Abstract
Clinical depression commonly emerges in adolescence, which is also a time of developing cognitive ability and related large-scale functional brain networks implicated in depression. In depressed adults, abnormalities in the dynamic functioning of frontoinsular networks, in particular, have been observed and linked to negative rumination. Thus, network dynamics may provide new insight into teen pathophysiology. Here, adolescents (nā=ā45, ages 13ā19) with varying severity of depressive symptoms completed a resting-state functional MRI scan. Functional networks were evaluated using co-activation pattern analysis to identify whole-brain states of spatial co-activation that recurred across participants and time. Measures included: dwell time (proportion of scan spent in that network state), persistence (volume-to-volume maintenance of a network state), and transitions (frequency of moving from state A to state B). Analyses tested associations between depression or trait rumination and dynamics of network states involving frontoinsular and default network systems. Results indicated that adolescents showing increased dwell time in, and persistence of, a frontoinsular-default network state involving insula, dorsolateral and medial prefrontal cortex, and posterior regions of default network, reported more severe symptoms of depression. Further, adolescents who transitioned more frequently between the frontoinsular-default state and a prototypical default network state reported higher depression. Increased dominance and transition frequency of frontoinsular-default network states were also associated with higher rumination, and rumination mediated the associations between network dynamics and depression. Findings support a model in which abnormal frontoinsular dynamics confer vulnerability to maladaptive introspection, which in turn contributes to symptoms of adolescent depression.
Similar content being viewed by others
Introduction
Major depression and related mood syndromes are some of the most prevalent and debilitating illnesses worldwide [1]. These serious disorders tend to emerge during adolescence [2], and early symptoms of depression are related to poorer emotion regulation and a more chronic and severe course of depression over the lifespan [3, 4]. The developmental timing of depression highlights the importance of investigating mood pathology during adolescence, when aberrations in key neurocognitive domains that characterize depression may first emerge [5, 6].
Depression across the lifespan is characterized by abnormalities in the coordinated functioning of large-scale brain networks involved in attention and attention regulation [7]. These include the default network (DN), comprising midline cortical regions, temporal-parietal regions, and areas of hippocampus that together are involved in introspection and autobiographical thinking [8]; the frontoparietal network (FN), including lateral prefrontal and posterior parietal regions that are recruited together in the service of goal-directed attention [9]; and the salience (or ventral attention) network (SN), including insula and mid-cingulate regions involved in salience-directed attention [10]). Coordination across regions of these prototypical networks is believed to reflect regulatory functions, e.g., allocating resources towards or away from other large-scale networks on the basis of salience of internal or external events, supporting regulation of attention towards introspection or towards the external world [11, 12]. In depression, meta-analytic research has revealed increased positive functional connectivity within the DN, weaker negative functional connectivity between the DN and the FN, and bidirectional abnormalities in functional connectivity between midline regions of the DN and insular regions of the SN [7]. Subsequent empirical work has yielded converging evidence for such network abnormalities in depression, and linked them to particular cognitive vulnerabilities. Specifically, adult depression was characterized by increased and more variable resting-state functional connectivity between regions of medial prefrontal cortex and insula, and these frontoinsular abnormalities were associated with the tendency towards negative, repetitive introspection (i.e., rumination) [13] and attention biases towards negative, self-referential information [14]. This evidence has motivated a neurocognitive model of depression in which abnormalities in frontoinsular circuits linking insula with lateral and medial prefrontal systems in the FNĀ and DN, are proposed to contribute to deficits regulating internally-oriented attention, which are cardinal to depression [15, 16].
In refining neurocognitive models of depression, an area of increasing interest is centered on dynamic properties of functional brain networks. Standard methods for estimating resting-state network functioning focus on āstaticā networks, e.g., networks defined by estimates of the overall correlation in activity among brain regions over extended periods of time [17]. While this approach has merit, it cannot capture dynamic patterns of functional coordination as networks form and dissolve, changes in the spatial organization of transient networks, or patterns of transition between networks over time [18]. Such dynamic properties may be critical for understanding regulatory relationships among regions of different static networks, or other qualities of brain functioning or organization [19, 20]. In recent years, advances in analytic methods have indicated that dynamic properties of resting-state network functioning are reliable [21], disrupted in psychiatric illnesses including mood disorders [13, 22], and associated with individual differences in cognitive functioning and rumination [13, 14]. Of note, the dynamic functioning of transient frontoinsular networks may be especially relevant to disorders characterized by poor attention regulation because according to network-switching models, the process by which regulatory regions allocate resources towards or away from other brain systems is inherently dynamic [16]. Therefore, considering dynamic qualities of frontoinsular networks may be particular informative for the pathophysiology of depression and maladaptive introspection.
