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...he CEN and DMN, and the dynamics of switching between these two networks. We used three functional magnetic resonance imaging (fMRI) experiments to examine the interaction between the SN, CEN, and DMN, with particular interest in the role of the FIC/ACC in regulating these networks. In the first experiment, we scanned 18 participants as they listened with focused attention to classical music symphonies inside the scanner. We analyzed brain responses during the occurrence of ‘‘movement transitions:’’ salient, orienting events arising from transitions between adjacent ‘‘movements’’ in the music (19). To specifically elucidate the role of the FIC in driving network changes, we used chronometry and Granger Causality Analysis (GCA), to provide information about the dynamics and directionality of signaling in cortical circuits (20–22). In the second experiment, we investigated the generality of network switching mechanisms involving the FIC by examining brain responses elicited during a visual “oddball” attention task (23). A third experiment examined whether the network switching mechanism could be observed during task-free resting state where there was no overt task and no behavioral respo...

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... to be accompanied by robust deactivation in the DMN at the movement transition [Fig. 1A and General Linear Model Analysis in supporting information (SI) Materials and Methods]. To further confirm that these regions constitute coherent networks, rather than isolated regional responses, we performed independent component analysis (ICA) on the task data, which revealed the existence of statistically independent CEN, SN, and DMN (Fig. 1B, see also Table S1) [ICA is a model-free analysis technique that produces a set of spatially independent components and associated time courses for each subject (25)]. In the following two sections, we examine the putative causal mechanisms involved in switching between activation and deactivation in the context of the three networks, identified above, using a combination of mental chronometry and GCA (21, 22). Latency Analysis Reveals Early Activation of the rFIC Relative to the CEN and DMN. First, we identified differences in the latency of the event-related fMRI responses across the entire brain using the method developed by Henson and colleagues (26). Briefly, this method provides a way to estimate the peak latency of the BOLD response at each voxel u...

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...al-Executive, and Default-Mode networks as assessed by Granger causality analysis revealed that the rFIC has a significantly higher net causal outflow than the CEN and DMN regions across tasks (conventions as in Fig. 2). Specifically, the rFIC had a significantly higher net causal outflow than almost all of the other CEN and DMN regions for the auditory segmentation and resting-state tasks, and the rDLPFC for the visual oddball task (two-sample t-test, q 0.05, indicated by (*), FDR corrected for multiple comparisons). 12572 www.pnas.orgcgidoi10.1073pnas.0800005105 Sridharan et al. ACC (7, 23, 35, 36). The differential role of each of these regions has been poorly understood (37) as few studies have used chronometric techniques or causal analyses to dissociate the temporal and network dynamics of responses in these regions. We found that although onset latencies in the rFIC and ACC did not differ significantly, as might be expected from their being part of the same (salience) network, the FIC did have a powerful causal influence on the ACC (and correspondingly, higher net causal outflow than the ACC) in all three datasets (Figs. 3 and 4). Even under conditions in which the ACC plays an imp...

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...vascular processes. Here, we focus on the neurobiological implications of our findings in the context of the three networks that we set out to examine; analyses of several other control regions (including the sensory and association cortices) that further clarify the crucial role of the FIC in the switching process are discussed in the SI Text. FIC-ACC Network Is Neuroanatomically Uniquely Positioned to Generate Control Signals. In primates, anatomical studies have revealed that the insular cortex is reciprocally connected to multiple sensory, motor, limbic, and association areas of the brain (30, 31). The FIC and ACC themselves share significant topographic reciprocal connectivity and form an anatomically tightly coupled network ideally placed to integrate information from several brain regions (9, 10, 32). Indeed, analysis of the auditory and visual experiments in our study found coactivation of these regions during task performance, as in many other studies involving cognitively demanding tasks (7). Previous neurophysiological and brain imaging studies have shown that the FIC-ACC complex moderates arousal during cognitively demanding tasks and that the rFIC, in particular, plays a criti...

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... shape a priori. The mean time-series extracted from each ROI for each subject was fitted with a sixth-order Fourier basis set (windowed with a Hanning function). Onset latencies were defined as the time at which the slope of the fitted response exceeded 10% of the maximum slope of the ascending part of the response. We then performed a two-sample t-test to identify brain regions significantly differing in the onsets of their neural activity (q 0.05, FDR corrected for multiple comparisons). Granger causality analysis (GCA). GCA was performed in accordance with the methods of Roebroeck et al. (11). First, the mean time course from each ROI was extracted for all subjects. This time course was then high-pass filtered at 0.5 cycles per minute. GCA was performed to test for causal influences between ROIs taken pairwise. The order of the autoregressive model used for computation of the influence measure was selected using the Bayesian information criterion. We report the raw values of the directed influence terms for the three tasks in Table S4 A.1, B.1, and C.1. We proceeded to construct a causal connectivity graph (Fig. 3, main text) from these raw F-values as described next. We performed...

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..., rather than isolated regional responses, we performed independent component analysis (ICA) on the task data, which revealed the existence of statistically independent CEN, SN, and DMN (Fig. 1B, see also Table S1) [ICA is a model-free analysis technique that produces a set of spatially independent components and associated time courses for each subject (25)]. In the following two sections, we examine the putative causal mechanisms involved in switching between activation and deactivation in the context of the three networks, identified above, using a combination of mental chronometry and GCA (21, 22). Latency Analysis Reveals Early Activation of the rFIC Relative to the CEN and DMN. First, we identified differences in the latency of the event-related fMRI responses across the entire brain using the method developed by Henson and colleagues (26). Briefly, this method provides a way to estimate the peak latency of the BOLD response at each voxel using the ratio of the derivative to canonical parameter estimates (see SI Materials and Methods for details). This analysis revealed that the event-related fMRI signal in the right FIC (rFIC) and ACC peaks earlier compared to the signal in the node...

