Impact of a mindfulness‐based intervention on neurobehavioral functioning and its association with large‐scale brain networks in preterm young adolescents

Adolescents born very preterm (VPT; <32 weeks of gestation) face an elevated risk of executive, behavioral, and socioemotional difficulties. Evidence suggests beneficial effects of mindfulness‐based intervention (MBI) on these abilities. This study seeks to investigate the association between the effects of MBI on executive, behavioral, and socioemotional functioning and reliable changes in large‐scale brain networks dynamics during rest in VPT young adolescents who completed an 8‐week MBI program.

http://onlinelibrary.wiley.com/doi/10.1111/pcn.13675/fullVery preterm (VPT) birth, as defined by a birth occurring before 32 weeks of gestation, affects the developmental trajectory of the brain.It is consequently associated with an increased risk of cognitive and behavioral difficulties across the lifespan. 1In a review study, Johnson and Marlow 2 found that when diagnostic psychiatric evaluations were employed, studies reported a threefold to fourfold increased risk for developing disorders during middle childhood.The most commonly observed were the inattentive subtype of attentiondeficit/hyperactivity disorder, anxiety disorders, and autism spectrum disorder. 2In light of these findings, they introduced the concept of the 'preterm behavioral phenotype', which is characterized by an augmented susceptibility to disorders and subclinical symptoms related to attention and executive functions, anxiety, and socioemotional difficulties.
Resting-state functional connectivity (FC) is now a commonly used technique for mapping large-scale networks in the human brain.It is characterized by the temporal dependence of neuronal activity patterns of anatomically separated brain regions occurring in the absence of goal-directed activity and stimulation. 3A set of functionally connected regions with synchronous and spontaneous neuronal activity observed in the resting state is referred to as resting-state networks. 4][8] More specifically, static FC studies using a seed-based correlation approach have shown altered FC of various brain regions in infants, children, adolescents, and adults born prematurely including the superior temporal, amygdala, posteromedial and lateral parietal, prefrontal, and lateral and superior sensorimotor regions. 7In VPT infants, overall cognitive scores at 6 months were predicted by medial prefrontal cortex-executive control connectivity strength. 9In VPT children and adults, increased and decreased FC of the amygdala with other brain regions including posterior cingulate cortex, precuneus, and superior temporal areas and thalamus have been associated with the capacity to recognize facial expression of anger and with social problems. 7,10,11Similarly, static FC studies using whole-brain datadriven approaches have found atypical resting-state networks associated with prematurity across the lifespan, especially FC of the salience, default mode, and frontal networks. 6,12In VPT children, Mossad et al. 13 showed that increased connectivity in the default mode network at the age of 6 was linked to social and working memory difficulties by the age of 8.Moreover, in VPT children and adolescents, intelligence quotient or poorer executive function abilities have been partially linked to FC strength between sensorimotor areas and those involved in higher-order cognitive functions (i.e.salience, central executive, and dorsal attention networks). 14tudies using dynamic FC-allowing identification of meaningful variations over time in FC between different brain regions-are still sparse in the VPT population and, to our knowledge, only conducted in VPT infants and children so far.Nevertheless, the findings are consistent with static FC with different patterns of brain dynamics between VPT groups and full-term (FT) controls. 15,16In FT controls, reduced involvement in specific brain networks correlated with improved socioemotional abilities; while in the VPT group, enhanced socioemotional abilities were associated with the coordination of activity across various functional networks, i.e. coupling duration between different pairs of networks. 8iven the significant long-term impact of deficits reflecting the preterm phenotype, greater efforts have focused on developing potential ways to reduce these difficulties.Mindfulness, commonly defined as the ongoing monitoring of present-moment experience while attending to it in an open and accepting way and without judgment, 17 is of particular interest.Mindfulness-based intervention (MBI), designed to improve mindfulness skills through diverse practices, has been linked to enhanced executive, behavioral and socioemotional functioning in typically developing children and adolescents, 18,19 as well as in clinical pediatric populations. 20,21Consistent with enhancements in behavioral outcomes, research indicates that MBI may induce FC changes.A recent review of the literature showed the wide impact of mindfulness and MBI on brain FC in healthy and clinical populations, especially FC related to prefrontal, rostral anterior cingulate, amygdala, and visual regions. 22Comparable results have been found during adolescence in typically developing as well as in clinical populations. 23,24There is limited research on the impact of mindfulness on dynamic FC.Nevertheless, a recent study found increased FC between the default mode network and the salience network in adults after 1 month of mindfulness meditation compared with a control intervention. 25Moreover, in children, adolescents, and adults, consistent findings showed that individuals with higher disposition to mindfulness or a mindfulness trait (i.e.corresponding to the average frequency with which individuals experience states of mindfulness) transitioned between brain states more frequently than those with low mindfulness disposition. 26,27n VPT young adolescents, a recent randomized controlled trial demonstrated advantages from an 8-week MBI on executive, behavioral, and socioemotional functioning. 28More precisely, the results suggest a beneficial effect of MBI on executive, behavioral, and socioemotional functioning in VPT young adolescents, as assessed through parent questionnaires.In addition, increased executive abilities were observed using a computerized task, reflecting improved processing speed following MBI.Building on our prior investigation and seeking a deeper comprehension of the neural underpinnings of neurobehavioral changes, the objective of this study is to evaluate the association between the benefits of MBI on neurobehavioral functioning and potential changes in large-scale brain dynamics, employing dynamic FC.To achieve this, we initially compared VPT and FT young adolescents across various measures of executive, behavioral, and socioemotional measures.Next, we assessed the benefit of the MBI using a before/after design on neurobehavioral measures that showed significant differences between the VPT and the FT groups (i.e.significant reduction in neurobehavioral symptoms in the VPT group compared with their FT peers).Of note, only VPT young adolescents (and not FT controls) completed the MBI.Finally, we explored associations between reliable change after MBI on neurobehavioral measures and reliable change after MBI on temporal characteristics of large-scale brain networks.
0][31] To address this limitation, dynamic approaches have been developed, offering the potential to identify significant temporal variations in FC among distinct brain regions.Moreover, a dynamic FC approach holds promise to provide information for both the identification of markers of cognitive development in the VPT population, 8,15,16 as well for the identification of mindfulness-related changes in brain functions. 26Among the multiple existing methods to investigate dynamic FC, 29 the innovation-driven coactivation patterns (iCAPs) framework allows capture of transient activations through spatiotemporal functional magnetic resonance imaging (fMRI) deconvolution, and then defines iCAPs network containing all brain voxels with the same transient behavior. 32,33This approach aligns conceptually with the hypothesis of discrete shifts between brain meta-states, 34 although states in the iCAPs framework can be temporally overlapping.In contrast to other dynamic FC approaches (e.g.sliding windows), iCAPs can detect instantaneous transients of activity of areas clustered together based on their activation pattern.This enables the dissection of brain activity patterns that temporally coincide by identifying consistent spatial patterns at the onset of deactivation or activation. 33