Although early exploration of resting-state network dynamics has yielded insights into depression and its cognitive correlates, there is an important developmental gap in this research: to our knowledge, resting-state network dynamics have not been examined in adolescent depression, despite evidence that adolescence is a critical period of brain network development. In the teen years, large-scale functional connections become more robust [6], and cross-network coordination becomes more dynamic at rest [23, 24] and more responsive to task demands [25]. Such network changes coincide with significant gains in self-regulation and learning to pursue goals and manage emotions [5]. According to neurocognitive-developmental models of depression, the convergent timing of these events is no coincidence: abnormal brain network maturation corresponds with impaired development of cognitive abilities (e.g., attention regulation) and rumination that contribute to depression [26]. Therefore, understanding depressive abnormalities in teen network dynamics may be an important research target.
The goal of the present study was to address this developmental gap, by testing the following hypotheses in adolescents with varying levels of depression severity (including individuals with current clinical depression). First, that resting-state dominance of network states involving frontoinsular and DN regions would be associated with higher severity of depression (hypothesis 1) and increased tendency towards rumination (hypothesis 2). Second, exploratory analyses were performed to examine the associations between network state transitions (to our knowledge, a new measure of functional network dynamics) and depression or trait rumination. These analyses tested the hypotheses that the frequency of moving between network states involving frontoinsular and DN regions would be associated with symptom severity (exploratory hypothesis 1), and trait rumination (exploratory hypothesis 2). Third, we predicted that results would support a model in which abnormal functional dynamics of frontoinsular and DN states contribute to depression via maladaptive cognitive style, i.e., that the associations between network dominance (hypothesis 3) or network state transitions (exploratory hypothesis 3) and depression would be mediated by rumination.
Materials and methods
Participants
Participants included 45 right-handed adolescents recruited from the Boston area and McLean Hospital programs. Participants were recruited on the basis of either having no history of depression or other psychiatric diagnoses (nā=ā22) or having a primary diagnosis of major depression (nā=ā23) (TableĀ 1, S1). This approach was designed to enhance variance in depression severity, supporting dimensional analyses (analyses that consider categorical diagnosis of depressionāyielding results consistent with dimensional analysesāare reported in the Supplement). Participants were excluded if they reported a history of mania or hypomania, moderate to severe substance use disorders, eating disorders, pervasive developmental disorders, psychosis, neurological impairment or injury, cognitive or language impairments, or current (past 6 weeks) use of benzodiazepines or stimulant medications. Medication status is reported in TableĀ 1, S1; overall medication use covaried with depression and it was not possible to investigate experimental effects in the absence of medications. Depressive symptoms were not significantly associated with age, self-identified gender, race and ethnicity, or parent education or income (psā>ā0.10). However, to control for potential developmental or gender differences across the sample, all analyses controlled for age and gender.
Procedures
The study included a testing session, which included clinical assessments and a magnetic resonance imaging (MRI) scan (see Supplement). Research procedures were approved by the Partners Institutional Review Board and were conducted in accordance with the provisions of the World Medical Association Declaration of Helsinki.
Measures
Depressive symptom severity
Current (past week) severity of depressive symptoms was assessed using the self-report Center for Epidemiological Studies Depression Scale (CESD [27]).
Trait rumination
Trait rumination was evaluated using the self-report Ruminative Responses Scale, Brooding subscale (RRSB [28]). (See Supplement for analyses using other RRS subscales).
Functional imaging
A Siemens Tim Trio 3T scanner and 32-channel head coil were used to collect a high-resolution T1-weighted anatomical image (TRā=ā2100āms, TEā=ā2.25āms, GRAPPA acceleration factor of 2, flip angleā=ā12,Ā 128 slices, field of viewā=ā256āmm, voxel size 1.0āĆā1.0āĆā1.3āmm), and ten minutes of eyes-open resting functional images using a Human Connectome Project sequence (TRā=ā720āms, TEā=ā30āms, GRAPPA acceleration factor of 2, flip angleā=ā66, 66 slices, field of viewā=ā212āmm, voxel size 2.5āĆā2.5āĆā2.5āmm, total volumesā=ā834) [29]. Resting state fMRI data were collected immediately after anatomical scanning, and prior to other functional scanning.
