Relation between patterns of intrinsic network connectivity, cognitive functioning, and symptom presentation in trauma‐exposed patients with major depressive disorder

Abstract Objective The present study investigated resting fMRI connectivity within the default mode (DMN), salience (SN), and central executive (CEN) networks in relation to neurocognitive performance and symptom severity in trauma‐exposed patients with major depressive disorder (MDD). Method Group independent component analysis was conducted among patients with MDD (n = 21), examining DMN, SN, and CEN connectivity in relation to neurocognitive performance and symptom severity. Activation in these networks was also compared between the patient group and healthy controls (n = 20). Results Among the patient group, higher levels of performance on measures of verbal memory and executive functioning were related to increased connectivity within the DMN (i.e., inferior parietal lobe; precuneus). Greater depression severity was related to reduced connectivity between the SN and a node of the DMN (i.e., posterior cingulate cortex) and higher depersonalization symptoms were related to enhanced connectivity between the SN and a node of the DMN (i.e., middle temporal gyrus). Higher symptoms of depersonalization were also associated with reduced integration of the DMN with the medial frontal gyrus. Relative to controls, patients with MDD showed greater connectivity of the ventromedial prefrontal cortex within the DMN. Conclusion Intrinsic connectivity network patterns are related to cognitive performance and symptom presentation among trauma‐exposed patients with MDD.