Participants
This study uses data from the Mindful Preterm Teens Study, a randomized controlled trial. 35A total of 63 VPT young adolescents (born before 32 gestational weeks) were enrolled in the study.Fiftytwo of them completed the MBI and the neurobehavioral assessment before and after the intervention.The participants, ranging from 10 to 14 years, were born between January 2003 and December 2008 at the Geneva University Hospital, Switzerland.They were under the care of the Division of Child Development and Growth at the Geneva University Hospital.Exclusions for VPT young adolescents involved an intelligence quotient below 70, sensory or physical disabilities (such as cerebral palsy, blindness, or hearing loss), or an inadequate proficiency in French.Of the 52 young adolescents, 39 completed an MRI scan both before and after the MBI.Seven were removed from the final analysis because of head motion, and a final sample of 32 VPT participants was finally included in the current resting-state fMRI (rs-fMRI) analyses (Supplementary Fig. S1).
Moreover, 24 FT and typically developing young adolescents aged between 10 and 14 years were recruited through the community and completed the neurobehavioral assessment and MRI scan (similar to the assessment completed by the VPT group before the MBI).
The current study conforms to the provisions of the Declaration of Helsinki.

Mindfulness-based intervention
The MBI was specifically created for the Mindful Preterm Teens Study and consisted of 8 weekly sessions in groups of up to 8 participants, lasting 90 min (for a detailed description of the MBI, see Supplementary Methods and Supplementary Table S1) 35 .