Analyses
Image preprocessing and corrections
See Supplement for information on image preprocessing, and calculation of motion, artifacts, and outlier volumes using SPM12 (http://www.fil.ion.ucl.ac.uk/spm/software/spm12/). Motion/outliers were not significantly associated with clinical variables (psā>ā0.10, Supplement). Motion/outlier scores were used in subsequent analyses (1) to evaluate associations between specific brain states and motion (so that brain states reflecting motion could be identified and removed from analysis, below), and (2) as covariates in group-level analyses, to control for individual differences in motion across the sample [30, 31].
Resting-state co-activation pattern (CAP) analysis
CAP analysis [32,33,34,35] is a data-driven analytic technique that uses the spatial distribution and magnitude of activation at each individual volume and location of whole-brain data as input to a clustering analysis to identify recurring states of relative-co-activation across the brain. CAP analyses were performed using Matlab (version R2016a, Mathworks, Natick, MA) (Fig.Ā 1). First, for each participant and each volume, activation (signal relative to the within-participant global mean at that spatial location) was calculated at each of 130 regions of interest using a whole-brain parcellation of cortex and striatum [36, 37] plus subcortical limbic regions as defined by the AAL atlas [38]. This step yielded a data vector of co-activation estimates for each volume at each ROI and for each participant. Second, co-activation data were concatenated across volumes and participants. Third, k-means clustering was used to partition the data into k brain states that represent recurring patterns of co-activation that emerge over participants and over time. Based on guidelines established in [32], the following range of k values was tested: kā=ā5, 7, 9, and 11 (see Supplement). Fourth, for each k clustering solution, the resulting co-activation brain states were compared against motion estimates and tested for cohesion of the clustering solution. To compare brain states with motion estimates, we calculated the average framewise displacement associated with each brain state (TableĀ S2): at kā=ā9 or kā=ā11, the clustering solution identified a high-motion brain state associated with framewise displacement >1 voxel (displacement estimates of 3.13āmmā3.58āmm). (Informed by [39]). Lower k values failed to identify high-motion brain states, therefore solutions kā=ā9 and kā=ā11 were deemed superior for isolating and removing motion contamination. Next, to test cluster cohesion, we calculated silhouette scores (a measure of how similar each volume of data is to the cluster in which it is grouped [40]) for clustering solutions kā=ā9 and kā=ā11. The kā=ā9 solution yielded an average silhouette score of 0.09 (SDā=ā0.03), and kā=ā11 yielded an average silhouette score of 0.08 (SDā=ā0.04), indicating somewhat better cluster cohesion for the kā=ā9 solution. (Ranges of silhouette scores were comparable to other research using CAP analysis [32, 35]). In sum, among all k solutions tested, the kā=ā9 clustering solution was superior both in terms of removing motion contamination and yielding more cohesive network states. Therefore, the kā=ā9 solution was selected, with eight of the brain states from this clustering solution being eligible for experimental analyses (i.e., excluding the high-motion brain-state). Of relevance to hypotheses were a frontoinsular-DN state involving co-activation of insula, dorsolateral and medial prefrontal cortex, posterior cingulate, and angular gyrus (State 1), and a prototypical DN state of co-activation across midline, temporal, and superior parietal cortex (State 4) (Fig.Ā 2). On average, participants spent 32.22% of scan time in one of these two brain states (see TablesĀ S2āS4, Figs.Ā S1āS5, for additional information on this and other k solutions).
First-level analyses: resting-state network dynamics
For first-level analysis, measures of resting-state network dominance and transitions were calculated for each participant. Measures of network state dominance included (1) overall dwell time in a network state (total proportion of volumes that the participant spent in that brain state over the scan series) and (2) persistence of a network state (total volume-to-volume maintenance of that brain state). The measure of network transitions was (3) total frequency of state-to-state transitions from one volume to the next (e.g., frequency of moving from state A to state B). Measures of network dynamics were calculated using Matlab and R.
Group-level analyses
Group-level analyses were performed using partial correlations and bootstrapped mediation analysis in SPSS, and included age, gender, and motion/outlier scores as covariates. All variables were centered using z-transformation or contrast-coding.
Analyses tested the hypotheses that dominance of transient network states involving frontoinsular and DN regions would be associated with depression and trait rumination, and that the association between network state dominance and depression severity would be mediated by rumination. (See Supplement for analyses conducted with other network states, about which we had no a priori hypotheses). These analyses were accomplished by correlating measures of dwell time or persistence in relevant network states (State 1 and State 4) first with depressive symptom severity (CESD), and second with rumination (RRSB). Third, the indirect effects of network dominance on depression severity through trait rumination were tested with a bootstrapped mediation analysis (10,000 samples) [41].