Trauma exposure impacts negatively on cognitive functioning (Olff, Polak, Witteveen, & Denys, 2014) and treatment outcome (Harkness, Bagby, & Kennedy, 2012) in patients with MDD and thus represents a critical variable to investigate in the context of depression. Here, we implement a symptom-driven approach to examine the relation between patterns of intrinsic neural connectivity, cognitive functioning and symptom presentation (e.g., dissociation) among patients with a primary diagnosis of MDD and a history of trauma exposure. Menon (2011) proposes a triple network model of psychopathology comprising three main intrinsic connectivity networks (ICNs) that together may underlie many of the neurocognitive and affective symptoms that characterize psychiatric disorders. This model describes the default mode network (DMN), the central executive network (CEN), and the salience network (SN). The DMN is defined most consistently by cortical midline structures (posterior cingulate cortex [PCC]: BA 23 and 31, ventromedial prefrontal cortex) (Buckner, Andrews-Hanna, & Schacter, 2008), and is involved in self-related processes, social cognition, and autobiographical memory. This network shows reductions in activation during the performance of cognitively demanding tasks (Greicius, Krasnow, Reiss, & Menon, 2003). By contrast, the CEN, consisting of the dlPFC and posterior parietal cortex, is instrumental in executive functioning and is engaged during cognitively demanding tasks requiring attention (Seeley et al., 2007). Finally, the SN is comprised of the ventrolateral prefrontal cortex, the anterior insula, and the dorsal anterior cingulate cortex (dACC) (Seeley et al., 2007) and plays a role in salience detection. The SN, in particular the anterior insula, is thought to be partly responsible for switching between the DMN and the CEN, thus facilitating the engagement of brain regions mediating higher-order cognitive processes (Menon, 2011;Sridharan, Levitin, & Menon, 2008). By examining the association between ICNs, cognitive dysfunction and symptom presentation in patients with MDD who have a history of trauma exposure, we hope to increase our understanding of the neural mechanisms underlying cognitive dysfunction and symptom presentation among a patient population that is often treatment resistant and presents with a heightened pattern of cognitive dysfunction (Harkness et al., 2012;Olff et al., 2014). Resting brain activity is related to behavioral performance on cognitive tasks in various populations, where preliminary results suggest that elevated connectivity within the DMN and within the CEN is related to enhanced performance on cognitive tasks. For example, connectivity within the DMN is positively associated with verbal working memory among healthy adults (Yakushev et al., 2013), and with memory performance (using a memory composite score) among older adults (Ward et al., 2014). Healthy controls also demonstrated an association between CEN connectivity and superior performance on Trails B, a measure of alternating attention (Seeley et al., 2007). In related studies, patients with Parkinson's disease show elevated DMN connectivity in association with faster processing speed, better executive functioning (Disbrow et al., 2014), and higher memory and visuospatial task scores (Tessitore et al., 2012). Heightened functional connectivity of executive control networks during rest was also related to a reduced Stroop effect (i.e., better executive control) among participants with Internet gaming disorder and healthy controls (Dong, Lin, & Potenza, 2015).
Only recently has the association between cognitive performance and resting-state connectivity been explored in patients with depression. For example, performance on a list-learning task was positively associated with increased connectivity of the parahippocampus with the amygdala and other subcortical structures, regions often showing weaker connectivity in MDD (Rao et al., 2016).
Resting-state fMRI studies in patients with depression have consistently identified abnormalities across ICNs, suggesting a reorganization of intrinsic functional connectivity that could contribute to symptoms of MDD (Manoliu et al., 2013). The majority of these studies have focused on the DMN, reporting that patients with MDD tend to show abnormal activation during goal-directed tasks, and increased functional connectivity during rest (for a review, see Broyd et al. (2009)). Overall, it appears that patients with MDD have difficulty downregulating activity within the DMN, which may account for symptoms such as increased rumination (Nejad, Fossati, & Lemogne, 2013) and impaired attentional control (Marchetti, Koster, Sonuga-Barke, & De Raedt, 2012). Moreover, unmedicated adults with MDD show increased connectivity of the DMN with the SN .
Aberrant connectivity of the CEN has also been observed during task performance (Fitzgerald et al., 2008) and at rest (Diener et al., 2012) in patients with MDD. Interestingly, increased activation of the anterior insula in response to negative stimuli has been shown in MDD (Strigo et al., 2008), and increased connectivity of the dorsal mid-insula cortex with limbic areas is positively correlated with depressive symptom severity (Avery et al., 2014) (but see Alexopoulos et al. (2012)). The right fronto-insular cortical network, however, was found to be less active at rest in patients with MDD as compared to controls (Hamilton et al., 2012). Finally, remitted youth with MDD demonstrate hyperconnectivity of the DMN and SN with the cognitive control network (CCN), as compared to controls (Jacobs et al., 2014).
Despite the high prevalence of trauma exposure in depression and its negative effects on cognitive functioning and treatment outcome, no studies have examined alterations in ICNs in relation to cognitive functioning and symptom presentation, including dissociation, in this patient population. This effort may assist in better understanding the neural mechanisms underlying the reduced treatment and functional outcomes observed in this population. Critically, trauma exposure has been shown to lead to changes in ICNs, even without the development of PTSD (Kennis, Rademaker, Van Rooij, Kahn, & Geuze, 2015;Wang et al., 2014). In addition, scores on the Dissociative Experiences Scale (indexing dissociative symptoms of PTSD including depersonalization and derealization) positively correlated with DMN connectivity with the dlPFC (a node of the CEN) in patients with PTSD related to early life trauma (Bluhm et al., 2009). Moreover, dissociative symptoms have been related to decreased integration of anterior and posterior DMN components . Despite the increasing focus on dissociative symptoms in MDD and their relation to more severe symptoms and trauma exposure (Molina-Serrano, Linotte, Amat, Souery, & Barreto, 2008;Žikić, Ćirić, & Mitković, 2009), it is unknown whether these symptoms are associated with altered network connectivity in patients with depression and a history of trauma.
In this study, we investigate those core neural networks thought to be central to higher-order cognitive functioning to determine if alterations in the connectivity of ICNs is related to neurocognitive performance and symptom presentation among trauma-exposed within the CCN prior to treatment was related to greater dysexecutive behavior after treatment (Alexopoulos et al., 2012). To date, however, no studies have examined the relation between these core neural networks and performance on standardized neuropsychological assessments tapping frontal-temporally mediated cognitive domains in patients with MDD and a history of trauma.

