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Triple Network Functional Connectivity During Acute Stress in Adolescents and the Influence of Polyvictimization

  • Rachel Corr
    Correspondence
    Address correspondence to Rachel Corr, Ph.D.
    Affiliations
    Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina

    Duke-UNC Brain Imaging and Analysis Center, Duke University Medical Center, Durham, North Carolina
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  • Sarah Glier
    Affiliations
    Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina

    Duke-UNC Brain Imaging and Analysis Center, Duke University Medical Center, Durham, North Carolina
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  • Joshua Bizzell
    Affiliations
    Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina

    Carolina Institute for Developmental Disabilities, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina

    Frank Porter Graham Child Development Institute, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina

    Duke-UNC Brain Imaging and Analysis Center, Duke University Medical Center, Durham, North Carolina
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  • Andrea Pelletier-Baldelli
    Affiliations
    Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina

    Duke-UNC Brain Imaging and Analysis Center, Duke University Medical Center, Durham, North Carolina
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  • Alana Campbell
    Affiliations
    Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina

    Carolina Institute for Developmental Disabilities, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
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  • Candace Killian-Farrell
    Affiliations
    Department of Child and Adolescent Psychiatry & Behavioral Health Sciences, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania
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  • Aysenil Belger
    Affiliations
    Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina

    Carolina Institute for Developmental Disabilities, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina

    Frank Porter Graham Child Development Institute, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina

    Duke-UNC Brain Imaging and Analysis Center, Duke University Medical Center, Durham, North Carolina
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Open AccessPublished:March 12, 2022DOI:https://doi.org/10.1016/j.bpsc.2022.03.003

      Abstract

      Background

      Exposure to both chronic and acute stressors can disrupt functional connectivity (FC) of the default mode network (DMN), salience network (SN), and central executive network (CEN), increasing risk for negative health outcomes. During adolescence, these stress-sensitive triple networks undergo critical neuromaturation that is altered by chronic exposure to general forms of trauma or victimization. However, no work has directly examined how acute stress affects triple network FC in adolescents or whether polyvictimization—exposure to multiple categories/subtypes of victimization—influences adolescent triple network neural acute stress response.

      Methods

      This functional magnetic resonance imaging study examined seed-to-voxel FC of the DMN, SN, and CEN during the Montreal Imaging Stress Task. Complete data from 73 participants aged 9 to 16 years (31 female) are reported.

      Results

      During acute stress, FC was increased between DMN and CEN regions and decreased between the SN and the DMN and CEN. Greater polyvictimization was associated with reduced FC during acute stress exposure between the DMN seed and a cluster containing the left insula of the SN.

      Conclusions

      These results indicate that acute stress exposure alters FC between the DMN, SN, and CEN in adolescents. In addition, FC changes during stress between the DMN and SN are further moderated by polyvictimization exposure.