Exploratory analyses focused on network state transitions. In these analyses, depressive symptom severity (CESD) or rumination (RRSB) were each correlated with the frequency of a given state-to-state transition. Participants who occupied a given network state for <5% of the timeseries were ineligible for these analyses, as estimates of network-to-network transitions would be suppressed in these cases due to low representation of that network state in the timeseries (this procedure resulted in no more than one participant removed from a given analysis). Finally, exploratory mediation analyses tested the indirect effects of network state-to-state transition frequency on depression severity through rumination.
Results
Network dominance
Dominance of a network state involving co-active frontoinsular and DN regions is related to depression severity
Both increased overall dwell time, r(40)ā=ā0.37, pā=ā0.01, and longer persistence, r(40)ā=ā0.36, pā=ā0.01, of network State 1 were associated with higher depressive symptom severity (Fig.Ā 3). However, dwell time and persistence of State 4 were not associated with symptom severity, r(40)ā=āā0.02, pā=ā0.89, and r(40)ā=āā0.01, pā=ā0.96. These effects indicate that resting-state dominance of a transient network involving co-active frontoinsular and DN regions (State 1) was significantly related to depression in adolescents, but dominance of a prototypical DN state (State 4) was not.
Associations between depression and dwell or persistence ofĀ other networks (about which we had no a priori hypotheses) are reported in TableĀ S3. In brief, decreased dwell time and shorter persistence of State 7 (involving primarily sensorimotor regions) and State 6 (involving activation in striatal regions) were both associated with higher severity of depression. (See Supplement for details).
Dominance of a network state involving co-active frontoinsular and DN regions is related to trait rumination
Complementing results above, both increased dwell time in, r(40)ā=ā0.37, pā=ā0.01, and longer persistence of, r(40)ā=ā0.34, pā=ā0.02, network State 1 were associated with higher tendency towards brooding rumination (Fig.Ā 3). However, neither dwell time nor persistence of State 4 were significantly associated with rumination, r(40)ā=āā0.17, pā=ā0.28 and r(40)ā=āā0.16, pā=ā0.31. Thus together, dominance of a transient network spanning frontoinsular and DN regions (State 1) was related to both depressive symptoms and to trait brooding rumination.
Network transitions
Frequency of network transitions involving frontoinsular and DN regions is related to depression severity
Higher frequency of State 1-to-State 4 transitions was correlated with higher severity of depression, r(39)ā=ā0.33, pā=ā0.04 (Fig.Ā 3). The association between frequency of State 4-to-State 1 transitions and depression did not reach significance, r(39)ā=ā0.28, pā=ā0.07. A Meng test [42] clarified, however, that correlations between depression and each type of state-to-state transition were not significantly different, zā=āā0.71, pā=ā0.47 (See also TableĀ S4).
Frequency of network transitions involving frontoinsular and DN regions is related to trait rumination
Higher frequency of State 1-to-State 4 transitions was correlated with increased tendency towards rumination, r(39)ā=ā0.41, pā<ā0.01. The association between higher frequency of State 4-to-State 1 transitions and rumination was not significant, r(39)ā=ā0.29, pā=ā0.07 (Fig.Ā 3). A Meng test revealed that correlations between rumination and each type of state-to-state transition were not significantly different, zā=āā1.60, pā=ā0.11.
Of note, neither depressive symptoms nor trait rumination were significantly related to overall frequency of network transitions, psā>ā0.10, and controlling for overall transitions in the above analyses did not alter the pattern or significance of effects. Together, these results indicate that the tendency to move frequently between a frontoinsular-DN state and a prototypical DN state is associated with both depressive symptoms and the trait tendency towards rumination; critically, these relationships cannot be explained by generally higher network switching.
Mediated effects of network dynamics
Indirect effect of frontoinsular-default network dominance on depression through rumination
Following the direct effects of State 1 dominance on depression reported above, we used a bootstrapping approach to estimate the indirect effects of network dominance (dwell time or persistence of State 1: X variable) on depressive symptom severity (CESD: Y variable) through brooding rumination (RRSB: M variable). Mediation analyses revealed significant indirect effects of both State 1 dwell (indirect effectā=ā5.92, SE(boot)ā=ā2.17, bias-corrected 95% CI: 1.96ā10.61) and State 1 persistence (indirect effectā=ā0.0074, SE(boot)ā=ā0.0032, bias-corrected 95% CI: 0.0017ā0.0143) via trait rumination on depressive symptoms (Fig.Ā 4).