| Aims of the study
Here, we examine patterns of intranetwork connectivity of the DMN, SN, and CEN in patients with MDD and a history of trauma relative to controls via independent components analysis (ICA). We also examine the association between scores on standardized neuropsychological assessments and measures of symptom severity (e.g., dissociation) and intranetwork connectivity within the patient group, across all three ICNs. Twenty-one right-handed patients (mean age: 40.2 (14.9), 10 males, 11 females) who met DSM-IV diagnostic criteria for a primary diagnosis of recurrent (i.e., ≥3 episodes) MDD on the Structured Clinical Interview for DSM-IV-TR Axis I Disorders (SCID-1; First, Spitzer, Gibbon, & Williams, 1997) and who had a history of trauma exposure, according to responses on the Clinician-Administered PTSD Scale (CAPS; Blake et al., 1995) and/or Childhood Trauma Questionnaire (CTQ; Bernstein et al., 2003) were recruited. Among patients with MDD, five met criteria for moderate-to-severe childhood abuse on the CTQ only, nine met criteria for lifetime PTSD or trauma exposure on the CAPS only, and seven met criteria for childhood trauma exposure on the CTQ and a diagnosis of PTSD or trauma exposure on the CAPS. Among those participants who met criteria for PTSD or trauma exposure on the CAPS, 11 experienced interpersonal trauma (e.g., abuse by caregiver) and five experienced single-blow, accidental trauma (e.g., car accident). Five participants met criteria for PTSD at time of testing. A control group consisted of 20 right-handed participants with no history of psychiatric illness or trauma exposure who did not differ from the patient group in age, gender, or education (mean age: 35.3 (14.1), 10 males, 10 females) (see Table 1 for demographic and clinical characteristics).

| Participants
Exclusion criteria included past or current diagnosis of bipolar disorder, a psychotic disorder, neurological disease, electroconvulsive or transcranial magnetic stimulation therapy in the last 12 months, any contraindication to MRI, traumatic brain injury and/or head injury with loss of consciousness (lasting more than 60 s), substance abuse in the last 6 months, current or lifetime history of substance dependence, and/or current or prior history of untreated significant medical illness.
Participants were instructed not to use benzodiazepines within 12 hrs prior to testing.

| Clinical assessments
In addition to the SCID-I, participants completed the 17-Item Hamilton Rating Scale for Depression (HAM-D; Hamilton, 1960). This interview assesses the severity of depressive symptoms over the past week. The CAPS (Blake et al., 1995) was also administered to assess current (i.e., past month) and past PTSD diagnostic status and symptom severity and to confirm a history of trauma exposure. Participants completed the CTQ (Bernstein et al., 2003), a 28-item self-report questionnaire that measures history of: (1) emotional abuse, (2) physical abuse, (3) sexual abuse, (4) emotional neglect, and (5) physical neglect. The CTQ has good internal consistency and convergent reliability with therapists' assessments of history of trauma is high (Bernstein et al., 2003).
Participants also completed the Multiscale Dissociation Inventory (MDI; Briere, 2002) a 30-item self-report questionnaire that assesses dissociative responses. The current study focused on MDI depersonalization and derealization subscales, as well as a composite score of the sum of these two subscales, as these symptoms have been associated with increased depressive symptomatology (Žikić et al., 2009) and form the basis of the recently described dissociative subtype of PTSD (Spiegel et al., 2013).

| Neuropsychological assessment battery
The following battery of standardized neuropsychological measures was administered to assess frontal-temporally mediated domains

| Imaging paradigm and acquisition
Participants underwent a 4-min eyes-open resting-state scan during which they were shown a black fixation cross on a gray screen to ensure greater reliability of within network connectivity as compared to eyesclosed conditions (Patriat et al., 2013), following standard procedures (Ros et al., 2013). All images were obtained using a 3.0 Tesla whole-body MRI scanner (General Electric, Milwaukee, WI, USA) using an 8-channel parallel receiver birdcase head coil (General Electric). For the resting state task, 34 axial slices (3 mm thick, no skip) across the whole brain were im- flip angle = 90°) to obtain a total of 80 volumes per participant. A TR of 3,000 ms was chosen to ensure enough slices per volume were acquired to obtain a full coverage of the brain and to minimize the risk of losing data due to larger head sizes of some participants.