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...e sensory and association cortices) that further clarify the crucial role of the FIC in the switching process are discussed in the SI Text. FIC-ACC Network Is Neuroanatomically Uniquely Positioned to Generate Control Signals. In primates, anatomical studies have revealed that the insular cortex is reciprocally connected to multiple sensory, motor, limbic, and association areas of the brain (30, 31). The FIC and ACC themselves share significant topographic reciprocal connectivity and form an anatomically tightly coupled network ideally placed to integrate information from several brain regions (9, 10, 32). Indeed, analysis of the auditory and visual experiments in our study found coactivation of these regions during task performance, as in many other studies involving cognitively demanding tasks (7). Previous neurophysiological and brain imaging studies have shown that the FIC-ACC complex moderates arousal during cognitively demanding tasks and that the rFIC, in particular, plays a critical role in the interoceptive awareness of both stimulus-induced and stimulus-independent changes in homeostatic states (9, 10). Furthermore, the FIC and ACC share a unique feature at the neuronal level: The hu...

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...(38, 39), the FIC is well positioned to trigger alternate cognitive control mechanisms via the CEN. Our findings therefore help to clarify an important controversy regarding the primacy and uniqueness of control signals in the prefrontal cortex (39). Brain regions in the right inferior frontal cortex, surrounding the FIC, have been implicated in a wide range of cognitive control mechanisms (40–42). For example, many of the paradigms involving response inhibition and inhibitory control have focused on ventrolateral regions (primarily within BA 47 and 45) within the right inferior frontal gyrus (43). However, the specific role of the right FIC has been less well studied perhaps because it is usually coactive with the lateral prefrontal cortex. A notable exception is a study by Dosenbach et al. (44) who used restingstate fMRI blocks, interspersed between task blocks, and graph theoretical analysis to underscore the distinctiveness of the FIC and its connectivity with the ACC. Further, a recent lesion study in humans has shown that the rFIC has an important role in cognitive control related to task switching. Using an oculomotorswitching task Hodgson and colleagues (45) showed that patient...

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...l stimulus precedes motor response, we have shown, using onset latency chronometric analysis, that the BOLD signal onsets earlier in sensory (visual), compared to motor areas. Similarly, GCA detected a causal influence from the visual to motor areas (13), as expected. (iii) Two recent studies have shown that the BOLD signal is tightly coupled with gamma (30–70 Hz) band-limited-power (BLP) of the intracranial EEG in the visual and auditory cortices (14, 15). Several previous studies have shown that there is increased gamma band activity during visual or tactile attention in primates and humans (16, 17), and during human conscious perception [intracranial EEG recordings, (18)]. Hence, it is plausible that the BOLD signal f luctuations in the CEN and DMN that appear to be caused by the rFIC (Fig. 3, main text) reflect attentional control mechanisms, mediated by gamma power coupling between these regions, that underlie the CENDMN switch. (iv) Consistent latency differences and causal effects were observed across three different datasets, each with a large number of subjects, using random effects analyses. (v) The brain regions probed in our study are served by multiple cerebral arteries, so th...

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..., rather than isolated regional responses, we performed independent component analysis (ICA) on the task data, which revealed the existence of statistically independent CEN, SN, and DMN (Fig. 1B, see also Table S1) [ICA is a model-free analysis technique that produces a set of spatially independent components and associated time courses for each subject (25)]. In the following two sections, we examine the putative causal mechanisms involved in switching between activation and deactivation in the context of the three networks, identified above, using a combination of mental chronometry and GCA (21, 22). Latency Analysis Reveals Early Activation of the rFIC Relative to the CEN and DMN. First, we identified differences in the latency of the event-related fMRI responses across the entire brain using the method developed by Henson and colleagues (26). Briefly, this method provides a way to estimate the peak latency of the BOLD response at each voxel using the ratio of the derivative to canonical parameter estimates (see SI Materials and Methods for details). This analysis revealed that the event-related fMRI signal in the right FIC (rFIC) and ACC peaks earlier compared to the signal in the node...

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... analyzed brain responses during the occurrence of ‘‘movement transitions:’’ salient, orienting events arising from transitions between adjacent ‘‘movements’’ in the music (19). To specifically elucidate the role of the FIC in driving network changes, we used chronometry and Granger Causality Analysis (GCA), to provide information about the dynamics and directionality of signaling in cortical circuits (20–22). In the second experiment, we investigated the generality of network switching mechanisms involving the FIC by examining brain responses elicited during a visual “oddball” attention task (23). A third experiment examined whether the network switching mechanism could be observed during task-free resting state where there was no overt task and no behavioral response (4). Our motivation for examining the resting-state fMRI data was the recent finding, based on computer simulation of large-scale brain networks, that even in the absence of external stimuli, certain nodes can regulate other nodes and function as hubs (24). Author contributions: V.M. designed research; D.S., D.J.L., and V.M. performed research; D.S. analyzed data; and D.S. and V.M. wrote the paper. The authors declare no...

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...nclude the dorsolateral prefrontal cortex (DLPFC), and posterior parietal cortex (PPC); (ii) the default-mode network (DMN), which includes the ventromedial prefrontal cortex (VMPFC) and posterior cingulate cortex (PCC); and (iii) a salience network (SN), which includes the ventrolateral prefrontal cortex (VLPFC) and anterior insula (jointly referred to as the fronto-insular cortex; FIC) and the anterior cingulate cortex (ACC) (1, 2, 4, 5). During the performance of cognitively demanding tasks, the CEN and SN typically show increases in activation whereas the DMN shows decreases in activation (1, 2, 6). However, what remains unknown is the crucial issue of how the operation of these networks, identified in the resting state, relate to their function during cognitive information processing. Furthermore, the cognitive control mechanisms that mediate concurrent activation and deactivation within these large-scale brain networks during task performance are poorly understood. In a recent meta-analysis, Dosenbach and colleagues hypothesized that several brain regions that overlap with the CEN and SN are important for multiple cognitive control functions, including initiation, maintenance, and adj...

