Associations Between Changes in Psychological Resilience and Resting-State Functional Connectivity Throughout Pediatric Concussion Recovery

doi:10.21203/rs.3.rs-3143238/v1

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Research Article

Associations Between Changes in Psychological Resilience and Resting-State Functional Connectivity Throughout Pediatric Concussion Recovery

https://doi.org/10.21203/rs.3.rs-3143238/v1

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published 14 Jun, 2024

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Purpose

This study investigated the association between psychological resilience and resting-state network functional connectivity in pediatric concussion.

Methods

This was a substudy of a randomized controlled trial, recruiting children with concussion and orthopedic injury. Participants completed the Connor-Davidson Resilience 10 Scale and underwent magnetic resonance imaging at 72 hours and 4-weeks post-injury. Seed-to-voxel analyses were used to explore associations between resilience and connectivity with the default-mode, central executive, and salience networks longitudinally and at both timepoints separately. Regions-of-interest analyses were used to explore associations between resilience and within-network connectivity.

Results

A total of 69 children with a concussion (median age = 12.81 [IQR: 11.79–14.36]; 46% female) and 30 with orthopedic injury (median age = 12.27 [IQR: 11.19–13.94]; 40% female) were included. Seed-to-voxel analyses detected a positive correlation between 72-hour resilience and central executive network connectivity in the concussion group, and a positive correlation between 72-hour resilience and salience network connectivity in the orthopedic injury group. Group was a moderator of 72-hour resilience and salience network connectivity, and a moderator of longitudinal resilience and default-mode network connectivity. Regions-of-interest analyses identified group as a moderator of longitudinal resilience and within-default-mode network connectivity. In the orthopedic injury group, longitudinal resilience was associated with within-default-mode network connectivity, while 72-hour resilience was associated with within-salience network connectivity.

Conclusions

These results suggest that resilience may be implicated in functional neuroimaging outcomes in pediatric concussion and should further be investigated for its clinical utility as a protective or restorative factor following injury.

pediatric

concussion

functional magnetic resonance imaging

resilience

Concussion affects the wellbeing and quality of life of children (Novak et al., 2016). Children with concussion that are highly resilient, defined as one’s ability to adapt when faced with adversity (Connor & Davidson, 2003), are more likely to report decreased post-concussion symptoms than less resilient children in the chronic phase of injury (Bunt et al., 2021; Durish et al., 2018). Resilience has been associated with the brain’s neurofunctional networks (Iadipaolo et al., 2017, 2018), while the same networks have been found to be disrupted post-concussion (Abbas et al., 2015; Borich et al., 2015; Brett et al., 2022; Iyer et al., 2019; Johnson et al., 2012; Mayer et al., 2011; Meier et al., 2017; Newsome et al., 2016; Plourde et al., 2021; Sours et al., 2013, 2015). Limited evidence exists on whether resilience can be protective to the neurophysiological deficits of those with a concussion.

Resilience reflects an individual’s accessible adaptive capacities for the successful coping of trauma or adversity that may otherwise threaten healthy functioning or development (Masten & Barnes, 2018). The most common functional networks associated with measures of resilience in children are the Default Mode Network (DMN; Iadipaolo et al., 2017, 2018), Central Executive Network (CEN; Iadipaolo et al., 2018), and Salience Network (SN; Iadipaolo et al., 2017). The DMN supports self-referential processes, emotional processing, and recollection of past experiences (Raichle, 2015). The CEN plays a role in executive functioning, sustained attention and working memory, response selection, and response suppression (Seeley et al., 2007). The salience network is theorized to integrate, identify, and prioritize the most relevant incoming stimuli, as well as switching between activation of the DMN and CEN (Goulden et al., 2014; Seeley et al., 2007). Greater psychological resilience has been associated with decreased within-network DMN FC in healthy adults (Hemington et al., 2018). Within- and between-network FC of the DMN and SN have also been reported as inversely associated with resilience (Altinok et al., 2021; Bolsinger et al., 2018; Hemington et al., 2018; Van der Werff et al., 2013). In healthy children and adolescents, decreased resilience was associated with increased FC of the DMN to the anterior cingulate cortex, a key node of the SN (Iadipaolo et al., 2017). A negative correlation was also identified in children and adolescents between resilience and a dynamic state of FC between the DMN and CEN (Iadipaolo et al., 2018). These reports indicate evidence of an inverse association between resilience and FC to the DMN, CEN, and SN in healthy individuals.