| Demographics, psychological, and cognitive characteristics
To assess group differences in demographic, clinical, and cognitive variables, data were first assessed for normality (p > .05, Shapiro-Wilk) and group comparisons were calculated using either independent-samples T A B L E 2 Neuropsychological performance of patients with MDD and trauma and healthy controls Characteristic MDD (n = 21)
Group differences in gender and employment status were assessed with chi-square tests. Analysis of demographic, psychological, and cognitive data was performed in IBM SPSS Version 22.0.

| Image preprocessing
Preprocessing of images (slice-timing correction, motion correction, spatial normalization, and smoothing) was performed using SPM8 (RRID:SCR_007037) (http://www.fil.ion.ucl.ac.uk/spm/) in MATLAB 8.3.0 (MathWorks Inc.) using standard procedures. Individual functional images were corrected for motion by realignment to the first volume of each session, resliced, and a mean functional volume created. The mean image was coregistered to the standard echo-planar imaging template in MNI space supplied by SPM8, the deformation matrix was then created and applied to the functional volumes. All functional volumes were smoothed using a full-width half-maximum Gaussian filter of 8 mm.

| Statistical comparison of spatial maps
Component z-score maps of interest were imported into SPM8 for group analysis. ROI analyses were carried out through the a priori defined standardized masks of the DMN (Shirer et al., 2012), CEN (Shirer et al., 2012) and SN (Kluetsch et al., 2014;Ros et al., 2013).
Cluster-level significance was denoted by pFDRc (false discovery rate), and voxel-level significance was denoted by pFDRv. Secondlevel multiple regression analyses were performed in SPM8 to determine the association between the components of interest and (1) neuropsychological test scores (raw) and (2) clinical variables (i.e., MDI depersonalization, derealization, and composite scores, and HAM-D total) among the trauma-exposed group with MDD. ROI analyses were again carried out and thresholded at pFDR < .05 to control for multiple comparisons using the a priori defined standardized masks.

| Participants
Groups did not differ in terms of age, years of education, gender distribution, or ethnicity. The groups differed with respect to employment status, where the trauma-exposed MDD group had a significantly higher proportion of unemployed participants (χ 2 (1,40) = 4.19, p < .05). The trauma-exposed MDD group scored significantly higher than the control group on all clinical subscales. See Table 1 for a description of the clinical and demographic characteristics of the study sample.

| Neuropsychological performance
Compared to controls, participants with MDD and comorbid trauma performed significantly worse on measures of verbal memory and executive functioning (i.e., mental flexibility, abstract reasoning, and forming concepts) (see Table 2). Specifically, patients retrieved significantly fewer words on the CVLT-II long-delay free recall subscale (t (39) = 2.1, p < .05) as compared to controls. On Color Trails 2, patients were significantly slower than controls (U = 90.0, p < .01).
Patients also made more total errors on the WCST than controls, however, these results did not reach statistical significance (U = 117.5, p = .07). No group differences emerged on the COWAT phonemic fluency, CPT-II number of commissions or omissions, Color Trails 1, CVLT-II total and short-delay free recall, or WCST perseverative error raw scores.

| Cognitive performance and spatial distribution
Second-level multiple regression analyses were performed among the group of trauma-exposed participants with MDD using their zscore spatial maps to examine the associations between cognitive