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... control signals in the prefrontal cortex (39). Brain regions in the right inferior frontal cortex, surrounding the FIC, have been implicated in a wide range of cognitive control mechanisms (40–42). For example, many of the paradigms involving response inhibition and inhibitory control have focused on ventrolateral regions (primarily within BA 47 and 45) within the right inferior frontal gyrus (43). However, the specific role of the right FIC has been less well studied perhaps because it is usually coactive with the lateral prefrontal cortex. A notable exception is a study by Dosenbach et al. (44) who used restingstate fMRI blocks, interspersed between task blocks, and graph theoretical analysis to underscore the distinctiveness of the FIC and its connectivity with the ACC. Further, a recent lesion study in humans has shown that the rFIC has an important role in cognitive control related to task switching. Using an oculomotorswitching task Hodgson and colleagues (45) showed that patients with lesions in the anterior rFIC were the most impaired in altering their behavior in accordance with the changing rules of the task. In normal healthy adults, functional brain imaging studies have su...

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...ing both model-based and model-free approaches, has suggested the existence of at least three canonical networks: (i) a centralexecutive network (CEN), whose key nodes include the dorsolateral prefrontal cortex (DLPFC), and posterior parietal cortex (PPC); (ii) the default-mode network (DMN), which includes the ventromedial prefrontal cortex (VMPFC) and posterior cingulate cortex (PCC); and (iii) a salience network (SN), which includes the ventrolateral prefrontal cortex (VLPFC) and anterior insula (jointly referred to as the fronto-insular cortex; FIC) and the anterior cingulate cortex (ACC) (1, 2, 4, 5). During the performance of cognitively demanding tasks, the CEN and SN typically show increases in activation whereas the DMN shows decreases in activation (1, 2, 6). However, what remains unknown is the crucial issue of how the operation of these networks, identified in the resting state, relate to their function during cognitive information processing. Furthermore, the cognitive control mechanisms that mediate concurrent activation and deactivation within these large-scale brain networks during task performance are poorly understood. In a recent meta-analysis, Dosenbach and colleagues hypot...

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...l stimulus precedes motor response, we have shown, using onset latency chronometric analysis, that the BOLD signal onsets earlier in sensory (visual), compared to motor areas. Similarly, GCA detected a causal influence from the visual to motor areas (13), as expected. (iii) Two recent studies have shown that the BOLD signal is tightly coupled with gamma (30–70 Hz) band-limited-power (BLP) of the intracranial EEG in the visual and auditory cortices (14, 15). Several previous studies have shown that there is increased gamma band activity during visual or tactile attention in primates and humans (16, 17), and during human conscious perception [intracranial EEG recordings, (18)]. Hence, it is plausible that the BOLD signal f luctuations in the CEN and DMN that appear to be caused by the rFIC (Fig. 3, main text) reflect attentional control mechanisms, mediated by gamma power coupling between these regions, that underlie the CENDMN switch. (iv) Consistent latency differences and causal effects were observed across three different datasets, each with a large number of subjects, using random effects analyses. (v) The brain regions probed in our study are served by multiple cerebral arteries, so th...

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...gh onset latencies in the rFIC and ACC did not differ significantly, as might be expected from their being part of the same (salience) network, the FIC did have a powerful causal influence on the ACC (and correspondingly, higher net causal outflow than the ACC) in all three datasets (Figs. 3 and 4). Even under conditions in which the ACC plays an important role in cognitive control (23, 36), the rFIC may generate the signals to trigger hierarchical control and previous studies, including ours, may have missed detecting these effects. Our data further suggest that when the ACC is dysfunctional (38, 39), the FIC is well positioned to trigger alternate cognitive control mechanisms via the CEN. Our findings therefore help to clarify an important controversy regarding the primacy and uniqueness of control signals in the prefrontal cortex (39). Brain regions in the right inferior frontal cortex, surrounding the FIC, have been implicated in a wide range of cognitive control mechanisms (40–42). For example, many of the paradigms involving response inhibition and inhibitory control have focused on ventrolateral regions (primarily within BA 47 and 45) within the right inferior frontal gyrus (43). Ho...

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...l brain imaging studies have suggested that the FIC and the ACC are together involved in a variety of cognitive control processes, including conflict and error monitoring, interference resolution, and response selection (23, 36, 40, 46–48). We hypothesize that in all these cases, the rFIC enables task-related information processing by initiating appropriate control signals to engage the ACC and the CEN. Our findings are inconsistent with the suggestion that the FIC-ACC provides stable ‘set-maintenance’ over entire task epochs whereas the fronto-parietal component initiates and adjusts control (49). In our view, it is the FIC-ACC-centered SN network that initiates key control signals in response to salient stimuli or events. As the lesion study by Hodgson and colleagues illustrates so dramatically, failure to generate these signals can have severe consequences for behavior. Our findings do not, however, preclude the possibility that after the FIC initiates changes in intra- and inter-network activity the CEN may carry out top-down important control functions either on its own or in association with the SN. Our findings help to synthesize these and other extant findings in the literature...

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...her, to provide concurrent validity to the GCA approach, we attempted to cluster the six ROIs pairwise to maximize the sum of mutual (pairwise) instantaneous influences (Fx.y). Across all experiments, the most optimal clusters (red boxes in Table S4 A.2, B.2, and C.2) were identical with the SN (rFIC, ACC), CEN (rDLPFC, rPPC), and DMN (VMPFC, PPC), further confirming the functional dissociation between these networks that we observed with ICA. Granger causality and network analyses with two other task paradigms. GCA was performed in two other datasets: (a) A visual ‘‘oddball’’ attention task (12) employing 13 participants, and (b) a resting state scan employing 22 participants. These data were chosen because they involve entirely different stimulus modalities and task requirements. The visual oddball task showed right-lateralized activation of the SN and CEN regions and deactivation of the DMN regions during the perception of the infrequent (as contrasted with frequent) stimuli (data not shown). Similarly, statistical parametric latency maps, as computed by the method of Henson et al. (7) revealed that the rFIC and ACC had earlier peak latency compared to other regions in the CEN and ...