      Keywords

      Perceiving and responding to stressors are vital for daily functioning, and dysregulated neurobiological acute stress responses (ASRs) are associated with adolescent development of psychiatric disorders (
      • Zhang X.
      • Ge T.T.
      • Yin G.
      • Cui R.
      • Zhao G.
      • Yang W.
      Stress-induced functional alterations in amygdala: Implications for neuropsychiatric diseases.
      ,
      • Shin L.M.
      • Liberzon I.
      The neurocircuitry of fear, stress, and anxiety disorders.
      ). Characterizing ASRs in adolescents is critical, because they experience increased exposure to intense and novel stressors and brain maturation in stress-sensitive circuits involved in emotional processing and executive control (
      • Seiffge-Krenke I.
      Causal links between stressful events, coping style, and adolescent symptomatology.
      ,
      • Romeo R.D.
      The teenage brain: The stress response and the adolescent brain.
      ,
      • Romeo R.D.
      The impact of stress on the structure of the adolescent brain: Implications for adolescent mental health.
      ,
      National Academies of Sciences, Engineering, and Medicine
      Fostering Healthy Mental, Emotional, and Behavioral Development in Children and Youth: A National Agenda.
      ). Acute stress exposure typically elicits temporary psychological, biological, and behavioral changes through the process of allostasis, which is terminated upon stressor cessation, allowing the body to recover to its homeostatic baseline (
      • McEwen B.S.
      • Gianaros P.J.
      Stress- and allostasis-induced brain plasticity.
      ). Chronic stress exposure associated with trauma can lead to allostatic load as the brain adapts to repeated stressors, resulting in blunted or prolonged neurobiological ASRs and increased risk for developing mood and anxiety disorders (
      • Wolfe D.A.
      Why polyvictimization matters.
      ,
      • Guidi J.
      • Lucente M.
      • Sonino N.
      • Fava G.A.
      Allostatic load and its impact on health: A systematic review.
      ). The cumulative burden of exposure to acutely stressful victimization events in different environments is reflected by polyvictimization (PV), defined as experiencing victimization across multiple categories/subtypes, including conventional crimes, child maltreatment, peer/sibling victimization, sexual victimization, and indirect victimization. The allostatic load associated with PV has been hypothesized to lead to long-term neurobiological changes to neural systems critical for regulating adaptive ASRs (
      • Wolfe D.A.
      Why polyvictimization matters.
      ). Yet, little is known about the neurobiological impacts of PV or how PV influences neural network responses to stress in adolescence, especially in the context of the rapid maturation of these networks during this developmental period. This study aims to elucidate these relationships and represents the first analysis of PV’s influence on neural network ASRs in adolescents.
      Previous studies of victimization in adolescents using functional magnetic resonance imaging (fMRI) typically only include a single type of victimization [i.e., neighborhood violence (
      • Miller G.E.
      • Chen E.
      • Armstrong C.C.
      • Carroll A.L.
      • Ozturk S.
      • Rydland K.J.
      • et al.
      Functional connectivity in central executive network protects youth against cardiometabolic risks linked with neighborhood violence.
      ) or victimization by peers (
      • Quinlan E.B.
      • Barker E.D.
      • Luo Q.
      • Banaschewski T.
      • Bokde A.L.W.
      • Bromberg U.
      • et al.
      Peer victimization and its impact on adolescent brain development and psychopathology.
      )], but studying the isolated influences of specific types of victimization may overestimate the impact of any individual category (
      • Haahr-Pedersen I.
      • Ershadi A.E.
      • Hyland P.
      • Hansen M.
      • Perera C.
      • Sheaf G.
      • et al.
      Polyvictimization and psychopathology among children and adolescents: A systematic review of studies using the Juvenile Victimization Questionnaire.
      ). Findings related to specific trauma subtypes may be confounded by PV, because adolescents experiencing a single victimization incident in one year are 2 to 3 times more likely to experience an additional subtype (
      • Finkelhor D.
      • Turner H.
      • Ormrod R.
      • Hamby S.L.
      Violence, abuse, and crime exposure in a national sample of children and youth.
      ). Furthermore, extant studies of trauma-related neural functional connectivity (FC)—the temporal correlation between activation of different brain regions, indicating their participation in a common network—typically compare binary groups: those with past trauma exposure and control subjects (
      • Weng Y.
      • Qi R.
      • Zhang L.
      • Luo Y.
      • Ke J.
      • Xu Q.
      • et al.
      Disturbed effective connectivity patterns in an intrinsic triple network model are associated with posttraumatic stress disorder.
      ,
      • Sheynin J.
      • Duval E.R.
      • Lokshina Y.
      • Scott J.C.
      • Angstadt M.
      • Kessler D.
      • et al.
      Altered resting-state functional connectivity in adolescents is associated with PTSD symptoms and trauma exposure.
      ). Such study designs do not allow for analysis of the cumulative impact of multiple forms of trauma exposure. Similarly, using a total victimization measure may conflate the neurobiological effects of exposure to multiple forms of trauma with frequent exposure to one form (
      • Hickman L.J.
      • Jaycox L.H.
      • Setodji C.M.
      • Kofner A.
      • Schultz D.
      • Barnes-Proby D.
      • Harris R.
      How much does “how much” matter? Assessing the relationship between children’s lifetime exposure to violence and trauma symptoms, behavior problems, and parenting stress.
      ,
      • Corr R.
      • Glier S.
      • Bizzell J.
      • Pelletier-Baldelli A.
      • Campbell A.
      • Killian-Farrell C.
      • Belger A.
      Stress-related hippocampus activation mediates the association between polyvictimization and trait anxiety in adolescents [published online ahead of print Dec 1].
      ). Hickman et al. (
      • Hickman L.J.
      • Jaycox L.H.
      • Setodji C.M.
      • Kofner A.
      • Schultz D.
      • Barnes-Proby D.
      • Harris R.
      How much does “how much” matter? Assessing the relationship between children’s lifetime exposure to violence and trauma symptoms, behavior problems, and parenting stress.
      ) found that PV independently predicted child posttraumatic stress symptoms and behavioral problems, even when models accounted for total lifetime victimization exposure or frequency of most individual PV categories (
      • Hickman L.J.
      • Jaycox L.H.
      • Setodji C.M.
      • Kofner A.
      • Schultz D.
      • Barnes-Proby D.
      • Harris R.
      How much does “how much” matter? Assessing the relationship between children’s lifetime exposure to violence and trauma symptoms, behavior problems, and parenting stress.
      ). Analyzing categorically defined PV enables measurement of victimization’s influence across spectra of cumulative burden and subtypes of trauma, rather than binarily analyzing trauma-exposed individuals versus control subjects.
      Even though the impact of PV on FC is unclear, early-life exposure to adverse events is linked with aberrant FC; trauma exposure can have long-lasting effects on adolescent FC both at rest (
      • Miller G.E.
      • Chen E.
      • Armstrong C.C.
      • Carroll A.L.
      • Ozturk S.
      • Rydland K.J.
      • et al.
      Functional connectivity in central executive network protects youth against cardiometabolic risks linked with neighborhood violence.
      ,
      • Silveira S.
      • Shah R.
      • Nooner K.B.
      • Nagel B.J.
      • Tapert S.F.
      • de Bellis M.D.
      • Mishra J.
      Impact of childhood trauma on executive function in adolescence—Mediating functional brain networks and prediction of high-risk drinking.
      ) and during emotional and cognitive tasks (
      • Marusak H.A.
      • Martin K.R.
      • Etkin A.
      • Thomason M.E.
      Childhood trauma exposure disrupts the automatic regulation of emotional processing.
      ). Recent research suggests that trauma exposure causes widespread alterations in broader networks, particularly the default mode network (DMN), salience network (SN), and central executive network (CEN) (
      • Weng Y.
      • Qi R.
      • Zhang L.
      • Luo Y.
      • Ke J.
      • Xu Q.
      • et al.
      Disturbed effective connectivity patterns in an intrinsic triple network model are associated with posttraumatic stress disorder.
      ,
      • Rakesh D.
      • Kelly C.
      • Vijayakumar N.
      • Zalesky A.
      • Allen N.B.
      • Whittle S.
      Unraveling the consequences of childhood maltreatment: Deviations from typical functional neurodevelopment mediate the relationship between maltreatment history and depressive symptoms.
      ,
      • McLaughlin K.A.
      • Weissman D.
      • Bitrán D.
      Childhood adversity and neural development: A systematic review.
      ,
      • Menon B.
      Towards a new model of understanding—The triple network, psychopathology and the structure of the mind.
      ,
      • Liu Y.
      • Li L.
      • Li B.
      • Feng N.
      • Li L.
      • Zhang X.
      • et al.
      Decreased triple network connectivity in patients with recent onset post-traumatic stress disorder after a single prolonged trauma exposure.
      ). The triple network model posits that these networks direct critical cognitive processes, including perception, emotional affect regulation, and social functioning, that are closely associated with areas of impairment often seen in victimized adolescents: the SN enables convergence of sensory and affective inputs; the DMN is responsible for introspection, retrospection, and prospection; and the CEN drives top-down attentional control and goal-directed behavior (
      • Menon B.
      Towards a new model of understanding—The triple network, psychopathology and the structure of the mind.
      ).
      The triple network model of posttraumatic stress disorder (PTSD) suggests that traumatic stress exposure is associated with 1) increased within-network SN FC, resulting in hyperarousal/heightened threat detection, and increased FC between the SN and the CEN and DMN, impairing the SN’s ability to modulate between the two networks when switching between task-relevant and task-irrelevant behaviors; 2) reduced within-network DMN FC and between-network connectivity with the CEN, resulting in intrusive symptoms, fear generalization, and an altered sense of self; and 3) reduced within-network CEN FC leading to cognitive deficits (
      • Akiki T.J.
      • Averill C.L.
      • Abdallah C.G.
      A network-based neurobiological model of PTSD: Evidence from structural and functional neuroimaging studies.
      ). Previous work indicates that FC in triple network regions shortly after trauma exposure can predict future development of PTSD symptoms (
      • Qin L.D.
      • Wang Z.
      • Sun Y.W.
      • Wan J.Q.
      • Su S.S.
      • Zhou Y.
      • Xu J.R.
      A preliminary study of alterations in default network connectivity in post-traumatic stress disorder patients following recent trauma.
      ). Adolescent resting-state FC (rsFC) studies have revealed that trauma exposure is associated with aberrant rsFC between these networks, particularly between the DMN and SN (
      • Sheynin J.
      • Duval E.R.
      • Lokshina Y.
      • Scott J.C.
      • Angstadt M.
      • Kessler D.
      • et al.
      Altered resting-state functional connectivity in adolescents is associated with PTSD symptoms and trauma exposure.
      ,
      • Marusak H.A.
      • Martin K.R.
      • Etkin A.
      • Thomason M.E.
      Childhood trauma exposure disrupts the automatic regulation of emotional processing.
      ).
      However, current analyses mainly address trauma’s influence at rest, and less is known about how trauma impacts these networks during stress in adolescents. Analyzing the triple networks during acute stress is particularly important, because increased vulnerability to stress, decreased CEN FC during acute stress, and an absence of decreased DMN FC during stress are found across a wide range of psychiatric disorders (
      • van Oort J.
      • Kohn N.
      • Vrijsen J.N.
      • Collard R.
      • Duyser F.A.
      • Brolsma S.C.A.
      • et al.
      Absence of default mode downregulation in response to a mild psychological stressor marks stress-vulnerability across diverse psychiatric disorders.
      ). Considering that aberrant FC within and between the triple networks is found in many psychiatric disorders (
      • Menon B.
      Towards a new model of understanding—The triple network, psychopathology and the structure of the mind.
      ,
      • Liu Y.
      • Li L.
      • Li B.
      • Feng N.
      • Li L.
      • Zhang X.
      • et al.
      Decreased triple network connectivity in patients with recent onset post-traumatic stress disorder after a single prolonged trauma exposure.
      ) and that these networks are impacted by both acute (
      • van Oort J.
      • Tendolkar I.
      • Hermans E.J.
      • Mulders P.C.
      • Beckmann C.F.
      • Schene A.H.
      • et al.
      How the brain connects in response to acute stress: A review at the human brain systems level.
      ,
      • Hermans E.J.
      • van Marle H.J.F.
      • Ossewaarde L.
      • Henckens M.J.A.G.
      • Qin S.
      • van Kesteren M.T.R.
      • et al.
      Stress-related noradrenergic activity prompts large-scale neural network reconfiguration.
      ) and chronic (
      • Zeev-Wolf M.
      • Levy J.
      • Goldstein A.
      • Zagoory-Sharon O.
      • Feldman R.
      Chronic early stress impairs default mode network connectivity in preadolescents and their mothers.
      ,
      • Fadel E.
      • Boeker H.
      • Gaertner M.
      • Richter A.
      • Kleim B.
      • Seifritz E.
      • et al.
      Differential alterations in resting state functional connectivity associated with depressive symptoms and early life adversity.
      ) stress exposure, it is important to elucidate the mechanisms by which PV moderates FC during acute stress yielding more sustained effects on cognition and behavior.
      This report examined modulation of FC within and between the triple networks during acute psychosocial stress (the Montreal Imaging Stress Task [MIST]) to determine PV’s influence on neural ASRs. Neural activation during MIST has been previously reported for this adolescent sample, who display a heterogenous range of psychiatric symptoms (
      • Corr R.
      • Glier S.
      • Bizzell J.
      • Pelletier-Baldelli A.
      • Campbell A.
      • Killian-Farrell C.
      • Belger A.
      Stress-related hippocampus activation mediates the association between polyvictimization and trait anxiety in adolescents [published online ahead of print Dec 1].
      ,
      • Corr R.
      • Pelletier-Baldelli A.
      • Glier S.
      • Bizzell J.
      • Campbell A.
      • Belger A.
      Neural mechanisms of acute stress and trait anxiety in adolescents.
      ). This FC analysis represents a necessary expansion on our prior work to better characterize adolescent neural ASRs. We hypothesized that during stress, adolescents would exhibit increased FC within and between the DMN and SN, as identified by studies of acute stress in healthy adults (
      • van Oort J.
      • Tendolkar I.
      • Hermans E.J.
      • Mulders P.C.
      • Beckmann C.F.
      • Schene A.H.
      • et al.
      How the brain connects in response to acute stress: A review at the human brain systems level.
      ). Prior work has primarily examined the influence of trauma on triple network FC at rest (
      • Akiki T.J.
      • Averill C.L.
      • Abdallah C.G.
      A network-based neurobiological model of PTSD: Evidence from structural and functional neuroimaging studies.
      ), and we expected that stress exposure would further exacerbate previously reported trauma-related differences in triple network FC; we predicted that during acute stress exposure individuals with greater PV history would exhibit higher within-network SN FC, reduced within-network DMN and CEN FC, and higher SN-CEN and SN-DMN between-network FC (
      • Akiki T.J.
      • Averill C.L.
      • Abdallah C.G.
      A network-based neurobiological model of PTSD: Evidence from structural and functional neuroimaging studies.
      ).