However, in concussion the DMN, CEN, and SN FC have been shown to be altered post-concussion (Abbas et al., 2015; Borich et al., 2015; Iyer et al., 2019; Johnson et al., 2012; Mayer et al., 2011; Meier et al., 2020; Newsome et al., 2016; Plourde et al., 2021; Sours et al., 2013, 2015). Click or tap here to enter text.Click or tap here to enter text.Click or tap here to enter text.Click or tap here to enter text.Click or tap here to enter text.Click or tap here to enter text.No known studies, have examined the functional correlates of resilience in concussion. The present study investigated the associations between changes in both resilience and resting-state FC of DMN, SN, and CEN from 72 hours (hrs) to 4-weeks post-injury, and whether these associations were moderated by group (concussion or orthopedic injury). Given that resilience can be malleable (Connor & Davidson, 2003), secondary objectives examined the associations between resilience and FC longitudinally and whether these associations were moderated by group.

Study Design

This is a secondary analysis of a larger randomized clinical trial, Pediatric Concussion Assessment of Rest and Exertion (PedCARE; Ledoux et al., 2019), where a subsample of children with a concussion or orthopedic injury underwent an MRI scan at 72hrs (+/- 48hrs) and 4-weeks (+/- 5 days) post-injury (Ledoux et al., 2019).Click or tap here to enter text. This study received approval by the Research Ethic Board and the Children’s Hospital of Eastern Ontario. All eligible children and adolescents capable of consenting on their own behalf provided written informed consent, while those unable to consent on their own behalf provided assent and parental consent.

Participants

Children with a concussion or an orthopedic injury (OI) were included in the study if they sustained a concussion or OI < 48hrs from their emergency department visit, were 10 to 17.99 years of age, and proficient in English. Concussion participants were excluded from the study if they presented with a Glasgow Coma Scale score of < = 13, had abnormalities on standard imaging, underwent intubation, or had a history of trauma prior to the injury. Children with an orthopedic injury were excluded if their injury was isolated to the lower extremity or if they experienced a concussion within the past year.

Any participants from either group were excluded if they met any of the following criteria: communication difficulties as a result of severe chronic neurological developmental delay; history of neurological disorder; intellectual disability; intoxication at the emergency department or during the imaging session; required sedation at or prior to the emergency department visit; required surgical operation; history of hospitalization for psychiatric illness; incapable of resuming physical activity; incapable of providing consent or assent; absent legal guardian; unavailable for data collection at both timepoints; medical contraindications to the MRI scanner; equipped with braces or metal implants.

Symptomatology assessments, including the Health and Behavior Inventory (HBI) and Connor-Davidson Resilience Scale 10 (CD-RISC 10) scoresClick or tap here to enter text. were recorded at both timepoints. MRI scanning was also conducted at both timepoints.

HBI

The HBI is a 4-point Likert self-report scale of symptomatology, with higher total scores indicating increased symptom severity. This scale was deemed to have strong construct validity and reliability (Ayr et al., 2009).

CD-RISC 10

The CD-RISC 10 is a validated 5-point Likert self-report scale of resilience (Campbell-Sills & Stein, 2007).Click or tap here to enter text. The sum of every item on the scale is interpreted as the degree of psychological resilience in the past month, with higher scores indicating increased resilience and lower scores indicating diminished resilience.⁴³

fMRI Acquisition

The fMRI acquisition used a 3-Tesla Siemens PET-MRI with a 12-channel head coil. A resting-state fMRI sequence was applied as part of the acquisition protocol. Participants were tasked with fixating on a crosshair and instructed to relax and try not to think of anything specific. The scanning parameters were as follows: resolution = 3.6x3.6x3.6 mm³, slices = 36, FOV = 23x23 cm², TR = 2000 ms, TE = 30 ms, measurement total = 241. The duration of the scanning was 8 minutes and 10 seconds. This sequence was identical for both scan sessions.