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...e sensory and association cortices) that further clarify the crucial role of the FIC in the switching process are discussed in the SI Text. FIC-ACC Network Is Neuroanatomically Uniquely Positioned to Generate Control Signals. In primates, anatomical studies have revealed that the insular cortex is reciprocally connected to multiple sensory, motor, limbic, and association areas of the brain (30, 31). The FIC and ACC themselves share significant topographic reciprocal connectivity and form an anatomically tightly coupled network ideally placed to integrate information from several brain regions (9, 10, 32). Indeed, analysis of the auditory and visual experiments in our study found coactivation of these regions during task performance, as in many other studies involving cognitively demanding tasks (7). Previous neurophysiological and brain imaging studies have shown that the FIC-ACC complex moderates arousal during cognitively demanding tasks and that the rFIC, in particular, plays a critical role in the interoceptive awareness of both stimulus-induced and stimulus-independent changes in homeostatic states (9, 10). Furthermore, the FIC and ACC share a unique feature at the neuronal level: The hu...

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... with a temporal accuracy of tens to hundreds of milliseconds (8–10) (ii) In a previous analysis of a Sternberg working memory task, wherein a visual stimulus precedes motor response, we have shown, using onset latency chronometric analysis, that the BOLD signal onsets earlier in sensory (visual), compared to motor areas. Similarly, GCA detected a causal influence from the visual to motor areas (13), as expected. (iii) Two recent studies have shown that the BOLD signal is tightly coupled with gamma (30–70 Hz) band-limited-power (BLP) of the intracranial EEG in the visual and auditory cortices (14, 15). Several previous studies have shown that there is increased gamma band activity during visual or tactile attention in primates and humans (16, 17), and during human conscious perception [intracranial EEG recordings, (18)]. Hence, it is plausible that the BOLD signal f luctuations in the CEN and DMN that appear to be caused by the rFIC (Fig. 3, main text) reflect attentional control mechanisms, mediated by gamma power coupling between these regions, that underlie the CENDMN switch. (iv) Consistent latency differences and causal effects were observed across three different datasets, each with ...

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...e FIC and ACC share a unique feature at the neuronal level: The human FIC-ACC network has a specialized class of neurons with distinctive anatomical and functional features that might facilitate the network switching process that we report here. The von Economo neurons (VENs) are specialized neurons exclusively localized to the FIC and ACC (33). Based on the dendritic architecture of the VENs, Allman and colleagues have proposed that ‘‘the function of the VENs may be to provide a rapid relay to other parts of the brain of a simple signal derived from information processed within FI and ACC.’’ (34). We propose that the VENs may, therefore, constitute the neuronal basis of control signals generated by the FIC and ACC in our study. Taken together, these findings suggest that the FIC and ACC, anchored within the SN, are uniquely positioned to initiate control signals that activate the CEN and deactivate the DMN. Differential Roles of the rFIC, ACC, and Lateral Prefrontal Cortex in Initiating Control Signals. Many previous studies of attentional and cognitive control have reported coactivation of the FIC and Fig. 4. Net Granger causal outflow (out-in degree) of the key nodes of the Salience...

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...degree: Difference between out-degree and in-degree is a measure of the net causal outflow from a node. d) Path length: Shortest path from a node to every other node in the network (normalized by the number of nodes minus one). Shorter path lengths indicate a more strongly interconnected or ‘‘hub-like’’ node. For the present analysis, we constructed a distribution of these metrics, across subjects, for each node of the network. The mean value of these metrics (and their standard errors) across subjects are reported in Table S5. Path length was computed using Dijkstra’s shortest path algorithm (53). A two-sample t-test was then applied on two key network metrics, the (out-in) degree and the path length, with FDR correction for multiple comparisons, to identify those nodes whose network metrics were significantly different from the other nodes. Sridharan et al. PNAS August 26, 2008 vol. 105 no. 34 12573 N EU RO SC IE N CE ACKNOWLEDGMENTS. We thank Mike Greicius for useful discussions and Elena Rykhlevskaia and Catie Chang for their comments on a preliminary draft of this manuscript. We acknowledge two anonymous reviewers for their insightful comments and suggestions. This researc...

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...ing both model-based and model-free approaches, has suggested the existence of at least three canonical networks: (i) a centralexecutive network (CEN), whose key nodes include the dorsolateral prefrontal cortex (DLPFC), and posterior parietal cortex (PPC); (ii) the default-mode network (DMN), which includes the ventromedial prefrontal cortex (VMPFC) and posterior cingulate cortex (PCC); and (iii) a salience network (SN), which includes the ventrolateral prefrontal cortex (VLPFC) and anterior insula (jointly referred to as the fronto-insular cortex; FIC) and the anterior cingulate cortex (ACC) (1, 2, 4, 5). During the performance of cognitively demanding tasks, the CEN and SN typically show increases in activation whereas the DMN shows decreases in activation (1, 2, 6). However, what remains unknown is the crucial issue of how the operation of these networks, identified in the resting state, relate to their function during cognitive information processing. Furthermore, the cognitive control mechanisms that mediate concurrent activation and deactivation within these large-scale brain networks during task performance are poorly understood. In a recent meta-analysis, Dosenbach and colleagues hypot...