      Methods and Materials

      Participants

      Data from 79 participants aged 9 to 16 years with PV and acute stress FC data were used for analysis from a sample of adolescents we previously studied (
      • Corr R.
      • Glier S.
      • Bizzell J.
      • Pelletier-Baldelli A.
      • Campbell A.
      • Killian-Farrell C.
      • Belger A.
      Stress-related hippocampus activation mediates the association between polyvictimization and trait anxiety in adolescents [published online ahead of print Dec 1].
      ,
      • Corr R.
      • Pelletier-Baldelli A.
      • Glier S.
      • Bizzell J.
      • Campbell A.
      • Belger A.
      Neural mechanisms of acute stress and trait anxiety in adolescents.
      ). Recruitment aimed to build a sample with a heterogenous range of psychiatric symptomology (see Supplemental Methods). The parent study was approved by the Institutional Review Boards of University of North Carolina at Chapel Hill and Duke University. Participants gave assent and legal guardians provided consent. Exclusionary criteria included MRI contraindications, medical conditions known to impact the stress response or neuroimaging, history of head injury, an IQ two standard deviations below the mean, lifetime or current DSM-IV-TR Axis I psychotic disorder, and current major depressive disorder, bipolar disorder, PTSD, or substance dependence. Trained researchers determined presence of DSM-IV Axis I disorders using an abbreviated form of the Structured Clinical Interview for DSM-IV (
      • First M.
      • Spitzer R.
      • Gibbon M.
      • Williams J.
      Structured Clinical Interview for the DSM-IV Axis I Disorders (SCID-I).
      ) and when applicable diagnoses were confirmed via electronic health records. Overall, 49% of subjects met diagnostic criteria for a DSM-IV disorder (including attention-deficit/hyperactivity disorder, generalized anxiety disorder, social anxiety disorder, panic disorder, obsessive-compulsive disorder, and adjustment disorder), and 33% were taking psychotropic medications known to impact neural activity (including stimulants, nonstimulant attention-deficit/hyperactivity disorder medication, antidepressants, antipsychotics, and anticonvulsants). Further demographic information can be found in Table 1.
      Table 1Sample Characteristics (N = 79)
      Characteristicn (%) or Mean ± SD
      Sex, Female33 (42%)
      Age, Years12.8 ± 2.2
      Race
       Black14 (18%)
       Other9 (11%)
       White56 (71%)
      On Medication26 (33%)
      DSM-IV Diagnosis39 (49%)
      Polyvictimization2.5 ± 1.4