Statistical Analyses

Between-group differences in age and resilience were tested using independent samples t-tests. Within-group differences in resilience at both time points were tested using paired samples t-tests. Group differences in both proportion of biological sex at birth and history of concussion were computed using a chi-square test. Outliers were defined as being 2.48 standard deviations from the mean (Cousineau & Chartier, 2010) and were Winsorized to the nearest score within their group. Two cases of 4-week resilience were missing from the concussion group and were imputed using expectation maximization (Dong & Peng, 2013).

Structural image quality checks were conducted based on guidelines proposed by Backhausen et al. (2016). The CONN toolbox, a Matlab-based software, was used for the preprocessing and both seed-to-voxel and ROI-to-ROI analyses of the resting-state data (see Supplementary Materials)(Whitfield-Gabrieli & Nieto-Castanon, 2012)Click or tap here to enter text.. We adopted a seed-to-voxel approach analysing FC between DMN, SN, and CEN seeds and every voxel of the brain. Based on previous reports suggesting an inverse association between resilience and resting-state FC (Altinok et al., 2021; Bolsinger et al., 2018; Hemington et al., 2018; Iadipaolo et al., 2017; Van der Werff et al., 2013), we also pursued a priori region-of-interest (ROI) analyses of within-network DMN, SN, and CEN FC.

Demographics

A total of 67/92 (73%) children with concussion (median age= 12.81[IQR: 11.79 – 14.36]; 46% female) and 30/46 (65%) children with orthopedic injury (median age=12.27 [IQR: 11.18 – 13.94]; 46% female) were included in this study (see Supplementary Materials Fig 1). Sports was identified as the main mechanism of injury for both the concussion (38/67 [57%]) and orthopedic injury (19/30 [63%]) group. There were no significant differences between groups with respect to age, sex, history of concussion, handedness, diagnostic history, 72hrs resilience, 4-week resilience, and resilience change scores (Table 1). There were no significant differences between 72hrs resilience and 4-week resilience scores within the concussion (t[66] = -1.58, p = 119) and orthopedic injury groups (t[29] = -.527, p = .602).

The total emergency department self-reported HBI scores were significantly higher in the concussion group than the orthopedic injury group, t(95) = 3.80, p < .001. The total 72hrs self-reported HBI scores were also significantly higher in the concussion group, t(95) = 5.62, p < .001. There was no significant difference in total 4-week HBI scores between groups, t(95) = 0.13, p = .898.

Seed-to-Voxel Analyses

Longitudinal Analyses of Resilience and FC

Group moderation analyses of the DMN using the right lateral parietal cortex seed revealed one significant cluster along the right cerebellum (cluster size = 237, MNI x y z = +02 -72 -34, F[1 89] = 30.69, FWE corrected p = .007; Fig 1). Group was thus a significant moderator between longitudinal resilience and FC, with a positive correlation in the orthopedic injury group (β = 0.033) and a negative correlation in the concussion group (β = -0.003).

In the orthopedic injury group, DMN analyses revealed one significant cluster: a positive correlation between longitudinal resilience and FC of the right lateral parietal cortex seed to the right cerebellum (cluster size = 327, MNI x y z = +02 -76 -28, F[1 26] = 39.92, FWE corrected p < .001, β = 0.033). In the concussion group, no significant associations between longitudinal resilience and FC were detected.

Analyses of 72hrs Resilience and FC

Group moderation analyses of the SN using the left anterior insula seed revealed one significant cluster along the posterior division of the cingulate gyrus (cluster size = 407, MNI x y z = +02 -30 +28, F[1 89] = 19.33, FWE corrected p < .001; Fig 2). Group was thus a significant moderator of 72hrs resilience and FC, with a positive correlation in the concussion group (β = 0.006) and a negative correlation in the orthopedic injury group (β = -0.019).

In the concussion group, analysis of the CEN revealed one significant cluster: a positive correlation between 72hrs resilience and FC of the left lateral prefrontal cortex seed with the left lateral occipital cortex (cluster size = 307, MNI x y z = -26 -70 +62, F[1, 61] = 29.92, FWE corrected p = .002, β = 0.015; Fig 3).