Indirect effect of frontoinsular-DN transitions on depression through rumination
Following the direct effects of network transitions on depression reported above, exploratory mediation analyses were performed to evaluate the indirect effect of network state-to-state transitions (frequency of transitions, State 1-to-State 4, or State 4-to-State 1: X variable) on depressive symptom severity (CESD: Y variable) through brooding rumination (RRSB: M variable). There was a significant indirect effect of State 1-to-State 4 transitions (indirect effectā=ā0.07, SE(boot)ā=ā0.02, bias-corrected 95% CI: 0.02ā0.12) via trait brooding rumination on depressive symptoms (Fig.Ā 4). The indirect effect of State 4-to-State 1 transitions via brooding on depressive symptoms did not reach statisticalĀ significance (indirect effectā=ā0.04, SE(boot)ā=ā0.02, bias-corrected 95% CI: 0.00ā0.08).
Discussion
Adolescent depression is an important target of neurocognitive research: achieving a better understanding of brain network dysfunction, and maladaptive cognitive styles that may be reflected in or fueled by such dysfunction, can provide important insight into early-stage mood pathology [5]. Towards this goal, the present study shows that teens characterized by resting-state dominance of a network state involving frontoinsular regions and areas of DN reported a greater tendency towards maladaptive rumination and more severe depressive symptoms. In addition, the present study provides novel evidence that adolescent depression and rumination are each associated with higher frequency of transitions between a (dominant) frontoinsular-DN state and a prototypical DN state. Finally, this study reveals mediated effects supporting a neurocognitive model in which abnormal frontoinsular dynamics make teens more prone to rumination, which in turn contributes to depressive symptoms. These results are consistent with prior findings [13, 14, 43] and extend that research by focusing on adolescence.
Intrinsic functional dominance of the DN has been previously observed in adults [7]. The present findings suggest, however, that the nature of DN-related dominance in adolescent depression is complex: here, more severely depressed teens showed increased dominance of a āmixedā network characterized by co-activation across regions of anterior insula (typically grouped within the SN), prefrontal cortex (including dorsolateral areas of the FN, and medial regions of the DN), and other posterior regions of the DN (i.e., posterior cingulate, angular gyrus), but did not exhibit differences in dominance of a network state that was restricted to the prototypical DN. Conceptually, these results are consistent with the idea that heightened depression is related to biases for frontoinsular regions to engage with areas of the DNāe.g., insula or dorsolateral systems acting to allocate resources towards midline and temporal regions of cortex, or receive salience-related signals from regions of the DN [44]. Coordination across frontoinsular and DN systems may play a role in directing attention towards or away from internal thoughts [12], making these regions especially relevant to biases towardsāor the capacity to disengage fromārumination. The dominance of frontoinsular-DN co-activation may reflect impaired ability to disengage from rumination, or amplified salience of ruminative thoughts (and this may apply not only to brooding, but also other forms of self-focused thinking during negative mood; see Supplement). In contrast, normative activity of a prototypical DN state suggests that networks recruited more generally for introspection (e.g., including other forms of mind wandering that are benign or less intrusive) may be less involved in rumination. Future research aimed at understanding various forms of introspection as they relate to different transient functional networks involving classic DN systems, along with other regulatory systems in insula or prefrontal cortex, may help to distinguish these possibilities.
In addition to highlighting frontoinsular and DN dominance, the present study provides evidence that dynamic transitions between network states may be an important dimension of abnormal brain functioning in adolescent depression. More severely depressed teens not only persisted longer in a frontoinsular-DN state, they also tended to transition more frequently between an frontoinsular-DN state and a prototypical DN state. These patterns of increased transition frequency may signify a functional tendency for regions of prefrontal cortex or insula to be deployed to regulate ongoing activity in the DN, for frontoinsular functioning to be influenced by midline or temporal cortical activation, or instability in the regulatory relationships among these regions (consistent with [13]). One interpretation that links transition frequency to cognitive processes is that for people prone to rumination, transient increases in intrusive, emotionally salient thoughts and/or efforts to direct attention away from emotional thoughts tends to contaminate introspection (reflected in shifts between frontoinsular-DN and DN states). The idea that ruminative thoughts are experienced as intrusive and inescapable is consistent with prior clinical research [45].
