ave tthe m the defa 20051.Blue regions m sing (Gusnard ct al.2001 task seltings. Gusnard Raichle 2001).Most importantly,the pa- Ingvar and Andreasen et al..they noted that the im. aged rest state is associated with lively mental activity nding its nan me,which,as oflate 2007 that includes "generation and manipulation of men es).u 1.1 tal images,reminiscence of past experiences based on ng plan ntially reported to be studied as a fundamental neurobiological system with physiological and cognitive properties that distin- Emergence of the Default Network as Its Own Research Area work is a brain system much like the ations by Raichle Gu 2001).A dominant theme in the field during the pre- in the liter vious decade concerned how to define an appropriate baseline condition for ncuroimaging studies This focus r(1995). on the ving con-

4 Annals of the New York Academy of Sciences FIGURE 2. The brain’s default network was originally identified in a meta-analysis that mapped brain regions more active in passive as compared to active tasks (of￾ten referred to as task-induced deactivation). The displayed positron emission tomography (PET) data include nine stud￾ies (132 participants) from Shulman et al. (1997; rean￾alyzed in Buckner et al. 2005). Images show the me￾dial and lateral surface of the left hemisphere using a population-averaged surface representation to take into ac￾count between-subject variability in sulcal anatomy (Van Es￾sen 2005). Blue represents regions most active in passive task settings. Ingvar and Andreasen et al., they noted that the im￾aged rest state is associated with lively mental activity that includes “generation and manipulation of men￾tal images, reminiscence of past experiences based on episodic memory, and making plans” and further noted that the subjects of their study “preferentially reported autobiographical episodes.” Emergence of the Default Network as Its Own Research Area The definitive recent event in the explication of the default network came with the a series of publi￾cations by Raichle, Gusnard, and colleagues (Raichle et al. 2001, Gusnard & Raichle 2001, Gusnard et al. 2001). A dominant theme in the field during the pre￾vious decade concerned how to define an appropriate baseline condition for neuroimaging studies.Thisfocus on the baseline state was central to the evolving con￾cept of a default network. Many argued that passive conditions were simply too unconstrained to be useful as control states. Richard Frackowiak summarized this widely held concern: “To call a ‘free-wheeling’ state, or even a state where you are fixating on a cross and dreaming about anything you like, a ‘control’ state, is to my mind quite wrong” (Frackowiak 1991). (For recent discussion of this ongoing debate see Morcom and Fletcher 2007, Buckner & Vincent 2007, Raichle & Snyder 2007). As a result of this uneasiness in inter￾preting passive task conditions, beyond the few earlier studies mentioned, there was a general trend not to thoroughly report or discuss the meaning of rest state activity. Raichle,Gusnard, and colleaguesreversed thistrend dramatically with three papers in 2001 (Raichle et al. 2001, Gusnard & Raichle 2001, Gusnard et al. 2001). Their papers directly considered the empirical and theoretical implications of defining baseline states and what the specific pattern of activity in the default net￾work might represent. Several lasting consequences on the study of the default network emerged. First, they distinguished between various forms of task-induced deactivation and separated deactivations defining the default network from other forms of deactivation (in￾cluding attenuation of activity in unattended sensory areas). Second, they compiled a considerable array of findings that drew attention to the specific anatomic regions linked to the default network and what their presence might suggest about its function. A key in￾sightwasthat the medial prefrontalregions consistently identified as part of the default network are associated with self-referential processing (Gusnard et al. 2001, Gusnard & Raichle 2001). Most importantly, the pa￾pers brought to the forefront the exploration of the default network as its own area of study (including pro￾viding its name, which, as of late 2007, has appeared as a keyword in 237 articles). Our use of the label “default network” in this review stems directly from their label￾ing the baseline rest condition as the “default mode.”b Their reviews made clear that the default network is to be studied as a fundamental neurobiological system with physiological and cognitive properties that distin￾guish it from other systems. The default network is a brain system much like the motor system or the visual system. It contains a set of interacting brain areas that are tightly functionally bReferences to the default mode appear in the literature on cognition prior to the introduction of the concept as an explanation for neural and metabolic phenomena. Giambra (1995), for example, noted that “Task￾unrelated images and thoughts may represent the normal default mode of operation of the self-aware.” Thus, the concept of a default mode is converged upon from both cognitive and neurobiological perspectives