In the orthopedic injury group, analysis of the SN revealed one significant cluster: a positive association between 72hrs resilience and FC of the left anterior insula seed with the right superior parietal lobule (cluster size = 416, MNI x y z = +44 -38 +54, F[1, 26] = 52.28, FWE corrected p < .001, β = 0.018; Fig 4).

ROI-to-ROI Analyses

Longitudinal Analyses of Resilience and Within-Network FC

Group moderation analyses of within-network DMN FC identified one significant cluster (F[2, 88] = 4.56, p-FDR = .026). The moderation cluster was comprised of three ROIs and three connections among them. The first connection between bilateral lateral parietal cortices was a positive correlation in both the concussion group (β = 0.001) and the orthopedic injury group (β = 0.018). The second connection between the right lateral parietal cortex and posterior cingulate cortex was a negative correlation in both the concussion group (β = -0.002) and the orthopedic injury group (β = -0.021). The third connection between the left lateral parietal cortex with the posterior cingulate cortex was a positive correlation in the concussion group (β = 6.80E-05) and a negative correlation in the orthopedic injury group (β = -0.015).

In the orthopedic injury group, longitudinal resilience was associated with longitudinal within-network DMN FC (F[2, 25] = 4.99, p-FDR = .030). This significant cluster comprised of three ROIs and three connections among them: a positive correlation between the right and left lateral parietal cortex (β = 0.018); a negative correlation between the right lateral parietal cortex and posterior cingulate cortex (β = -0.021); as well as a negative correlation between the left lateral parietal cortex and the posterior cingulate cortex (β = -0.015). In the concussion group, no significant associations between longitudinal resilience and within-network FC were detected.

Analyses of 72hrs Resilience and Within-Network FC

In the orthopedic injury group, analyses of within-network SN FC identified one significant cluster (F[1, 26] = 8.98, p-FDR = .036). The cluster comprised of three ROIs and three connections among them: a negative correlation between 72hrs resilience and FC of the right anterior insula with the anterior cingulate cortex (β = -0.012); a negative correlation between 72hrs resilience and FC of the left and right anterior insula (β = -0.016); and a negative correlation between 72hrs resilience and FC of the left anterior insula with the anterior cingulate cortex (β = -0.015). The group moderation analyses of within-network FC detected no significant clusters. In the concussion group, analyses did not detect any significant associations between 72hrs resilience and FC.

Seed-to-voxel and ROI-to-ROI analyses did not detect any significant group moderations or associations between 4-week resilience and FC.

This study found a positive association between resilience and CEN FC in children with concussion. Positive associations were also identified between resilience and both SN and DMN FC in orthopedic-injured children. Group, or pediatric injury type, moderated associations between resilience and both SN and DMN FC.

Results for our primary objective suggest that pediatric injury type moderates the associations between longitudinal resilience and longitudinal DMN FC, that is FC of the right lateral parietal cortex with the right cerebellum. The lateral parietal cortex plays a role in various cognitive processes including attention, working memory, spatial cognition, and social cognition (Cabeza et al., 2012; Desmurget et al., 2009; Humphreys & Lambon Ralph, 2015; Tumati et al., 2019). A recent functional MRI study identified the cerebellum and corticocerebellar connections as being integral to episodic memory for emotionally arousing visual information (Fastenrath et al., 2022). Furthermore, this study found a significant positive correlation between longitudinal resilience and FC with the same regions within orthopedic-injured children. As longitudinal resilience did not differ between our samples of concussion and orthopedic injury children, perhaps the difference of associations between groups may be attributed to concussion-related changes to FC. Our a priori analyses indicate that associations between longitudinal resilience and within-DMN FC are also moderated by pediatric injury type. Our results similarly found that such associations were significant in orthopedic-injured children. The effects of pediatric concussion might thus contribute towards a diminished association between longitudinal resilience and within-DMN FC.Click or tap here to enter text.