There are several limitations of the present study. First, the relative contribution of state versus trait-like properties to estimates of network functioning are unknown [46]. During resting-state, frontoinsular-DN dominance or transitions may reflect brain functions that correspond with in vivo ruminative thinking, or intrinsic functioning of these networks that confers vulnerability to rumination. This issue challenges the interpretation of any resting-state study, but may be addressed with procedures such as thought-sampling or repeated within-person measurement to evaluate the stability of resting-state (including dynamic) properties. Second, although these results converge with previous research using other dynamic methods [13, 43], future research that integrates multiple methodological approaches will help to illustrate the attributes (or weaknesses) of various methods while also providing a clearer sense of what are meaningful dimensions of network dynamics. In parallel, future research may focus on other transient networks, e.g., involving sensorimotor or striatal regions that were implicated in this study but fell beyond the scope of a priori hypotheses (see Supplement). Third, adolescents with current major depression were the primary users of psychoactive medications in this study, and we could not disentangle general medication use from depression severity. Research that evaluates brain network functioning in unmedicated teens may provide additional information. Fourth, the sample included adolescents with an anxiety disorder secondary to major depression (nā=ā7). Excluding these subjects did not alter the pattern of effects (see Supplement), but future research should investigate the moderating effect of anxiety on associations between depression, introspection (including worry) and network functioning. Fifth, the study sample size was not large enough to examine developmental effects, and although analyses covaried age, pubertal stage was not evaluated. Prior research has shown that resting network dynamics change over adolescent development [25], and the onset of puberty is related to increased rumination and heightened risk of depressionāespecially for girls [47, 48]. Future research that targets pubertal stage and gender may provide new insight into the etiology and timing of network abnormalities. Together, the present findings constitute a preliminary exploration of network dynamics; future research in larger, independent samples is needed to evaluate the reliability of these effects.
In conclusion, this study provides evidence that teens characterized by dominant activation in frontoinsular-default networks, and frequent transitions between networks involving frontoinsular and DN systems, are more prone to rumination and report more severe symptoms of depression. Mediation results support a neurocognitive model in which abnormal frontoinsular network dynamics make teens more prone to rumination, which in turn exacerbates depressive symptoms. Future research in larger samples that evaluates network dynamics over the course of adolescent development may provide insight into neurocognitive dimensions that reflect or contribute to mood health.
References
Kessler RC. The costs of depression. Psychiatr Clin North Am. 2012;35:1ā14.
Kessler RC, Avenevoli S, Costello EJ, Georgiades K, Green JG, Gruber MJ, et al. Prevalence, persistence, and sociodemographic correlates of DSM-IV disorders in the national comorbidity survey replication adolescent supplement. Arch Gen Psychiatry. 2012;69:372ā80.
Pine DS, Cohen P, Gurley D, Brook J, Ma YJ. The risk for early-adulthood anxiety and depressive disorders in adolescents with anxiety and depressive disorders. Arch Gen Psychiatry. 1998;55:56ā64.
Pine DS, Cohen E, Cohen P, Brook J. Adolescent depressive symptoms as predictors of adult depression: Moodiness or mood disorder? Am J Psychiatry. 1999;156:133ā5.
Casey BJ, Jones RM, Levita L, Libby V, Pattwell SS, Ruberry EJ, et al. The storm and stress of adolescence: insights from human imaging and mouse genetics. Dev Psychobiol. 2010;52:225ā35.
Power JD, Fair DA, Schlaggar BL, Petersen SE. The development of human functional brain networks. Neuron. 2010;67:735ā48.
Kaiser RH, Andrews-Hanna JR, Wager TD, Pizzagalli DA. Large-scale network dysfunction in major depressive disorder a meta-analysis of resting-state functional connectivity. Jama Psychiatry. 2015;72:603ā11.
Andrews-Hanna JR, Smallwood J, Spreng RN, editors. The default network and self-generated thought: component processes, dynamic control, and clinical relevance. Ann N Y Acad Sci. 2014;1316:29ā52.
Zanto TP, Gazzaley A. Fronto-parietal network: flexible hub of cognitive control. Trends Cogn Sci. 2013;17:602ā3.
Corbetta M, Patel G, Shulman GL. The reorienting system of the human brain: from environment to theory of mind. Neuron. 2008;58:306ā24.
Sridharan D, Levitin DJ, Menon V. A critical role for the right fronto-insular cortex in switching between central-executive and default-mode networks. Proc Natl Acad Sci USA. 2008;105:12569ā74.
Dixon ML, De la Vega A, Mills C, Andrews-Hanna J, Spreng RN, Cole MW, et al. Heterogeneity within the frontoparietal control network and its relationship to the default and dorsal attention networks. Proc Natl Acad Sci USA. 2018;115:E1598ā607.
Kaiser RH, Whitfield-Gabrieli S, Dillon DG, Goer F, Beltzer M, Minkel J, et al. Dynamic resting-state functional connectivity in major depression. Neuropsychopharmacology. 2016;41:1822ā30.