      PV and Demographic Measures

      Victimization was evaluated using the Juvenile Victimization Questionnaire, a 34-item questionnaire that measures a range of traumatic exposures experienced by children and adolescents over their lifetime (
      • Finkelhor D.
      • Hamby S.L.
      • Ormrod R.
      • Turner H.
      The Juvenile Victimization Questionnaire: Reliability, validity, and national norms.
      ). Questions fall within five categories/subscales: nine questions about conventional crime, four about child maltreatment, seven about sexual victimization, six about peer or sibling victimization, and eight about indirect/witnessing victimization. As described in our previous work (
      • Corr R.
      • Glier S.
      • Bizzell J.
      • Pelletier-Baldelli A.
      • Campbell A.
      • Killian-Farrell C.
      • Belger A.
      Stress-related hippocampus activation mediates the association between polyvictimization and trait anxiety in adolescents [published online ahead of print Dec 1].
      ), PV was defined as the total number of Juvenile Victimization Questionnaire categories/subscales within which subjects endorsed experiencing at least one type of victimization (with possible values ranging from 0 to 5) (
      • Hickman L.J.
      • Jaycox L.H.
      • Setodji C.M.
      • Kofner A.
      • Schultz D.
      • Barnes-Proby D.
      • Harris R.
      How much does “how much” matter? Assessing the relationship between children’s lifetime exposure to violence and trauma symptoms, behavior problems, and parenting stress.
      ,
      • Fisher H.L.
      • Caspi A.
      • Moffitt T.E.
      • Wertz J.
      • Gray R.
      • Newbury J.
      • et al.
      Measuring adolescents’ exposure to victimization: The Environmental Risk (E-Risk) Longitudinal Twin Study.
      ). Owing to the negatively skewed distribution of PV values, the PV variable was square root transformed for analysis.
      Supplementary analyses examined other variables that may impact PV or acute stress-related FC. Connections were evaluated between PV and sex (Welch’s t test), age (Pearson correlation), psychotropic medication use (Welch’s t test), psychiatric diagnosis (Welch’s t test), parental socioeconomic status (defined using average parental education; Spearman’s correlation), and race (defined categorically as Black, Other, or White; analysis of variance).

      Montreal Imaging Stress Task

      MIST was conducted similarly to adult studies (
      • Pruessner J.C.
      • Dedovic K.
      • Khalili-Mahani N.
      • Engert V.
      • Pruessner M.
      • Buss C.
      • et al.
      Deactivation of the limbic system during acute psychosocial stress: Evidence from positron emission tomography and functional magnetic resonance imaging studies.
      ,
      • Khalili-Mahani N.
      • Dedovic K.
      • Engert V.
      • Pruessner M.
      • Pruessner J.C.
      Hippocampal activation during a cognitive task is associated with subsequent neuroendocrine and cognitive responses to psychological stress.
      ,
      • Kogler L.
      • Gur R.C.
      • Derntl B.
      Sex differences in cognitive regulation of psychosocial achievement stress: Brain and behavior.
      ) using our published protocol (
      • Corr R.
      • Glier S.
      • Bizzell J.
      • Pelletier-Baldelli A.
      • Campbell A.
      • Killian-Farrell C.
      • Belger A.
      Stress-related hippocampus activation mediates the association between polyvictimization and trait anxiety in adolescents [published online ahead of print Dec 1].
      ,
      • Corr R.
      • Pelletier-Baldelli A.
      • Glier S.
      • Bizzell J.
      • Campbell A.
      • Belger A.
      Neural mechanisms of acute stress and trait anxiety in adolescents.
      ). In brief, MIST used a block design with three 6-minute runs of the task, each of which included three sets of alternating rest, control, and experimental conditions. During the rest condition, subjects focused on a screen displaying a static task dial image. For the control condition, participants were told their performance was not recorded as they completed math problems, rotating the onscreen dial using a button box to submit their answers. During the experimental/stress condition, researchers instructed participants to complete math problems quickly within the permitted response time window. Between each run, experimenters provided negative feedback telling the participant their experimental condition performance was below average compared with their peers and it was important that they try harder. Further MIST information is available in our prior publication (
      • Corr R.
      • Pelletier-Baldelli A.
      • Glier S.
      • Bizzell J.
      • Campbell A.
      • Belger A.
      Neural mechanisms of acute stress and trait anxiety in adolescents.
      ) and in the Supplemental Methods.

      Assessment of FC

      fMRI Acquisition

      MRI scans were acquired on a 3T GE MR750 scanner with an 8-channel head-coil at the Duke-UNC Brain Imaging and Analysis Center. High-resolution T1-weighted images were collected using a three-dimensional fast spoiled gradient-recalled sequence (repetition time/echo time = 8.2/3.22 ms; fractional anisotropy = 12°; field of view = 240 × 240 × 166 mm2; matrix size = 256 × 256 × 166; slice thickness = 1 mm). Functional images during MIST were acquired using a spiral-in sensitivity encoding interleaved sequence (repetition time/echo time = 2000/30 ms, fractional anisotropy = 60°, field of view = 24 cm, acquisition matrix = 64 × 64, slice thickness = 4 mm, 34 slices) (
      • Corr R.
      • Pelletier-Baldelli A.
      • Glier S.
      • Bizzell J.
      • Campbell A.
      • Belger A.
      Neural mechanisms of acute stress and trait anxiety in adolescents.
      ).

      fMRI Preprocessing and Denoising

      The CONN Toolbox (v20.b) (
      • Whitfield-Gabrieli S.
      • Nieto-Castanon A.
      Conn: A functional connectivity toolbox for correlated and anticorrelated brain networks.
      ) was used for preprocessing, denoising, quality assurance, and statistical analysis. Images were processed following the default CONN preprocessing pipeline, including spatial realignment; unwarping; ART-based identification of outlier scans for scrubbing; gray matter, white matter, and cerebrospinal fluid segmentation; Montreal Neurological Institute normalization; and spatial smoothing using a 6-mm full width at half maximum Gaussian kernel. The denoising step used single-subject linear regressions to remove movement artifacts (12 motion parameters; rigid body transformations and their first-order temporal derivatives) and physiological effects (5 parameters each from principal component analysis of white matter and cerebrospinal fluid time courses). The single-subject matrix included regressors for each task condition (rest, control, stress). High-pass filtering (0.008 Hz) was applied after denoising. Visual quality assurance was conducted on structural and functional normalization and registration and after denoising FC value distribution. MIST data from 79 subjects included in our prior PV analysis (
      • Corr R.
      • Glier S.
      • Bizzell J.
      • Pelletier-Baldelli A.
      • Campbell A.
      • Killian-Farrell C.
      • Belger A.
      Stress-related hippocampus activation mediates the association between polyvictimization and trait anxiety in adolescents [published online ahead of print Dec 1].
      ) were initially preprocessed. Subjects with >25% of their volumes scrubbed were removed from analysis (
      • Ferré P.
      • Jarret J.
      • Brambati S.
      • Bellec P.
      • Joanette Y.
      Functional connectivity of successful picture-naming: Age-specific organization and the effect of engaging in stimulating activities.
      ), resulting in the exclusion of six individuals for a final sample of 73 subjects.