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...gns, to show that the relative timing between onsets of the BOLD responses between different regions can be used as a predictor of differences in neural activity onset, and can resolve these differences with a temporal accuracy of tens to hundreds of milliseconds (8–10) (ii) In a previous analysis of a Sternberg working memory task, wherein a visual stimulus precedes motor response, we have shown, using onset latency chronometric analysis, that the BOLD signal onsets earlier in sensory (visual), compared to motor areas. Similarly, GCA detected a causal influence from the visual to motor areas (13), as expected. (iii) Two recent studies have shown that the BOLD signal is tightly coupled with gamma (30–70 Hz) band-limited-power (BLP) of the intracranial EEG in the visual and auditory cortices (14, 15). Several previous studies have shown that there is increased gamma band activity during visual or tactile attention in primates and humans (16, 17), and during human conscious perception [intracranial EEG recordings, (18)]. Hence, it is plausible that the BOLD signal f luctuations in the CEN and DMN that appear to be caused by the rFIC (Fig. 3, main text) reflect attentional control mechani...

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...ing both model-based and model-free approaches, has suggested the existence of at least three canonical networks: (i) a centralexecutive network (CEN), whose key nodes include the dorsolateral prefrontal cortex (DLPFC), and posterior parietal cortex (PPC); (ii) the default-mode network (DMN), which includes the ventromedial prefrontal cortex (VMPFC) and posterior cingulate cortex (PCC); and (iii) a salience network (SN), which includes the ventrolateral prefrontal cortex (VLPFC) and anterior insula (jointly referred to as the fronto-insular cortex; FIC) and the anterior cingulate cortex (ACC) (1, 2, 4, 5). During the performance of cognitively demanding tasks, the CEN and SN typically show increases in activation whereas the DMN shows decreases in activation (1, 2, 6). However, what remains unknown is the crucial issue of how the operation of these networks, identified in the resting state, relate to their function during cognitive information processing. Furthermore, the cognitive control mechanisms that mediate concurrent activation and deactivation within these large-scale brain networks during task performance are poorly understood. In a recent meta-analysis, Dosenbach and colleagues hypot...

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...vascular processes. Here, we focus on the neurobiological implications of our findings in the context of the three networks that we set out to examine; analyses of several other control regions (including the sensory and association cortices) that further clarify the crucial role of the FIC in the switching process are discussed in the SI Text. FIC-ACC Network Is Neuroanatomically Uniquely Positioned to Generate Control Signals. In primates, anatomical studies have revealed that the insular cortex is reciprocally connected to multiple sensory, motor, limbic, and association areas of the brain (30, 31). The FIC and ACC themselves share significant topographic reciprocal connectivity and form an anatomically tightly coupled network ideally placed to integrate information from several brain regions (9, 10, 32). Indeed, analysis of the auditory and visual experiments in our study found coactivation of these regions during task performance, as in many other studies involving cognitively demanding tasks (7). Previous neurophysiological and brain imaging studies have shown that the FIC-ACC complex moderates arousal during cognitively demanding tasks and that the rFIC, in particular, plays a criti...

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...erior frontal gyrus (43). However, the specific role of the right FIC has been less well studied perhaps because it is usually coactive with the lateral prefrontal cortex. A notable exception is a study by Dosenbach et al. (44) who used restingstate fMRI blocks, interspersed between task blocks, and graph theoretical analysis to underscore the distinctiveness of the FIC and its connectivity with the ACC. Further, a recent lesion study in humans has shown that the rFIC has an important role in cognitive control related to task switching. Using an oculomotorswitching task Hodgson and colleagues (45) showed that patients with lesions in the anterior rFIC were the most impaired in altering their behavior in accordance with the changing rules of the task. In normal healthy adults, functional brain imaging studies have suggested that the FIC and the ACC are together involved in a variety of cognitive control processes, including conflict and error monitoring, interference resolution, and response selection (23, 36, 40, 46–48). We hypothesize that in all these cases, the rFIC enables task-related information processing by initiating appropriate control signals to engage the ACC and the CEN. O...

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...re into a common network dynamical framework and they suggest a causal, and potentially critical, role for the rFIC in cognitive control. We propose that one fundamental mechanism underlying such control is a transient signal from the rFIC, which engages the brain’s attentional, working memory and higher-order control processes while disengaging other systems that are not task-relevant. We predict that disruptions to these processes may constitute a key aspect of psychopathology in several neurological and psychiatric disorders, including frontotemporal dementia, autism, and anxiety disorders (34, 50, 51). More generally, our study illustrates the power of a unified network approach—wherein we first specify intrinsic brain networks and then analyze interactions among anatomically discrete regions within these networks during cognitive information processing—for understanding fundamental aspects of human brain function and dysfunction. Materials and Methods Experimental Design. We used data from three different experiments. The first experiment involved auditory event segmentation and detection of salient event boundaries in passages of music by the Baroque composer William Boyce. Eighteen righ...

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...istinct networks. From left to right: Salience Network (rFIC and ACC), Central-Executive Network (rDLPFC and rPPC), and Default-Mode Network (VMPFC and PCC). Activations height and extent thresholded at the P 0.001 level (uncorrected). The ICA prunes out extraneous activation and deactivation clusters visible in the GLM analysis to reveal brain regions that constitute independent and tightly coupled networks. 12570 www.pnas.orgcgidoi10.1073pnas.0800005105 Sridharan et al. predictability of signal changes in one brain region based on the time-course of responses in another brain region (28). We performed GCA using a bivariate model (22) on the timecourses extracted from the six key regions used in the onset latency analysis. We used bootstrap techniques (29) to create null distributions of influence terms (F-values) and their differences (22). A causal connectivity graph was constructed using the thickness of connecting arrows to indicate the strengths of the causal influences (Fig. 3A, ‘‘raw’’ F-values normalized by the maximum F-value; raw F-values reported in Table S4). Only links that showed significant directed connectivity (influence terms) at the group-level (Mann-Whitney...

