Default-mode network activity distinguishes Alzheimer's disease from healthy aging: Evidence from functional mrl Michael D.Greicius Gaurav Srivastava,Allan LReiss and Vinod Menon ienes and Wahington Univery hene.MdFerry0or of brain ptatednhsant the PCC.bila ork.se nfe eral te cortex. wn de ed m the default-r nged.du (AD). ork in a we did not ind conc re other MTL structu the hippo hin ntoaataeodeiauitemodenet ate repos tud oi ggests that activi y ir 150y- ode rk not on specific biomarker for incipient AD. R eed posterio ulat (PCC)activit dings in pos tomograph n this data se ivity MR the po AD)(1-3. detect co vatio net Thi invo 6 within it and us tha AD a analys d in t the cA)to e more datade network n t e grou ee criti 名 lobe (MTL)structures, of th ork ork is abnot y(3.9).This hypothesis and the MTL()as vell as h Methods orted this the mon AD,Ab ng (19). the PCCf hould he addreed f-m us@stanford.cdu "default mode"brain network.We subsequently used a 2004 by The National Academy of Sciences of the USA www./cgi/doi/10.1073/ pNA51Mer30,2041vol.1011no.1314637-464 Default-mode network activity distinguishes Alzheimer’s disease from healthy aging: Evidence from functional MRI Michael D. Greicius†‡§, Gaurav Srivastava‡¶, Allan L. Reiss‡
††, and Vinod Menon‡
†† Departments of †Neurology and Neurological Sciences, ‡Psychiatry and Behavioral Sciences, and ¶Electrical Engineering,
Program in Neurosciences, and ††Stanford Brain Research Institute, Stanford University School of Medicine, Stanford, CA 94305-5719 Edited by Marcus E. Raichle, Washington University School of Medicine, St. Louis, MO, and approved February 4, 2004 (received for review December 23, 2003) Recent functional imaging studies have revealed coactivation in a distributed network of cortical regions that characterizes the resting state, or default mode, of the human brain. Among the brain regions implicated in this network, several, including the posterior cingulate cortex and inferior parietal lobes, have also shown decreased metabolism early in the course of Alzhei￾mer’s disease (AD). We reasoned that default-mode network activity might therefore be abnormal in AD. To test this hypoth￾esis, we used independent component analysis to isolate the network in a group of 13 subjects with mild AD and in a group of 13 age-matched elderly controls as they performed a simple sensory-motor processing task. Three important findings are reported. Prominent coactivation of the hippocampus, detected in all groups, suggests that the default-mode network is closely involved with episodic memory processing. The AD group showed decreased resting-state activity in the posterior cingu￾late and hippocampus, suggesting that disrupted connectivity between these two regions accounts for the posterior cingulate hypometabolism commonly detected in positron emission to￾mography studies of early AD. Finally, a goodness-of-fit analysis applied at the individual subject level suggests that activity in the default-mode network may ultimately prove a sensitive and specific biomarker for incipient AD. Reduced posterior cingulate cortex (PCC) activity is among the most common findings in positron emission tomography (PET) and single-photon emission computerized tomography (SPECT) studies of early Alzheimer’s disease (AD) (1–3). Other studies have shown hypometabolism in the PCC in cognitively intact subjects with genetic susceptibility to AD (4–6). Most recently, functional deactivation profiles in the PCC were shown to differ between patients with AD and healthy controls in a semantic classification task (7). The consistency with which the PCC is implicated in these studies is puzzling in that this region is not among the first to show the neuropathological changes of AD (8). The leading hypothesis is that decreased PCC activity in incipient AD reflects decreased connectivity with medial tem￾poral lobe (MTL) structures, such as the entorhinal cortex and hippocampus, which are among the first regions targeted by AD pathology (3, 9). This hypothesis is supported by data from the animal literature showing prominent connectivity between the PCC and the MTL (10–13) as well as hypometabolic changes in PCC after rhinal cortex ablation (14). Human studies have supported this hypothesis as well (15–17). Although the PCC shows decreased resting-state activity in incipient AD, it tends to be among the most metabolically active regions in healthy subjects resting with their eyes closed (18). Furthermore, the PCC is among the most commonly ‘‘deacti￾vated’’ brain regions, often showing increased activity during rest or a cognitively simple baseline task compared to a cognitively demanding experimental task (19). This combination of at￾tributes led Raichle et al. (18) to propose that the PCC forms part of a ‘‘default mode’’ brain network. We subsequently used a functional connectivity analysis of functional MRI (fMRI) data to demonstrate significant resting-state coactivation of several regions within this putative network, including the PCC, bilateral inferior parietal cortex, left inferolateral temporal cortex, and ventral anterior cingulate cortex (20). We also demonstrated that the default-mode network persisted, virtually unchanged, during a sensory task with little cognitive demand (passive viewing of a flashing or still checkerboard). Although we detected a small cluster of coactivation within the most posterior aspect of the parahippocampal gyrus, we did not find conclusive evidence, at a field strength of 3 T, for connectivity between the PCC and other MTL structures such as the hippocampus or entorhinal cortex. Nonetheless, the prominent role of the PCC in this network led us to suspect that it might be abnormal in AD. To test our hypothesis that the default-mode network might be abnormal in AD, we examined a dataset (#2-2000-1118W) from the fMRI data center (www.fmridc.org), an international repos￾itory of freely accessible raw fMRI data. These data were generously contributed by Buckner et al. (21), who studied healthy young subjects, healthy elderly subjects, and patients with very mild to mild AD during a simple sensory-motor task. Having previously detected the default-mode network not only during an eyes-closed resting condition but also during a simple visual processing task, we reasoned that the minimal cognitive requirements of this sensory-motor task would not disrupt the default-mode network, and that it would therefore be detectable in this data set. In our previous study, we used a functional connectivity MRI analysis to detect coactivation in the network. This involves specifying a region-of-interest (ROI), averaging the time series of all of the voxels within it and using that time series as a covariate of interest in a whole-brain linear regression statistical parametric analysis. In the current study, we adapted indepen￾dent component analysis (ICA) to derive the default-mode network in a more data-driven fashion (i.e., without requiring a priori specification of a seed region). Examination of the default￾mode network in these groups revealed three critical findings: there is significant coactivation of the hippocampus in the default-mode network, the network is abnormal in the mildest stages of AD compared to healthy aging, and network activity holds potential as a noninvasive biomarker of incipient AD. Methods As a proof of concept, we first applied ICA to our previously published resting-state data (referred to herein as Stanford This paper was submitted directly (Track II) to the PNAS office. Abbreviations: AD, Alzheimer’s disease; DLPFC, dorsolateral prefrontal cortex; ICA, inde￾pendent component analysis; PCC, posterior cingulate cortex; ROI, region of interest; fMRI, functional MRI; MTL, medial temporal lobe; SPECT, single-photon emission computerized tomography; PET, positron-emission tomography. §To whom correspondence should be addressed. E-mail: greicius@stanford.edu. © 2004 by The National Academy of Sciences of the USA www.pnas.orgcgidoi10.1073pnas.0308627101 PNAS March 30, 2004 vol. 101 no. 13 4637–4642 NEUROSCIENCE