      Generalized Psychophysiological Interaction Analyses

      Generalized psychophysiological interaction analyses were conducted using bivariate regressions (
      • Whitfield-Gabrieli S.
      • Nieto-Castanon A.
      Conn: A functional connectivity toolbox for correlated and anticorrelated brain networks.
      ). Five regions of interest (ROIs) were selected as seeds (Figure 1), matching the 6-mm spherical ROIs used in prior research examining seed-to-voxel FC of these networks (
      • Mueller F.
      • Musso F.
      • London M.
      • de Boer P.
      • Zacharias N.
      • Winterer G.
      Pharmacological fMRI: Effects of subanesthetic ketamine on resting-state functional connectivity in the default mode network, salience network, dorsal attention network and executive control network.
      ,
      • Woodward N.D.
      • Rogers B.
      • Heckers S.
      Functional resting-state networks are differentially affected in schizophrenia.
      ,
      • Pereira J.F.A.
      Resting-State functional connectivity in individuals with Williams syndrome. Conectividade Funcional Redes Neuronais Repouso Indivíduos Sindrome Williams.
      ). The DMN hub was the posterior cingulate cortex (PCC) (1, −55, 17), SN hubs were the left and right frontoinsular cortex (FIC) (−32, 26, −14/38, 22, −10), and CEN hubs were the left and right dorsolateral prefrontal cortex (dlPFC) (−42, 34, 20/44, 36, 20). Second-level seed-to-voxel analyses contrasted FC values between stress and control conditions, controlling for sex, age, medication use, and presence/absence of psychiatric diagnosis using a familywise error (FWE) rate–corrected cluster-level threshold p-FWE < .05 after voxelwise height thresholding of p-uncorrected < .005 (
      • Berger P.
      • Bitsch F.
      • Nagels A.
      • Straube B.
      • Falkenberg I.
      Personality modulates amygdala and insula connectivity during humor appreciation: An event-related fMRI study.
      ). Separate seed-to-voxel analyses for each ROI examined FC changes associated with acute stress and their relationship with PV. Supplementary seed-to-voxel analyses assessed if there were relationships between stress-related FC from each seed and sex, age, medication use, or psychiatric diagnosis (Tables S1–S4).
      Figure thumbnail gr1
      Figure 1Axial (A), superior (B), and sagittal (C) renderings depicting triple network 6-mm spherical seeds used for functional connectivity analysis. The posterior cingulate cortex seed was used for the default mode network (purple; 1, −55, 17), the left and right frontoinsular cortexes for the salience network (yellow; 32, 26, −14/38, 22, −10), and the right dorsolateral prefrontal cortexes for the central executive network (green; −42, 34, 20/44, 36, 20).

      Results

      Participant Characteristics

      A total of 73 adolescents were included in the neuroimaging analyses. At least one form of victimization was experienced by 87.7% (n = 64) of subjects, 75.3% (n = 55) reported exposure to two or more categories of victimization, and 28.8% (n = 21) reported exposure to four or more of the five victimization categories. PV was not significantly associated with sex (Welch’s t67.6 = 1.02, p = .310), psychiatric diagnosis (Welch’s t66.0 = −1.57, p = .121), race (F2,70 = 0.33, p = .717), or parental socioeconomic status (rs68 = −0.079, p = .516). However, PV was associated with age (r71 = 0.24, p = .042) and medication use (Welch’s t41.82 = −2.44, p = .019), with individuals taking medication reporting greater PV.

      Triple Network FC During Acute Stress

      Seed-to-voxel analyses revealed that the acute stress condition, as compared with the control condition, elicited altered neural FC between triple network regions (t68 > 2.90, p-FWE ≤ .05) (Table 2). Specifically, the DMN PCC seed was associated with increased FC during acute stress in CEN clusters containing the left and right middle frontal gyrus and right frontal pole and exhibited mixed FC patterns with regions in other networks, e.g., the dorsal attention network (DAN) (Figure 2A). The SN left FIC seed was associated with decreased FC during stress in DMN regions including the precuneus, PCC, and left angular gyrus and with CEN regions including the left frontal pole and superior frontal gyrus (Figure 2B). The SN right FIC and CEN left dlPFC seeds did not exhibit relationships with triple network regions during stress. However, the right FIC seed did demonstrate stress-related FC increases with the right paracingulate and decreases with the left superior parietal lobule of the DAN (Figure 2C), and FC increased between the left dlPFC seed and visual and motor regions (Figure 2D). The CEN right dlPFC seed exhibited increased stress-related FC with DMN clusters, including the precuneus, PCC, and medial PFC (Figure 2E). Supplementary seed-to-voxel analyses revealed no significant relationships between seed FC with triple network regions during acute stress and sex, age, medication use, or psychiatric diagnosis (p-FWE ≥ .05) (Tables S1–S4), with one exception; females exhibited greater stress-related FC than males within the DMN (t68 > 2.90, p-FWE = .005).
      Table 2Stress Effects on Triple Network Seed Functional Connectivity
      SeedMNIDirectionRegionNetworkkp-FWE
      xyz
      Default Mode Network: Posterior Cingulate Cortex−16−5052L precentral gyrusMotor1516<.000001
      L postcentral gyrusMotor
      −26−6242L superior lateral occipital cortexsLOC794<.000001
      L superior parietal lobuleDAN
      −462232L middle frontal gyrusCEN790<.000001
      02244L paracingulatePaCi458.000105
      422830R middle frontal gyrusCEN274.005876
      R frontal poleCEN
      58−2628L anterior supramarginal gyrusaSMG231.016896
      34−5454R superior parietal lobuleDAN223.020691
      42−6012R inferior lateral occipital cortexVisual209.029639
      Salience Network: L Insular Cortex−8−5230PrecuneusDMN917<.000001
      Posterior cingulate cortexDMN
      −50−6020L angular gyrusDMN312.001998
      −2658−8L frontal poleCEN265.006185
      −45036L superior frontal gyrusCEN202.031172
      Salience Network: R Insular Cortex432−16R paracingulatePaCi201.027587
      −20−4664L superior parietal lobuleDAN184.044158
      Central Executive Network: L Dorsolateral Prefrontal Cortex−34−1068L postcentral gyrusMotor380.000464
      L precentral gyrusMotor
      −4−88−8L lingual gyrusVisual313.002094
      Central Executive Network: R Dorsolateral Prefrontal Cortex−10−6622PrecuneusDMN979<.000001
      Posterior cingulate cortexDMN
      056−12Medial frontal cortexDMN328.001613
      Voxel threshold p-uncorrected < .005 and cluster size p-FWE < .05. Region labels and network membership were defined using the CONN Atlas, which provides network grouping based on resting-state analysis of the Cambridge 1000-connectomes dataset using 132 regions from a combination of the Harvard-Oxford cortical and subcortical atlases and the AAL atlas cerebellar parcellation (
      • Whitfield-Gabrieli S.
      • Nieto-Castanon A.
      Conn: A functional connectivity toolbox for correlated and anticorrelated brain networks.
      ). For clusters with multiple corresponding regions, only regions containing ≥25% of the cluster volume are listed.
      aSMG, anterior supramarginal gyrus; CEN, central executive network; DAN, dorsal attention network; DMN, default mode network; FWE, familywise error; L, left; MNI, Montreal Neurological Institute; PaCi, paracingulate; R, right; sLOC, superior lateral occipital cortex.
      Figure thumbnail gr2
      Figure 2Results from the seed-to-voxel analyses examining triple network connectivity during acute stress from the posterior cingulate cortex (A) representing the default mode network, left (B) and right (C) frontoinsular cortex representing the salience network, and left (D) and right (E) dorsolateral prefrontal cortex representing the central executive network. Statistical maps represent region t scores (voxel threshold p-uncorrected < .005 and cluster size p-familywise error < .05).