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...ing both model-based and model-free approaches, has suggested the existence of at least three canonical networks: (i) a centralexecutive network (CEN), whose key nodes include the dorsolateral prefrontal cortex (DLPFC), and posterior parietal cortex (PPC); (ii) the default-mode network (DMN), which includes the ventromedial prefrontal cortex (VMPFC) and posterior cingulate cortex (PCC); and (iii) a salience network (SN), which includes the ventrolateral prefrontal cortex (VLPFC) and anterior insula (jointly referred to as the fronto-insular cortex; FIC) and the anterior cingulate cortex (ACC) (1, 2, 4, 5). During the performance of cognitively demanding tasks, the CEN and SN typically show increases in activation whereas the DMN shows decreases in activation (1, 2, 6). However, what remains unknown is the crucial issue of how the operation of these networks, identified in the resting state, relate to their function during cognitive information processing. Furthermore, the cognitive control mechanisms that mediate concurrent activation and deactivation within these large-scale brain networks during task performance are poorly understood. In a recent meta-analysis, Dosenbach and colleagues hypot...

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...gh onset latencies in the rFIC and ACC did not differ significantly, as might be expected from their being part of the same (salience) network, the FIC did have a powerful causal influence on the ACC (and correspondingly, higher net causal outflow than the ACC) in all three datasets (Figs. 3 and 4). Even under conditions in which the ACC plays an important role in cognitive control (23, 36), the rFIC may generate the signals to trigger hierarchical control and previous studies, including ours, may have missed detecting these effects. Our data further suggest that when the ACC is dysfunctional (38, 39), the FIC is well positioned to trigger alternate cognitive control mechanisms via the CEN. Our findings therefore help to clarify an important controversy regarding the primacy and uniqueness of control signals in the prefrontal cortex (39). Brain regions in the right inferior frontal cortex, surrounding the FIC, have been implicated in a wide range of cognitive control mechanisms (40–42). For example, many of the paradigms involving response inhibition and inhibitory control have focused on ventrolateral regions (primarily within BA 47 and 45) within the right inferior frontal gyrus (43). Ho...

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...al-Executive, and Default-Mode networks as assessed by Granger causality analysis revealed that the rFIC has a significantly higher net causal outflow than the CEN and DMN regions across tasks (conventions as in Fig. 2). Specifically, the rFIC had a significantly higher net causal outflow than almost all of the other CEN and DMN regions for the auditory segmentation and resting-state tasks, and the rDLPFC for the visual oddball task (two-sample t-test, q 0.05, indicated by (*), FDR corrected for multiple comparisons). 12572 www.pnas.orgcgidoi10.1073pnas.0800005105 Sridharan et al. ACC (7, 23, 35, 36). The differential role of each of these regions has been poorly understood (37) as few studies have used chronometric techniques or causal analyses to dissociate the temporal and network dynamics of responses in these regions. We found that although onset latencies in the rFIC and ACC did not differ significantly, as might be expected from their being part of the same (salience) network, the FIC did have a powerful causal influence on the ACC (and correspondingly, higher net causal outflow than the ACC) in all three datasets (Figs. 3 and 4). Even under conditions in which the ACC plays an imp...

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...that the rFIC has a significantly higher net causal outflow than the CEN and DMN regions across tasks (conventions as in Fig. 2). Specifically, the rFIC had a significantly higher net causal outflow than almost all of the other CEN and DMN regions for the auditory segmentation and resting-state tasks, and the rDLPFC for the visual oddball task (two-sample t-test, q 0.05, indicated by (*), FDR corrected for multiple comparisons). 12572 www.pnas.orgcgidoi10.1073pnas.0800005105 Sridharan et al. ACC (7, 23, 35, 36). The differential role of each of these regions has been poorly understood (37) as few studies have used chronometric techniques or causal analyses to dissociate the temporal and network dynamics of responses in these regions. We found that although onset latencies in the rFIC and ACC did not differ significantly, as might be expected from their being part of the same (salience) network, the FIC did have a powerful causal influence on the ACC (and correspondingly, higher net causal outflow than the ACC) in all three datasets (Figs. 3 and 4). Even under conditions in which the ACC plays an important role in cognitive control (23, 36), the rFIC may generate the signals to ...

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... Series Extraction. ROI analysis was performed using the Marsbar software package (http://marsbar.sourceforge. net). Spherical ROIs were defined as the sets of voxels contained in 6–10-mm spheres centered on the peaks of activation clusters obtained from the ICA analysis (Table S1). These same ROIs were used throughout all of the subsequent analyses (onset latency, GCA, and network analyses). The mean time course in each ROI was extracted by averaging the time courses of all of the voxels contained in the ROI. Granger Causality Analysis. GCA was performed using the Causal Connectivity Toolbox (52), with modifications based on the methods proposed by Roebroeck et al. (22). GCA was performed on the timeseries extracted from ROIs to test for causal influences between ROIs taken pairwise using the difference of influence term (Fx3y Fy3x) (22). We performed statistical inference on the causal connections using bootstrap analysis: An empirical null distribution of the difference of influence terms was estimated using block-randomized time series (22). For each subject, dominant (difference of influence) connections that passed a P 0.05 significance level (bootstrap threshold) were used f...

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... with a temporal accuracy of tens to hundreds of milliseconds (8–10) (ii) In a previous analysis of a Sternberg working memory task, wherein a visual stimulus precedes motor response, we have shown, using onset latency chronometric analysis, that the BOLD signal onsets earlier in sensory (visual), compared to motor areas. Similarly, GCA detected a causal influence from the visual to motor areas (13), as expected. (iii) Two recent studies have shown that the BOLD signal is tightly coupled with gamma (30–70 Hz) band-limited-power (BLP) of the intracranial EEG in the visual and auditory cortices (14, 15). Several previous studies have shown that there is increased gamma band activity during visual or tactile attention in primates and humans (16, 17), and during human conscious perception [intracranial EEG recordings, (18)]. Hence, it is plausible that the BOLD signal f luctuations in the CEN and DMN that appear to be caused by the rFIC (Fig. 3, main text) reflect attentional control mechanisms, mediated by gamma power coupling between these regions, that underlie the CENDMN switch. (iv) Consistent latency differences and causal effects were observed across three different datasets, each with ...