Analyses for our secondary objective indicate that the effects of 72hrs resilience on SN FC are moderated by pediatric injury type. This significant moderation was identified in FC between the left anterior insula of the SN and the posterior division of the cingulate gyrus, a node of the DMN. In a study investigating whether damage to white matter tracts of the SN disrupts regulation of associated networks, structural connectivity within the SN was a significant predictor of DMN function (Bonnelle et al., 2012). Specifically, integrity of a tract connecting the right anterior insula to the presupplementary motor area and dorsal anterior cingulate cortex was correlated with abnormal posterior cingulate cortex activation in traumatic brain injury patients. The authors concluded that structural integrity of the SN is imperative for regulation of DMN activity. ^31,32Pediatric concussion, might diminish the association between resilience and SN FC to the DMN, contributing to a deregulation of DMN activity. This might, in turn, partially explain the discrepancy of significant DMN FC associations between our samples of children concussion and orthopedic-injury.

A significant positive correlation was reported between 72hrs resilience and FC of the CEN, specifically the left lateral prefrontal cortex, with the left lateral occipital cortex in children with concussion. Interestingly, a recent study identified increased FC between the right lateral prefrontal cortex and right occipital pole in concussion youth with resolved headache symptoms when compared to concussion youth with persisting headache symptoms (Lemme et al., 2021). This recent study, however, did not incorporate a measure of resilience. It is possible that their sample of concussion youth with resolved headache symptoms had increased resilience relative to those with persisting headache symptoms. This warrants further investigation into the effects of resilience on CEN FC in concussion. Meanwhile, in orthopedic-injured children, 72hrs resilience was positively correlated with SN FC. Additional a priori analyses found that 72hrs resilience was also significantly associated with within-SN FC in orthopedic-injured children. This is consistent with previous reports of negative correlations between resilience and within-SN FC in healthy populations (Altinok et al., 2021; Bolsinger et al., 2018). As suggested by Altinok et al. (2021), highly-resilient individuals might have decreased switching of the SN between networks responsible for processing self-relevant information. Highly-resilient individuals might thus maintain a reasonable emotional response to trauma, allowing for an increased capacity to focus on their current mental state and successfully cope without interference from internal and external stressors. Unfortunately, these results were not identified in the concussion group, which might suggest that biomechanical injury to the head contributes to a disruption of this association otherwise identified in non-concussed individuals. As such, only results from the orthopedic-injury group, as opposed to the concussion group, are largely consistent with the resilience literature using non-injured participants. Additional research is necessary to understand the effects of such associations on clinical symptoms post-injury in both orthopedic injury and concussion group.

There were no significant results to report with respect to 4-week resilience and FC. Associations between resilience and resting-state FC might thus only be pertinent or detectable within the acute phase of injury. Research using non-injured pediatric samples reported various associations between resilience and resting-state FC of the SN with the DMN and CEN (Iadipaolo et al., 2018). Considering this, the underlying mechanism that may explain the progressive changes in associations between resilience and FC during pediatric concussion recovery remain unclear.

Although this study provides insight as to the effects of resilience on DMN, CEN, and SN FC following pediatric concussion, the identified patterns in resting-state connectivity might be affected by our selection of spatial seeds in the seed-based correlations. It is known that subtle differences in selection of spatial seed voxel locations for seed-based correlation analyses of resting-state networks can have a significant effect on the variability of resulting associations in network connectivity (Buckner et al., 2008; Cole et al., 2010; Hayasaka & Laurienti, 2010). Future research of this sort should seek to apply similar spatial seeds as the ones selected for this study to replicate these findings.

Our results provide insight of the associations between resilience and FC in the sub-acute phase of pediatric concussion. We report several differences between our samples of children with orhtopedic-injury and concussion, whereby significant associations between resilience and FC were identified in the former but not the latter. These findings indicate that resilience might play a role in the functional neuroimaging results of pediatric concussion and should be further examined to determine its potential usefulness in clinical settings as a protective or restorative element after injury. Currently, there is insufficient congruency of evidence in the literature to deduce whether these patterns of results are truly indicative of improved or worsened neurophysiological functioning post-injury. Additional investigations are warranted to determine the potential of resilience as a factor linked to an optimal recovery from pediatric concussion.

Acknowledgments: The authors would like to acknowledge and thank the MRI technologists and physicist at the Brain Imaging Centre at the Royal Mental Health Centre in Ottawa, Ontario.