      PV Is Associated With Reduced DMN-SN Stress-Related FC

      Greater PV was associated with reduced stress-related FC between the DMN PCC seed and a cluster containing the left insula of the SN (−42, −2, 2; t67 > 2.90, p-FWE = .023, k = 218) (Figure 3). This pattern was also seen between the PCC and right insula, although it did not survive multiple-comparison corrections (38, −16, 10; t67 > 2.90, p-uncorrected = .002, p-FWE = .167, k = 144) There were no significant relationships between PV and SN or CEN seed-to-voxel FC during stress (p-FWE ≥ .518).
      Figure thumbnail gr3
      Figure 3Greater polyvictimization was associated with reduced functional connectivity between the posterior cingulate cortex (PCC) node of the default mode network and a cluster containing the left (L) insula of the salience network (coronal slice Z = 2). Connectivity values displayed reflect adjustment of the polyvictimization variable for skew and are corrected for sex, age, medication use, and diagnosis.

      Discussion

      This is the first study to directly examine changes in triple network FC during acute stress in an adolescent population and probe how PV may influence stress-related FC in these networks. Acute stress was associated with increased DMN-CEN FC and decreased FC between the SN and the CEN and DMN. Greater PV exposure predicted lower acute stress-related DMN-SN FC, specifically reduced FC between the DMN PCC hub and the left insula of the SN. Dysfunctional triple network FC is associated with a wide range of psychiatric symptoms (
      • Menon B.
      Towards a new model of understanding—The triple network, psychopathology and the structure of the mind.
      ,
      • Liu Y.
      • Li L.
      • Li B.
      • Feng N.
      • Li L.
      • Zhang X.
      • et al.
      Decreased triple network connectivity in patients with recent onset post-traumatic stress disorder after a single prolonged trauma exposure.
      ), and elucidating how PV influences these circuits and their ability to adapt under stressful conditions is critical for understanding how PV can contribute to long-term negative health outcomes.

      Triple Network Connectivity During Acute Stress

      The insula is a critical hub of the SN and functions as a switch between the DMN and the CEN during different task demands, typically activating the CEN and suppressing the DMN during cognitive tasks (
      • Menon B.
      Towards a new model of understanding—The triple network, psychopathology and the structure of the mind.
      ). While DMN and CEN regions generally exhibit opposing activation patterns as mediated by the SN, increased DMN-CEN coupling is associated with internally directed attentional processes (
      • Menon B.
      Towards a new model of understanding—The triple network, psychopathology and the structure of the mind.
      ,
      • Beaty R.E.
      • Benedek M.
      • Kaufman S.B.
      • Silvia P.J.
      Default and executive network coupling supports creative idea production.
      ). In this study, increased DMN-CEN FC may arise from subjects’ increased self-focus and judgment due to poor achievement and negative feedback on MIST (
      • Andrews-Hanna J.R.
      • Smallwood J.
      • Spreng R.N.
      The default network and self-generated thought: Component processes, dynamic control, and clinical relevance.
      ). Negative FC between the SN and the DMN and CEN may reflect impaired ability to switch between these networks during stress (
      • Goulden N.
      • Khusnulina A.
      • Davis N.J.
      • Bracewell R.M.
      • Bokde A.L.
      • McNulty J.P.
      • Mullins P.G.
      The salience network is responsible for switching between the default mode network and the central executive network: Replication from DCM.
      ).
      The relationship between the SN and the DMN and CEN varies across psychological conditions, and notably a large portion of stress-related FC studies focus on changes in rsFC before and after stress rather than FC during a stress task (
      • van Oort J.
      • Tendolkar I.
      • Hermans E.J.
      • Mulders P.C.
      • Beckmann C.F.
      • Schene A.H.
      • et al.
      How the brain connects in response to acute stress: A review at the human brain systems level.
      ). Our SN between-network FC results are in line with some of these studies showing that after acute stress exposure, the SN exhibits decreased rsFC with the dlPFC of the CEN (
      • Zhu Y.
      • Wang Y.
      • Yang Z.
      • Wang L.
      • Hu X.
      Endogenous cortisol-related alterations of right anterior insula functional connectivity under acute stress.
      ), and reduced SN-DMN rsFC after stress exposure predicts longitudinal increases in perceived stress levels (
      • Zhang W.
      • Kaldewaij R.
      • Hashemi M.M.
      • Koch S.B.J.
      • Smit A.
      • van Ast V.
      • et al.
      Acute-stress induced change in salience network coupling prospectively predicts post-trauma symptom-development.
      ). Contrary to our results, Vaisvaser et al. (
      • Vaisvaser S.
      • Modai S.
      • Farberov L.
      • Lin T.
      • Sharon H.
      • Gilam A.
      • et al.
      Neuro-epigenetic indications of acute stress response in humans: The case of microRNA-29c.
      ) reported increased DMN-SN and decreased DMN-CEN FC during stress. However, their analysis used a ventromedial PFC seed to represent the DMN (
      • Vaisvaser S.
      • Modai S.
      • Farberov L.
      • Lin T.
      • Sharon H.
      • Gilam A.
      • et al.
      Neuro-epigenetic indications of acute stress response in humans: The case of microRNA-29c.
      ), and differences in ventral and dorsal DMN connectivity patterns may explain these discrepant findings (
      • Lee S.
      • Parthasarathi T.
      • Kable J.W.
      The ventral and dorsal default mode networks are dissociably modulated by the vividness and valence of imagined events.
      ). Temporal FC analyses during a cognitive task revealed increased FC between the PCC and SN at the beginning of the task, followed by increased FC between the PCC and CEN regions as the task progressed (
      • Beaty R.E.
      • Benedek M.
      • Kaufman S.B.
      • Silvia P.J.
      Default and executive network coupling supports creative idea production.
      ). Between-network FC may shift during the MIST, and, in addition to exploring other triple network regions, future analyses should explore changes in MIST FC over progression of the task.
      Contrary to our hypotheses, acute stress was not associated with FC within any network, as has been identified in adult studies (
      • van Oort J.
      • Tendolkar I.
      • Hermans E.J.
      • Mulders P.C.
      • Beckmann C.F.
      • Schene A.H.
      • et al.
      How the brain connects in response to acute stress: A review at the human brain systems level.
      ). Within-network correlations may not have been found in our sample because the DMN, SN, and CEN are less cohesive in adolescents and typically become more defined and segregated with maturation (
      • Ho T.C.
      • Dennis E.L.
      • Thompson P.M.
      • Gotlib I.H.
      Network-based approaches to examining stress in the adolescent brain.
      ) or because network hubs can shift throughout adolescence (
      • Oldham S.
      • Fornito A.
      The development of brain network hubs.
      ). Although our analysis did not reveal significant differences in triple network FC associated with age, a longitudinal study is necessary to explore whether neurodevelopment during adolescence increases within-network FC during acute stress. Furthermore, while not the primary focus of this analysis, it is important to note that triple network hubs exhibited varied FC with regions outside the triple networks. During stress, the PCC DMN seed also displayed decreased FC with visual and motor network regions and the anterior supramarginal gyrus and increased FC with DAN regions, the superior lateral occipital cortex, and the paracingulate. The right FIC SN seed showed stress-related increases in FC with the paracingulate and decreases with the superior parietal lobule of the DAN, and the left dlPFC exhibited increased FC with visual and motor network regions. The DAN is important for goal-directed control of visuospatial attention (
      • Vossel S.
      • Weidner R.
      • Driver J.
      • Friston K.J.
      • Fink G.R.
      Deconstructing the architecture of dorsal and ventral attention systems with dynamic causal modeling.
      ), which may be important for success on MIST. While the DAN has not been well characterized during stress, it has been implicated in recovery after stress exposure (
      • Broeders T.A.A.
      • Schoonheim M.M.
      • Vink M.
      • Douw L.
      • Geurts J.J.G.
      • van Leeuwen J.M.C.
      • Vinkers C.H.
      Dorsal attention network centrality increases during recovery from acute stress exposure.
      ). Future work should examine if alterations in DAN and motor and visual network FC are a specific artifact of MIST or are more broadly relevant to ASRs.