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...vascular processes. Here, we focus on the neurobiological implications of our findings in the context of the three networks that we set out to examine; analyses of several other control regions (including the sensory and association cortices) that further clarify the crucial role of the FIC in the switching process are discussed in the SI Text. FIC-ACC Network Is Neuroanatomically Uniquely Positioned to Generate Control Signals. In primates, anatomical studies have revealed that the insular cortex is reciprocally connected to multiple sensory, motor, limbic, and association areas of the brain (30, 31). The FIC and ACC themselves share significant topographic reciprocal connectivity and form an anatomically tightly coupled network ideally placed to integrate information from several brain regions (9, 10, 32). Indeed, analysis of the auditory and visual experiments in our study found coactivation of these regions during task performance, as in many other studies involving cognitively demanding tasks (7). Previous neurophysiological and brain imaging studies have shown that the FIC-ACC complex moderates arousal during cognitively demanding tasks and that the rFIC, in particular, plays a criti...

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...ns unknown is the crucial issue of how the operation of these networks, identified in the resting state, relate to their function during cognitive information processing. Furthermore, the cognitive control mechanisms that mediate concurrent activation and deactivation within these large-scale brain networks during task performance are poorly understood. In a recent meta-analysis, Dosenbach and colleagues hypothesized that several brain regions that overlap with the CEN and SN are important for multiple cognitive control functions, including initiation, maintenance, and adjustment of attention (7). However, no studies to date have directly assessed the temporal dynamics and causal interactions of specific nodes within the CEN, SN, and DMN. Converging evidence from a number of brain imaging studies across several task domains suggests that the FIC and ACC nodes of the SN, in particular, respond to the degree of subjective salience, whether cognitive, homeostatic, or emotional (4, 8–11). The CEN, on the other hand, is critical for the active maintenance and manipulation of information in working memory, and for judgment and decision making in the context of goal directed behavior (12–18)...

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...e sensory and association cortices) that further clarify the crucial role of the FIC in the switching process are discussed in the SI Text. FIC-ACC Network Is Neuroanatomically Uniquely Positioned to Generate Control Signals. In primates, anatomical studies have revealed that the insular cortex is reciprocally connected to multiple sensory, motor, limbic, and association areas of the brain (30, 31). The FIC and ACC themselves share significant topographic reciprocal connectivity and form an anatomically tightly coupled network ideally placed to integrate information from several brain regions (9, 10, 32). Indeed, analysis of the auditory and visual experiments in our study found coactivation of these regions during task performance, as in many other studies involving cognitively demanding tasks (7). Previous neurophysiological and brain imaging studies have shown that the FIC-ACC complex moderates arousal during cognitively demanding tasks and that the rFIC, in particular, plays a critical role in the interoceptive awareness of both stimulus-induced and stimulus-independent changes in homeostatic states (9, 10). Furthermore, the FIC and ACC share a unique feature at the neuronal level: The hu...

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...riment, we investigated the generality of network switching mechanisms involving the FIC by examining brain responses elicited during a visual “oddball” attention task (23). A third experiment examined whether the network switching mechanism could be observed during task-free resting state where there was no overt task and no behavioral response (4). Our motivation for examining the resting-state fMRI data was the recent finding, based on computer simulation of large-scale brain networks, that even in the absence of external stimuli, certain nodes can regulate other nodes and function as hubs (24). Author contributions: V.M. designed research; D.S., D.J.L., and V.M. performed research; D.S. analyzed data; and D.S. and V.M. wrote the paper. The authors declare no conflict of interest. This article is a PNAS Direct Submission. ‡To whom correspondence may be addressed at: Program in Neuroscience and Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, 780 Welch Road, Room 201, Stanford, CA 94305-5778. E-mail: dsridhar@stanford.edu or menon@ stanford.edu. This article contains supporting information online at www.pnas.org/cgi/content/full/ 0800005105/DC...

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...riment, we investigated the generality of network switching mechanisms involving the FIC by examining brain responses elicited during a visual “oddball” attention task (23). A third experiment examined whether the network switching mechanism could be observed during task-free resting state where there was no overt task and no behavioral response (4). Our motivation for examining the resting-state fMRI data was the recent finding, based on computer simulation of large-scale brain networks, that even in the absence of external stimuli, certain nodes can regulate other nodes and function as hubs (24). Author contributions: V.M. designed research; D.S., D.J.L., and V.M. performed research; D.S. analyzed data; and D.S. and V.M. wrote the paper. The authors declare no conflict of interest. This article is a PNAS Direct Submission. ‡To whom correspondence may be addressed at: Program in Neuroscience and Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, 780 Welch Road, Room 201, Stanford, CA 94305-5778. E-mail: dsridhar@stanford.edu or menon@ stanford.edu. This article contains supporting information online at www.pnas.org/cgi/content/full/ 0800005105/DC...

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...C-ACC complex moderates arousal during cognitively demanding tasks and that the rFIC, in particular, plays a critical role in the interoceptive awareness of both stimulus-induced and stimulus-independent changes in homeostatic states (9, 10). Furthermore, the FIC and ACC share a unique feature at the neuronal level: The human FIC-ACC network has a specialized class of neurons with distinctive anatomical and functional features that might facilitate the network switching process that we report here. The von Economo neurons (VENs) are specialized neurons exclusively localized to the FIC and ACC (33). Based on the dendritic architecture of the VENs, Allman and colleagues have proposed that ‘‘the function of the VENs may be to provide a rapid relay to other parts of the brain of a simple signal derived from information processed within FI and ACC.’’ (34). We propose that the VENs may, therefore, constitute the neuronal basis of control signals generated by the FIC and ACC in our study. Taken together, these findings suggest that the FIC and ACC, anchored within the SN, are uniquely positioned to initiate control signals that activate the CEN and deactivate the DMN. Differential Roles of th...