Buckner eta:The Brain's Default Network 5 TABLE 1.Core regions associated with the brain's default network REGION ABREV INCLUDED BRAIN AREAS n( connected and distinct from other systems within the comprises multiple interacting hubs and subsystems brain.In the remainder of this review,we dehne the These anatomic observations provide the foundation default network in more detail,speculate on its func- on which the upcoming sections explore the functions of the default network suggest th ork has important Blocked Task-Induced Deactivation Because PET imaging requires about a minute of ll.Anatomy of the Default Network was The anatomy of the brain's default r characterized using multiple a paches.The defaul network was originally identified by its consistent ac ivity was averaged over blocks of multiple sequential tivity increases during passive task states as compared ask trials ence the label "blocked."Shulman et al. to a wide range of active tasks (e.g,Shulman et al. (1997)and Mazoyer et al.(2001)published two semi- more recent ap- poac中tha n regions co work (Greicius et al.2003,2004).More broadly the Shulman et al 1907)and auditory and visual modal. default network is hypothesized to represent a brain ities(Mazoyer et al.2001).In total,data from 195 system (or closely interacting subsystems)involving subjects were aggregated across 18 studies in the two interacting brain areas meta-analyse should be critically informed by original data ofShulman et al omy fre of n data m)are highly similar.FIGURE3 shov aches a third meta-analysis of blocked task data from a se to defining the default network and consider the spe ries of 4 MRI data sets from 92 young-adult subjects cific anatomy that arises from these approaches in the (Shannon 2006).In this meta-analysis of fMRI data the passive tasks were all visual fixation and the active the monk y.We highlg ht two asks involved approa ork th 004Ac all th is largely consistent with available infor ation abou istent set o广rgi ns in reases activity during connectional anatomy (TABLE 1).Second,the intrin- sive tasks when individuals are left undirected to think sic architecture of the default network suggests that it to themselves

Buckner et al.: The Brain’s Default Network 5 TABLE 1. Core regions associated with the brain’s default network REGION ABREV INCLUDED BRAIN AREAS Ventral medial prefrontal cortex vMPFC 24, 10 m/10 r/10 p, 32ac Posterior cingulate/retosplenial cortex PCC/Rsp 29/30, 23/31 Inferior parietal lobule IPL 39, 40 Lateral temporal cortex† LTC 21 Dorsal medial prefrontal cortex dMPFC 24, 32ac, 10p, 9 Hippocampal formation†† HF+ Hippocampus proper,EC, PH Notes: Region, abbreviation, and approximate area labels for the core regions associated with the default network in humans. Labels correspond to those originally used by Brodmann for humans with updates by Petrides and Pandya (1994), Vogt et al. (1995), Morris et al. (2000), and Ong ¨ ur¨ et al. (2003). Labels should be considered approximate because of the uncertain boundaries of the areas and the activation patterns. †LTC is particularly poorly characterized in humans and is therefore the most tentative estimate. ††HF+ includes entorhinal cortex (EC) and surrounding cortex (e.g., parahippocampal cortex; PH). connected and distinct from other systems within the brain. In the remainder of this review, we define the default network in more detail, speculate on its func￾tion both during passive and active cognitive states, and evaluate accumulating data that suggest that un￾derstanding the default network has important clinical implications for brain disease. II. Anatomy of the Default Network The anatomy of the brain’s default network has been characterized using multiple approaches. The default network was originally identified by its consistent ac￾tivity increases during passive task states as compared to a wide range of active tasks (e.g., Shulman et al. 1997, Mazoyer et al. 2001, FIG. 2). A more recent ap￾proach that identifies brain systems via intrinsic activity correlations (e.g., Biswal et al. 1995) has also revealed a similar estimate of the anatomy of the default net￾work (Greicius et al. 2003, 2004). More broadly, the default network is hypothesized to represent a brain system (or closely interacting subsystems) involving anatomically connected and interacting brain areas. Thus, its architecture should be critically informed by studies of connectional anatomy from nonhuman pri￾mates and other relevant sources of neurobiological data. In this section, we review the multiple approaches to defining the default network and consider the spe￾cific anatomy that arises from these approaches in the context of architectonic and connectional anatomy in the monkey. We highlight two observations. First, all neuroimaging approaches converge on a similar es￾timate of the anatomy of the default network that is largely consistent with available information about connectional anatomy (TABLE 1). Second, the intrin￾sic architecture of the default network suggests that it comprises multiple interacting hubs and subsystems. These anatomic observations provide the foundation on which the upcoming sections explore the functions of the default network. Blocked Task-Induced Deactivation Because PET imaging requires about a minute of data accumulation to construct a stable image, the brain’s default network was initially characterized us￾ing blocked task paradigms. Within these paradigms, extended epochs of active and passive tasks were com￾pared to one another. During these epochs brain ac￾tivity was averaged over blocks of multiple sequential task trials—hence the label “blocked.” Shulman et al. (1997) and Mazoyer et al. (2001) published two semi￾nal meta-analyses based on blocked PET methods to identify brain regions consistently more active during passive tasks as compared to a wide range of active tasks. Tasks spanned verbal and nonverbal domains (Shulman et al. 1997) and auditory and visual modal￾ities (Mazoyer et al. 2001). In total, data from 195 subjects were aggregated across 18 studies in the two meta-analyses. FIGURE 2 displays the original data of Shulman et al. visualized on the cortical surface to illustrate the topog￾raphy of the default network; the data from Mazoyer et al. (not shown) are highly similar. FIGURE 3 shows a third meta-analysis of blocked task data from a se￾ries of 4 fMRI data sets from 92 young-adult subjects (Shannon 2006). In this meta-analysis of fMRI data, the passive tasks were all visual fixation and the active tasks involved making semantic decisions on visually presented words (data from Gold & Buckner 2002, Lustig & Buckner 2004). Across all the variations, a consistent set of regions increases activity during pas￾sive tasks when individuals are left undirected to think to themselves