      PV and Stress-Related FC

      During acute stress, adolescents with greater PV exposure exhibited reduced FC between the DMN PCC hub and the left insula of the SN. There is limited research examining the relationship between forms of chronic stress exposure and stress-related FC, although some rsFC studies have examined trauma’s impact on these networks. In a healthy sample characterized as experiencing mild levels of childhood trauma, greater early-life stress was associated with greater reductions in rsFC between SN and DMN regions after acute stress exposure, but no prestress differences (
      • Wang H.
      • van Leeuwen J.M.C.
      • de Voogd L.D.
      • Verkes R.J.
      • Roozendaal B.
      • Fernández G.
      • Hermans E.J.
      Mild early-life stress exaggerates the impact of acute stress on corticolimbic resting-state functional connectivity [published online ahead of print Nov 22].
      ). However, lower DMN-SN rsFC was found at rest, without the influence of acute stress, in an adolescent sample with more severe trauma experiences (
      • Marusak H.A.
      • Martin K.R.
      • Etkin A.
      • Thomason M.E.
      Childhood trauma exposure disrupts the automatic regulation of emotional processing.
      ). In the light of this literature, this study’s findings—that acute stress elicits reduced DMN-SN FC, which is further reduced in individuals with PV—suggest that greater DMN-SN reductions may represent PV-induced neural adaptations that impact ability to respond to stress. Polyvictimized individuals have experienced exposure to stressors across different contexts, and repeated trauma exposure is known to alter neurobiological ASRs (
      • Wolfe D.A.
      Why polyvictimization matters.
      ,
      • Guidi J.
      • Lucente M.
      • Sonino N.
      • Fava G.A.
      Allostatic load and its impact on health: A systematic review.
      ). Therefore, the allostatic load associated with PV may lead to increased DMN-SN reactivity to stress. It is important to note that our findings should be considered preliminary, because PV results (p-FWE = .023) would not reach statistical significance if additional corrections were included to adjust for the five ROIs tested. Future analyses should explore if PV similarly impacts DMN-SN FC at rest or if PV is linked to reduced FC between these networks only when they are perturbed by acute stress exposure.