Kaiser RH, Snyder HR, Goer R, Clegg R, Ironside M, Pizzagalli DA. Attention bias in rumination and depression: cognitive mechanisms and brain networks. Clin Psychol Sci. 2018;6:765ā82.
Kaiser RH. Neurocognitive markers of depression. Biol Psychiatry. 2017;81:e29ā31.
Menon V. Large-scale brain networks and psychopathology: a unifying triple network model. Trends Cogn Sci. 2011;15:483ā506.
Biswal B, Yetkin FZ, Haughton VM, Hyde JS. Functional connectivity in the motor cortex of resting human brain using echo-planar MRI. Magn Reson Med. 1995;34:537ā41.
Hutchison RM, Womelsdorf T, Allen EA, Bandettini PA, Calhoun VD, Corbetta M, et al. Dynamic functional connectivity: promise, issues, and interpretations. Neuroimage. 2013;80:360ā78.
Bray S, Arnold A, Levy RM, Iaria G. Spatial and temporal functional connectivity changes between resting and attentive states. Hum Brain Mapp. 2015;36:549ā65.
Chang C, Liu ZM, Chen MC, Liu X, Duyn JH. EEG correlates of time-varying BOLD functional connectivity. Neuroimage. 2013;72:227ā36.
Calhoun VD, Miller R, Pearlson G, Adali T. The Chronnectome: time-varying connectivity networks as the next frontier in fMRI data discovery. Neuron. 2014;84:262ā74.
Rashid B, Arbabshirani MR, Damaraju E, Cetin MS, Miller R, Pearlson GD, et al. Classification of schizophrenia and bipolar patients using static and dynamic resting-state fMRI brain connectivity. Neuroimage. 2016;134:645ā57.
Faghiri A, Stephen JM, Wang YP, Wilson TW, Calhoun VD. Changing brain connectivity dynamics: from early childhood to adulthood. Hum Brain Mapp. 2018;39:1108ā17.
Marusak HA, Calhoun VD, Brown S, Crespo LM, Sala-Hamrick K, Gotlib IH, et al. Dynamic functional connectivity of neurocognitive networks in children. Hum Brain Mapp. 2017;38:97ā108.
Hutchison RM, Morton JB. Tracking the brainās functional coupling dynamics over development. J Neurosci. 2015;35:6849ā59.
Kaiser RH, Pizzagalli DA. Dysfunctional connectivity in the depressed adolescent brain. Biol Psychiatry. 2015;78:594ā5.
Radloff LS. The use of the center for epidemiologic studies depression scale in adolescents and young-adults. J Youth Adolesc. 1991;20:149ā66.
Treynor W, Gonzalez R, Nolen-Hoeksema S. Rumination reconsidered: a psychometric analysis. Cogn Ther Res. 2003;27:247ā59.
Smith SM, Vidaurre D, Beckmann CF, Glasser MF, Jenkinson M, Miller KL, et al. Functional connectomics from resting-state fMRI. Trends Cogn Sci. 2013;17:666ā82.
Power JD, Schlaggar BL, Petersen SE. Recent progress and outstanding issues in motion correction in resting state fMRI. Neuroimage. 2015;105:536ā51.
Yan CG, Cheung B, Kelly C, Colcombe S, Craddock RC, Di Martino A, et al. A comprehensive assessment of regional variation in the impact of head micromovements on functional connectomics. Neuroimage. 2013;76:183ā201.
Chen JE, Chang C, Greicius MD, Glover GH. Introducing co-activation pattern metrics to quantify spontaneous brain network dynamics. Neuroimage. 2015;111:476ā88.
Liu X, Chang C, Duyn JH. Decomposition of spontaneous brain activity into distinct fMRI co-activation patterns. Front Syst Neurosci. 2013;7:11.
Liu X, Duyn JH. Time-varying functional network information extracted from brief instances of spontaneous brain activity. Proc Natl Acad Sci USA. 2013;110:4392ā7.
Liu X, Zhang NY, Chang CT, Duyn JH. Co-activation patterns in resting-state fMRI signals. Neuroimage. 2018;180:485ā94.
Choi EY, Yeo BTT, Buckner RL. The organization of the human striatum estimated by intrinsic functional connectivity. J Neurophysiol. 2012;108:2242ā63.
Yeo BTT, Krienen FM, Sepulcre J, Sabuncu MR, Lashkari D, Hollinshead M, et al. The organization of the human cerebral cortex estimated by intrinsic functional connectivity. J Neurophysiol. 2011;106:1125ā65.