| DISCUSSION
To our knowledge, this is the first study to examine the functional connectivity of the CEN, SN, and DMN in relation to cognitive showed enhanced connectivity in our patient group is particularly relevant given the role of the vmPFC in depressive self-referential focus (Lemogne et al., 2012). Clinically, this may manifest as increased rumination during the resting-state task in our patient group.
We found significant correlations between cognitive variables and connectivity within both the SN and DMN among the trauma-exposed participants with MDD. Better performance on the Color Trail Making Test-Part 1, a measure of attention and processing speed, was related to greater connectivity of the left STG within the SN. The role of the STG in cognitive tasks has been demonstrated in patients with multiple sclerosis (Achiron et al., 2012) and healthy controls (Bayless, Gaetz, Cheyne, & Taylor, 2006;Paulus, Feinstein, Leland, & Simmons, 2005).
Specifically, the STG is activated during cognitive tasks requiring decision-making and thickness of the left STG correlates with information processing speed on the Mindstreams Computerized Cognitive Battery (Achiron et al., 2012). Given the role of the STG in cognitive processing, our results suggest that increased functional connectivity of the SN with this region may be a protective factor against impairments in attention and processing speed among patients with MDD.
By contrast, decreased connectivity would be expected to result in cognitive processing impairments.
Within the DMN, increased connectivity with the left IPL was related to better performance on the CVLT-II long-delay free recall condition, measuring delayed verbal memory. Notably, patients performed significantly worse than controls in the CVLT-II long-delay free recall condition. The posterior parietal cortex is involved in attention and episodic memory retrieval, and is activated during verbal memory tasks (Hutchinson, Uncapher, & Wagner, 2009). Moreover, the IPL (BA 40) is considered to be a core component of the DMN (Buckner et al., 2008). As previously noted, patients with depression tend to show increased connectivity within the DMN as compared to controls, which is often viewed as reflecting increased self-referential focus and difficulty disengaging the task-negative state when needed.
In our sample, however, increased integration of the DMN with a core region of this network was related to better neuropsychological performance. Interestingly, studies in other populations, such as in patients with Parkinson's disease (Disbrow et al., 2014;Tessitore et al., 2012), healthy older adults (Ward et al., 2014), and healthy controls (Yakushev et al., 2013) have reported that greater connectivity within the DMN is associated with better performance on different memory tasks. Our results are also consistent with recent findings suggesting that among patients with depression, but not healthy controls, better performance on a delayed recall trial of list learning was predictive of greater connectivity between the parahippocampus and subcortical structures (Rao et al., 2016). Taken together, these results suggest that greater connectivity among regions supporting memory retrieval (e.g., IPL and parahippocampus) and other brain areas may be conducive to enhanced retrieval among patients with MDD.
Similarly, our results indicate that increased connectivity of the precuneus (a core component of the DMN) within the DMN was related to better performance on Color Trail Making Test-Part 2. This task measures processing speed, mental flexibility, and working memory, and compared to controls, the patient group was significantly slower at completing this task, reflecting poorer performance. Hence, consistent with our findings on the CVLT-II and DMN connectivity, we again see increased integration of the DMN associated with superior performance on a cognitive task. Importantly, the precuneus is involved in mental processes and self-operations (Cavanna & Trimble, 2006).
Finally, within the DMN, increased integration of the middle occipital gyrus was related to worse performance on our measure of verbal fluency, the COWAT phonemic fluency subscale. The left middle occipital gyrus has been implicated in working memory processes in PTSD, where increased connectivity between this region and the mPFC was present during a working memory task (Daniels et al., 2010). Veer et al. (2010) found reduced connectivity of visual regions in patients with depression, but noted that this region is rarely implicated in depression and interpretations would therefore be speculative. Although our results suggest that increased connectivity of the DMN with this region is related to poorer verbal fluency, further research will be required to interpret these findings.