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...tion and inverse Fourier transform for each time point into 64 64 28 image matrices (voxel size 3.125 3.125 4.5 mm). A linear shim correction was applied separately for each slice during reconstruction using a magnetic field map acquired automatically by the pulse sequence at the beginning of the scan (1). fMRI data acquisition was synchronized to stimulus presentation using a TTL pulse sent by EPRIME to the scanner timing board. fMRI data analysis. fMRI data were preprocessed using SPM2 (http://www.fil.ion.ucl.ac.uk/spm). Functional volumes were corrected for movement-related effects (3), spatially normalized to stereotaxic Talairach coordinates, resampled every 2 mm using sinc interpolation, and smoothed with a 4-mm Gaussian kernel to reduce spatial noise. For the first (auditory segmentation) and second (visual oddball) experiments, statistical analysis was performed using the general linear model (GLM) and the theory of Gaussian random fields as implemented in SPM2. A withinsubjects procedure was used to model all of the effects of interest for each subject. Confounding effects of fluctuations in global mean were removed by proportional scaling where, for each time point, ...

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...ed that the event-related fMRI signal in the right FIC (rFIC) and ACC peaks earlier compared to the signal in the nodes of the CEN and DMN, indicating that the neural responses in the rFIC and ACC precede the CEN and DMN (see Fig. S1 and Table S2). To provide converging quantitative evidence, we estimated the onset latency of the blood oxygen level dependent (BOLD) response in these regions using the method of Sterzer and Kleinschmidt (27). Previous studies have used differences in the onset latency of the BOLD response as a measure of the difference in onset of the underlying neural activity (20, 21, 27). We first defined regions of interest (ROIs) in six key nodes of the SN, CEN, and DMN based on the peaks of the ICA clusters (see Materials and Methods); all subsequent analyses was confined to these six canonical nodes of the SN, CEN, and DMN (see also SI Text for a discussion on the choice of regions of interest and control analyses on regions not included in the main analysis). We extracted the mean timecourse in each of these six nodes, and used a sixth-order Fourier model to fit the event related BOLD response for each subject and event, and averaged the fitted responses across events an...

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...s. The group map was height thresholded at P 0.025 uncorrected, and only regions comprising at least ten contiguous voxels are reported. Calculation of onset latency differences. Differences in peak latency of the BOLD response between regions may arise from differences in either the onset or the duration of neural activity (7). Onset latency of the BOLD response provides a means, in principle, of decoupling these possibilities so as to uncover the underlying pattern of neural activity onsets (7–10). We calculated onset latencies according to the method developed by Sterzer and Kleinschmidt (8). This method uses a Fourier model that fits the BOLD response as a linear combination of Fourier basis functions; this removes the need for assuming a response shape a priori. The mean time-series extracted from each ROI for each subject was fitted with a sixth-order Fourier basis set (windowed with a Hanning function). Onset latencies were defined as the time at which the slope of the fitted response exceeded 10% of the maximum slope of the ascending part of the response. We then performed a two-sample t-test to identify brain regions significantly differing in the onsets of their neural act...

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...etric analysis, that the BOLD signal onsets earlier in sensory (visual), compared to motor areas. Similarly, GCA detected a causal influence from the visual to motor areas (13), as expected. (iii) Two recent studies have shown that the BOLD signal is tightly coupled with gamma (30–70 Hz) band-limited-power (BLP) of the intracranial EEG in the visual and auditory cortices (14, 15). Several previous studies have shown that there is increased gamma band activity during visual or tactile attention in primates and humans (16, 17), and during human conscious perception [intracranial EEG recordings, (18)]. Hence, it is plausible that the BOLD signal f luctuations in the CEN and DMN that appear to be caused by the rFIC (Fig. 3, main text) reflect attentional control mechanisms, mediated by gamma power coupling between these regions, that underlie the CENDMN switch. (iv) Consistent latency differences and causal effects were observed across three different datasets, each with a large number of subjects, using random effects analyses. (v) The brain regions probed in our study are served by multiple cerebral arteries, so the timing of vascular changes are unlikely to be coupled in any significant...

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...e that produces a set of spatially independent components and associated time courses for each subject (25)]. In the following two sections, we examine the putative causal mechanisms involved in switching between activation and deactivation in the context of the three networks, identified above, using a combination of mental chronometry and GCA (21, 22). Latency Analysis Reveals Early Activation of the rFIC Relative to the CEN and DMN. First, we identified differences in the latency of the event-related fMRI responses across the entire brain using the method developed by Henson and colleagues (26). Briefly, this method provides a way to estimate the peak latency of the BOLD response at each voxel using the ratio of the derivative to canonical parameter estimates (see SI Materials and Methods for details). This analysis revealed that the event-related fMRI signal in the right FIC (rFIC) and ACC peaks earlier compared to the signal in the nodes of the CEN and DMN, indicating that the neural responses in the rFIC and ACC precede the CEN and DMN (see Fig. S1 and Table S2). To provide converging quantitative evidence, we estimated the onset latency of the blood oxygen level dependent (BOLD)...

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...re into a common network dynamical framework and they suggest a causal, and potentially critical, role for the rFIC in cognitive control. We propose that one fundamental mechanism underlying such control is a transient signal from the rFIC, which engages the brain’s attentional, working memory and higher-order control processes while disengaging other systems that are not task-relevant. We predict that disruptions to these processes may constitute a key aspect of psychopathology in several neurological and psychiatric disorders, including frontotemporal dementia, autism, and anxiety disorders (34, 50, 51). More generally, our study illustrates the power of a unified network approach—wherein we first specify intrinsic brain networks and then analyze interactions among anatomically discrete regions within these networks during cognitive information processing—for understanding fundamental aspects of human brain function and dysfunction. Materials and Methods Experimental Design. We used data from three different experiments. The first experiment involved auditory event segmentation and detection of salient event boundaries in passages of music by the Baroque composer William Boyce. Eighteen righ...