Tzourio-Mazoyer N, Landeau B, Papathanassiou D, Crivello F, Etard O, Delcroix N, et al. Automated anatomical labeling of activations in SPM using a macroscopic anatomical parcellation of the MNI MRI single-subject brain. Neuroimage. 2002;15:273ā89.
Rummel C, Verma RK, Schopf V, Abela E, Hauf M, Berruecos JFZ, et al. Time course based artifact identification for independent components of resting-state fMRI. Front Hum Neurosci. 2013;7:8.
Rousseeuw PJ. Silhouettes - a graphical aid to the interpretation and validation of cluster-analysis. J Comput Appl Math. 1987;20:53ā65.
Preacher KJ, Hayes AF. SPSS and SAS procedures for estimating indirect effects in simple mediation models. Behav Res Methods Instrum Comput. 2004;36:717ā31.
Meng XL, Rosenthal R, Rubin DB. Comparing correlated correlation coefficients. Psychol Bull. 1992;111:172ā5.
Hamilton JP, Furman DJ, Chang C, Thomason ME, Dennis E, Gotlib IH. Default-mode and task-positive network activity in major depressive disorder: implications for adaptive and maladaptive rumination. Biol Psychiatry. 2011;70:327ā33.
Menon V, Uddin LQ. Saliency, switching, attention and control: a network model of insula function. Brain Struct Funct. 2010;214:655ā67.
Papageorgiou C, Wells A. Metacognitive beliefs about rumination in recurrent major depression. Cogn Behav Pr. 2001;8:160ā4.
Geerligs L, Rubinov M, Henson RN, Cam CAN. State and trait components of functional connectivity: individual differences vary with mental state. J Neurosci. 2015;35:13949ā61.
Nolen-Hoeksema S. The emergence of gender differences in depression during adolescence. Psychol Bull. 1994;115:424ā43.
Nolen-Hoeksema S, Watkins ER. A heuristic for developing transdiagnostic models of psychopathology: explaining multifinality and divergent trajectories. Perspect Psychol Sci. 2011;6:589ā609.
Funding and disclosure
Supported by the Phyllis and Jerome Lyle Rappaport Fellowship (R.H.K.), NIMH grants F32MH106262, 1R56MH117131-01 (R.H.K.) and 5R37MH095809 (D.A.P). R.P.A. was partially supported by K23MH097786. The authors declared no conflicts of interest with respect to the authorship or the publication of this article. Over the past three years, D.A.P received consulting fees from Akili Interactive Labs, BlackThorn Therapeutics, Boehringer Ingelheim, Posit Science and Takeda Pharmaceuticals USA and honoraria from Alkermes for activities unrelated to the current study. A subset of analyses reported here were presented (by R.H.K.) at the 2017 annual meetings of the Society of Biological Psychiatry and the Society for Research on Psychopathology.
Author information
Authors and Affiliations
Contributions
RHK developed the study concept and RHK and DAP contributed to the study design; RHK and RMH contributed to analytic design. Testing and data collection were performed by RHK, MK, FG, and RC; and JV, EE, BA, and RPA provided support in recruitment and evaluation of inclusion/exclusion criteria. Data analysis was conducted by RHK and interpretation of analyses was performed by RHK, MK, and DAP. Funding provided by RHK and DAP. RHK drafted the paper, and all other authors provided critical revisions. All authors approved the final version of the paper for submission.
Corresponding author
Additional information
Publisherās note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary information
Rights and permissions
About this article
Cite this article
Kaiser, R.H., Kang, M., Lew, Y. et al. Abnormal frontoinsular-default network dynamics in adolescent depression and rumination: a preliminary resting-state co-activation pattern analysis. Neuropsychopharmacol. 44, 1604ā1612 (2019). https://doi.org/10.1038/s41386-019-0399-3
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/s41386-019-0399-3
This article is cited by
-
Spatiotemporal dynamics of hippocampal-cortical networks underlying the unique phenomenological properties of trauma-related intrusive memories
Molecular Psychiatry (2024)
-
Sex-specific resting state brain network dynamics in patients with major depressive disorder
Neuropsychopharmacology (2024)
-
The co-activation patterns of multiple brain regions in Juvenile Myoclonic Epilepsy
Cognitive Neurodynamics (2024)
-
Aberrant resting-state co-activation network dynamics in major depressive disorder
Translational Psychiatry (2024)
-
A three-dimensional model of neural activity and phenomenal-behavioral patterns
Molecular Psychiatry (2023)