Significant correlations also emerged between clinical variables (i.e., HAM-D and MDI) and each of the three ICNs. Within the SN, higher HAM-D scores were associated with reduced connectivity of the PCC, suggesting that greater depression severity is related to decreased integration of the SN within a node of the DMN. These results are contrary to earlier studies in patients with MDD, where it was reported that depression was associated with an increased integration of the SN with the DMN Jacobs et al., 2014). A possible factor accounting for the discrepancy in findings could be the history of trauma-exposure in our patient sample. For example, Wang and colleagues found that compared to patients with MDD without a history of trauma, those with trauma displayed a more widespread reduction in functional connectivity strength (Wang et al., 2014). Moreover, among patients with PTSD, abberant resting-state connectivity between the DMN and SN has been observed (Bluhm et al., 2009;Lanius et al., 2010). As suggested by Daniels, Frewen, McKinnon, and Lanius (2011), early-life trauma may impact negatively on the integration of the DMN, and thus could also impact inter-network connectivity. Despite the heterogeneity among trauma subtype in our sample, the majority did report experiencing childhood trauma. Within the SN, increased integration of the right MTG, a component of the DMN (Laird et al., 2009), was related to higher scores on the MDI composite score (i.e., sum of depersonalization and derealization symptoms). The right MTG has been implicated in dissociative states, where patients with PTSD who dissociated during an fMRI traumatic script-driven imagery paradigm demonstrated heightened levels of activation in this region, compared to controls (Lanius et al., 2002).
This supports what has been termed the temporal lobe hypothesis of dissociation, based largely on epilepsy literature (Devinsky, Putnam, Grafman, Bromfield, & Theodore, 1989;Kenna & Sedman, 1965). On balance, these findings suggest that an enhanced connectivity of the right MTG within the SN, normally responsible for switching between the CEN and DMN, may underlie trait-like dissociative symptoms in depression.
Depersonalization symptoms of dissociation, as assessed by the MDI, correlated negatively with connectivity of the medial frontal gyrus within the DMN. This region has been linked to self-referential processing in depression (Lemogne et al., 2012). Interestingly, this finding suggests that higher levels of depersonalization (i.e., feeling as though one is disconnected from his/her body) are related to decreased connectivity of this core region associated with self-referential processing. Similar findings have been reported in patients with PTSD . Depersonalization is an important feature of de- The current study has several limitations. Most of the patients were taking psychotropic medications at time of testing (although they refrained from benozdiazepines for 12 hr prior to testing). There is a lack of knowledge and often inconsistent results surrounding the impact of antidepressants on resting state activity in MDD (Dutta, Mckie, & Deakin, 2014) and future studies should carefully control for medication status. Furthermore, we did not include a trauma-exposed control group, or a nontrauma-exposed MDD group. The sample size is small, yet similar to other neuroimaging studies examining restingstate ICNs in psychiatric disorders. Unlike ROI analyses which rely on prior anatomic hypotheses, ICA is a data-driven analysis. There are strengths and weaknesses inherent in both methods (Rosazza et al., 2012); therefore, future studies may wish to include network homogeneity and seed-based functional connectivity analyses as alternate methods of examining network connectivity. In addition, we employed a 4-minute resting state scan, which is sufficient to reliably estimate network connectivity. Given that increasing scan length can further improve reliability and reduce the risk of type II errors, longer resting conditions may be warranted (Van Dijk et al., 2010). In addition, we used a TR of 3,000 ms. This may be considered a limitation as larger TRs increase the risk of confounding physiological frequencies (Lowe, Mock, & Sorenson, 1998). Regarding our assessments, we measured symptoms of depression and dissociation, yet we did not assess state symptoms experienced during scanning or neuropsychological testing, which may have helped further elucidate the relation between these variables and ICNs. In addition, our assessments of trauma history were self-report retrospective tools, which may present a memory bias.
To our knowledge, this is the first study to examine the association between neuropsychological performance and symptom presentation with resting-state ICNs in a trauma-exposed sample with MDD. This study is an important first step toward better understanding the neurobiological mechanisms underlying transdiagnostic features, such as cognitive dysfunction and dissociation, which are characteristic of depression and trauma-related disorders. Importantly, our findings suggest that both cognitive performance and symptoms of depression and dissociation are related to DMN, SN, and CEN connectivity.
Studies must continue to explore alterations in ICNs as a function of cognitive and clinical characteristics in this population with the goal of initiating treatment efforts that target altered functioning in these ICNs. Lanius et al. have proposed neuroscientifically informed treatment interventions to improve the functioning of the CEN, SN, and DMN in patients with PTSD, which may also have relevance to symptom domains of MDD . Here, the authors proposed interventions such as top-down cognitive remediation strategies, body scan meditations, and neurofeedback which may help to restore these neural networks and their related clinical and cognitive dysfunction.
By increasing our understanding of the neural mechanisms underlying transdiagnostic variables characteristic of depression and traumarelated disorders, we will be able to move forward and propose treatment efforts aimed at restoring these core networks altered by psychiatric illness.