Author Contributions: Author contributors included conception and study design (OB, AS, RZ, AAL), data collection or acquisition (KH, RZ), statistical analysis (OB, ZF, AAL), interpretation of results (OB, AS, AAL), drafting the manuscript work (OB, AS, AAL), and approval of final version to be published (All authors).

Funding Sources: This work was supported by the OSSU IMPACT Award; PSI Foundation Award

Compliance with Ethical Standards: This study received approval by the Research Ethic Board and the Children’s Hospital of Eastern Ontario. All eligible children and adolescents capable of consenting on their own behalf provided written informed consent, while those unable to consent on their own behalf provided assent and parental consent.

Conflict of Interest: Roger Zemek has received competitively-funded research grants from Canadian Institutes of Health Research (CIHR), Ontario Neurotrauma Foundation (ONF), Physician Services Incorporated (PSI) Foundation, CHEO Foundation, Ontario Brain Institute (OBI), and Ontario SPOR Support Unit (OSSU), and the National Football League (NFL) Scientific Advisory Board, and he is supported by a Clinical Research Chair in Pediatric Concussion from University of Ottawa. He is the co-founder, Scientific Director and a minority shareholder in 360 Concussion Care, an interdisciplinary concussion clinic. All other co-authors have no conflict of interest.

Data Availability Statement: The data cannot be shared due to legal, ethical or privacy restrictions.

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Table 1: Demographic Data
	Concussion N(%)	Orthopedic Injury N (%)	Group Differences p-value
Age, median(IQR)	12.87(11.79 – 14.36)	12.27(11.19 – 13.94)	.292
History of concussion	16(24.40)	6(20.69)	.726
Sex			.566
Male	36(54)	18(60)
Female	31(46)	12(40)
Handedness			.113
Left	9(13)	8 (27)
Right	58(87)	21(73)
Diagnostic History
Anxiety	10(15)	3(10)	.510
Depression	3(5)	1(3)	.793
Attention-deficit/hyperactivity disorder	9(13)	4(13)	.989
Mechanism of Injury
Fall from elevation	1	1
Fall down stairs	2	1
Sport	38	19
Fall from standing/walking/running	8	2
Ran into stationary object	7	0
Bike collision/fall while riding	0	1
Other mechanism	12	6
IQR: Interquartile range

Table 1: Demographic Data continued
	Concussion N(%)	Orthopedic Injury N (%)	Group Differences p-value
Resilience 72hrs post-injury, median(IQR)	24(17 – 31.5)	12(2.5– 30.50)	.557
Resilience 4-weeks post-injury, median(IQR)	28(21.5 – 34)	28(21.5 – 33)	.987
Resilience change scores, median(IQR)	1(-3 – 5)	0(-2 – 2)	.483
HBI at ED, median(IQR)	23(16.5 – 29.5)	14(8.5 – 21)	< .001
HBI at 72hrs post-injury, median(IQR)	24(17 – 31.5)	12(2.5 – 20)	< .001
HBI at 4-weeks post-injury, median(IQR)	12(2.76 – 18.80)	10(3 – 18)	.898
Hours between ED and 72hrs scan, median(IQR)	75.50(53.43 – 90.75)	108.5(69.77 – 120.11)
Days between ED and 4-week scan, median(IQR)	30.25(28.56 – 32.08)	30.38(27.92 – 32.25)
ED: Emergency department; HBI: Health Behaviour Inventory; IQR: Interquartile range

Competing interest reported. Roger Zemek has received competitively-funded research grants from Canadian Institutes of Health Research (CIHR), Ontario Neurotrauma Foundation (ONF), Physician Services Incorporated (PSI) Foundation, CHEO Foundation, Ontario Brain Institute (OBI), and Ontario SPOR Support Unit (OSSU), and the National Football League (NFL) Scientific Advisory Board, and he is supported by a Clinical Research Chair in Pediatric Concussion from University of Ottawa. He is the co-founder, Scientific Director and a minority shareholder in 360 Concussion Care, an interdisciplinary concussion clinic. All other co-authors have no conflict of interest.

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Associations Between Changes in Psychological Resilience and Resting-State Functional Connectivity Throughout Pediatric Concussion Recovery

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