      Limitations and Future Directions

      We identified seeds following several previous triple network studies (
      • Mueller F.
      • Musso F.
      • London M.
      • de Boer P.
      • Zacharias N.
      • Winterer G.
      Pharmacological fMRI: Effects of subanesthetic ketamine on resting-state functional connectivity in the default mode network, salience network, dorsal attention network and executive control network.
      ,
      • Woodward N.D.
      • Rogers B.
      • Heckers S.
      Functional resting-state networks are differentially affected in schizophrenia.
      ,
      • Pereira J.F.A.
      Resting-State functional connectivity in individuals with Williams syndrome. Conectividade Funcional Redes Neuronais Repouso Indivíduos Sindrome Williams.
      ,
      • Joo S.H.
      • Lee C.U.
      • Lim H.K.
      Apathy and intrinsic functional connectivity networks in amnestic mild cognitive impairment.
      ,
      • Guo W.
      • Liu F.
      • Chen J.
      • Wu R.
      • Zhang Z.
      • Yu M.
      • et al.
      Resting-state cerebellar-cerebral networks are differently affected in first-episode, drug-naive schizophrenia patients and unaffected siblings.
      ,
      • Blackford J.U.
      • Clauss J.A.
      • Avery S.N.
      • Cowan R.L.
      • Benningfield M.M.
      • VanDerKlok R.M.
      Amygdala–cingulate intrinsic connectivity is associated with degree of social inhibition.
      ). However, other triple network research has used ROI-to-ROI analytic techniques with predefined nodes for each network (
      • Dégeilh F.
      • Bernier A.
      • Leblanc É.
      • Daneault V.
      • Beauchamp M.H.
      Quality of maternal behaviour during infancy predicts functional connectivity between default mode network and salience network 9 years later.
      ,
      • Krönke K.M.
      • Wolff M.
      • Shi Y.
      • Kräplin A.
      • Smolka M.N.
      • Bühringer G.
      • Goschke T.
      Functional connectivity in a triple-network saliency model is associated with real-life self-control.
      ) or identified networks based on independent component analyses of resting-state data (
      • Hermans E.J.
      • van Marle H.J.F.
      • Ossewaarde L.
      • Henckens M.J.A.G.
      • Qin S.
      • van Kesteren M.T.R.
      • et al.
      Stress-related noradrenergic activity prompts large-scale neural network reconfiguration.
      ,
      • Zhang W.
      • Hashemi M.M.
      • Kaldewaij R.
      • Koch S.B.J.
      • Beckmann C.
      • Klumpers F.
      • Roelofs K.
      Acute stress alters the ‘default’ brain processing.
      ). Our seed-to-voxel analyses allowed for exploration of interactions between critical nodes of the triple network and all brain regions, but the stricter statistical threshold used for whole-brain analysis may have reduced our ability to detect meaningful within-network FC. Within-network connectivity may have been absent because these networks are less functionally segregated in adolescents (
      • Ho T.C.
      • Dennis E.L.
      • Thompson P.M.
      • Gotlib I.H.
      Network-based approaches to examining stress in the adolescent brain.
      ). Furthermore, even though prior adolescent work has used these seeds (
      • Pereira J.F.A.
      Resting-State functional connectivity in individuals with Williams syndrome. Conectividade Funcional Redes Neuronais Repouso Indivíduos Sindrome Williams.
      ,
      • Pelletier-Baldelli A.
      • Bernard J.A.
      • Mittal V.A.
      Intrinsic functional connectivity in salience and default mode networks and aberrant social processes in youth at ultra-high risk for psychosis.
      ,
      • Martz M.E.
      • Cope L.M.
      • Hardee J.E.
      • Brislin S.J.
      • Weigard A.
      • Zucker R.A.
      • Heitzeg M.M.
      Frontostriatal resting state functional connectivity in resilient and non-resilient adolescents with a family history of alcohol use disorder.
      ), coordinates were based on adult research, and ROIs derived specifically from adolescent studies may yield different results (
      • Fair D.A.
      • Cohen A.L.
      • Power J.D.
      • Dosenbach N.U.F.
      • Church J.A.
      • Miezin F.M.
      • et al.
      Functional brain networks develop from a “local to distributed” organization.
      ). Future work should examine triple network connectivity through other FC methods to explore if within-network connectivity is altered during acute stress, in addition to using longitudinal methods to test if within-network FC increases with neurodevelopment.
      One strength of our heterogenous sample of adolescents is that they exhibited a range of PV values, enabling a dimensional analysis. However, to enable this PV variability, subjects taking psychotropic medications known to impact neural activation were included (
      • Weyandt L.
      • Swentosky A.
      • Gudmundsdottir B.G.
      Neuroimaging and ADHD: fMRI, PET, DTI findings, and methodological limitations.
      ). While we found greater PV in individuals on medication, all analyses did control for medication status, and supplementary analyses indicated that medication was not significantly associated with triple network FC. Future analyses in a medication-naïve population or examining the interactions between PV, stress-related FC, and specific medications would be necessary to ensure that medications did not influence results.
      Furthermore, while participants did exhibit a range of PV exposures, participants were excluded from the parent study if they had a PTSD diagnosis. This reduces the generalizability of our findings to individuals with PTSD, and future PV studies should include these individuals to examine if the relationship between PV and triple network FC predicts development of posttraumatic stress symptoms. Analyses did control for psychiatric diagnostic status, and no significant relationship was found between diagnostic status and acute stress-related FC. However, participants exhibited a range of different anxiety and attention-deficit/hyperactivity disorder diagnoses and symptom loads, often having comorbid conditions, and examining binary presence/absence of diagnostic status collapsed variation across mental illnesses. A larger sample with subjects experiencing specific psychiatric disorders, including PTSD, is needed to more comprehensively understand how different psychopathologies may uniquely impact triple network ASRs.
      In addition, while analyses controlled for sex and age, owing to sex-dependent differential neural and psychological development that occurs during puberty, future analysis should directly explore interactions between PV, stress-related FC, pubertal development, and sex hormone levels, especially given the fluidity of functional hub roles throughout adolescence (
      • Oldham S.
      • Fornito A.
      The development of brain network hubs.
      ). PV was associated with age, with older individuals reporting greater PV—an unsurprising finding given that older adolescents have had more opportunities to be exposed to victimization. In addition to subject age, the age and developmental stage during which an individual was exposed to PV impacts their likelihood of exhibiting psychiatric symptoms (
      • Dierkhising C.B.
      • Ford J.D.
      • Branson C.
      • Grasso D.J.
      • Lee R.
      Developmental timing of polyvictimization: Continuity, change, and association with adverse outcomes in adolescence.
      ). Future studies examining the frequency, duration, and developmental timing of PV events are necessary to further elucidate the varying impacts of PV exposure on neurodevelopment and psychopathology.
      This PV analysis focused on the cumulative burden of experiencing multiple forms of victimization, but it is possible that specific victimization types have a stronger influence on stress-related FC than others. Structural equation modeling or similar analysis techniques could be used to test the relative influence of different forms of victimization exposure on stress-related FC. Future work should also explore if altered DMN-SN FC mediates the well-documented relationship between PV and psychiatric symptoms (
      • Haahr-Pedersen I.
      • Ershadi A.E.
      • Hyland P.
      • Hansen M.
      • Perera C.
      • Sheaf G.
      • et al.
      Polyvictimization and psychopathology among children and adolescents: A systematic review of studies using the Juvenile Victimization Questionnaire.
      ).

      Conclusions

      This study demonstrates that during acute stress exposure, adolescents exhibit changes in FC between regions of the triple network; acute stress is associated with increased DMN-CEN FC and decreased connectivity between the SN and the DMN and CEN. Adolescents with greater PV exposure exhibited further reduced stress-related FC between the DMN and SN, possibly reflecting the neural impacts of the cumulative burden of exposure to different forms of victimization. Understanding the relationship between PV and triple network FC during acute stress is important for understanding how PV impacts the adolescent brain and elucidating the neurobiological pathways through which PV leads to negative health outcomes.

      Acknowledgments and Disclosures

      This work was supported by the National Institutes of Mental Health (Grant No. R01MH103790-01A1 [to AB]), Child Health and Human Development (Grant Nos. T32HD040127 [to AP-B] and T32HD007376 [to RC]), and Neurologic Disorders and Stroke (Grant No. T32NS007431 [to RC and SG]).
      We thank Dr. Jens Pruessner for providing the MIST program, Dr. Joe Schaffer for adapting the MIST for adolescents and for our operating system, and Erik Savereide for proofreading and editing. We also would like to acknowledge project contributions from former lab members, including Mae Nicopolis Yefimov, Ashley Williams, Hannah Waltz, Louis Murphy, Carina Guerra, and Kathryn Scott.
      The authors report no biomedical financial interests or potential conflicts of interest.

      Supplementary Material

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