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Mindfulness intervention in preterms Neurobehavioral outcome measures Participants' executive, behavioral, and socioemotional functioning were assessed.Table 1 provides an overview of the assessment (see Supplementary Table S2 for a comprehensive description of each measure).Importantly, all outcome measures assessed and utilized in our prior randomized controlled trial were also retained in the current study.The rationale for choosing these outcome measures is described thoroughly in the feasibility study and the effectiveness of the randomized controlled trial. 28,35I acquisition and preprocessing MRI acquisition MRI data were acquired using a Siemens 3T Magnetom Prisma scanner (Siemens, Erlangen, Germany) including structural T1-weighted MP-RAGE sequences, resting-state functional images T2*-weighted with a multislice gradient echo-planar imaging sequence, and a fieldmap (see Supplementary Methods for a detailed description).
During the rs-fMRI sequence, young adolescents from the VPT and FT groups received identical instructions.They were asked to keep Evaluates behavior and socioemotional abilities in everyday life.The SDQ total difficulty score was used.Higher SDQ total scores reflect increased behavioral and socioemotional difficulties SDQ total Self-reported questionnaires KIDSCREEN-27 42 Evaluates health-related quality of life.The total raw score was used.Higher total scores reflect increased quality of life and well-being KIDSCREEN total Social Goal Scale (SGS 43 ) Evaluates social responsiveness.The total raw score was used.Higher total scores reflect increased social goal in daily life

Social goal
Self-Compassion Scale -Short form (SCS 44 ) Evaluates self-compassion.The total raw score was used.Higher total scores reflect increased self-compassion rs-fMRI data preprocessing rs-fMRI data were preprocessed using SPM12 (Wellcome Department of Imaging Neuroscience) in MATLAB R2016a (The MathWorks, Inc.), following the preprocessing pipeline previously described (see Supplementary Methods for a detailed description). 36,37In short, rs-fMRI findings were spatially realigned and unwarped using the fieldmap images acquired, respectively.Functional images were then coregistered to their corresponding structural images in subject space.Structural images were segmented with the SPM12 segmentation algorithm, and a study-specific template was generated using DARTEL 38 that was used in the iCAPs framework described below.Finally, the first five rs-fMRI scans were excluded.For each participant, preprocessed functional images were also checked individually for inclusion of the whole cerebrum and of the cerebellum.For rs-fMRI data, head motion from volume to volume for each participant was computed using the mean framewise displacement. 39,40Head motion was considered following the recommendation of Power et al. 40 and described thoroughly in the Supplementary Methods.

iCAPs and extraction of iCAPs activation measures iCAPs
The iCAP analysis is an advanced tool for rs-fMRI that identifies moments of significantly changing brain activity to extract large-scale brain networks and their dynamic properties. 33We tailored the openly available code (https://c4science.ch/source/iCAPs/) in MATLAB R2016a to apply the iCAPs framework in VPT young adolescents including both before and after MBI rs-fMRI.In short, total activation applies a voxelwise hemodynamically informed deconvolution 32,41 and S3).Time courses for all iCAPs were generated using spatiotemporal transient-informed regression. 42APs' labelling and temporal properties 4][45][46] For each participant before MBI and after MBI, we obtained iCAPs' temporal characteristics by back projecting each iCAP into participants' activity-inducing signals before and after MBI: (i) the total duration: total duration of overall activation as a percentage of the total nonmotion scanning time, a metric describing the amount of sustained activity (or functional 'engagement') for that specific iCAP; (ii) the occurrences: the number of activation blocks for each pair of iCAPs; (iii) the coupling: samesigned coactivation; and (iv) the anticoupling: opposite-signed coactivation.Couplings and anticouplings were calculated using the Jaccard score, i.e percent of joint activation time of two respective iCAPs reflecting the amount of overlap between the activity, in the same or the opposite signs, respectively, of each pair of iCAPs.

Static properties of inter-iCAPs interactions
As supplementary analyses, a static measure of inter-iCAPs interactions was calculated and compared before and after MBI for the eight identified networks (Supplementary Methods and Supplementary Table S9).

Statistical analyses
Statistical analyses were completed using R version 4.0.3, 47RStudio version 1.3.1093, 48and MATLAB R2019b.The following steps were completed for statistical analyses: 1 Comparison of the VPT and FT groups on neurobehavioral measures Comparisons between the VPT and the FT groups were performed using linear regressions for all neurobehavioral measures.Each neurobehavioral measure was modeled as the outcome variable, with the group serving as a fixed effect.P-values were corrected for multiple comparisons with the false discovery rate (q-values <0.1 49 ).Secondary analyses were conducted to evaluate the impact of general intellectual abilities on outcome measures using the same linear regressions and adding the General Ability Index (GAI) as covariate.
2 Assessment of the effect of MBI on neurobehavioral measures significantly affected in the VPT group The effect of MBI on neurobehavioral measures, which exhibited significant reductions in VPT participants compared with FT participants, was assessed using linear regressions.We modeled the neurobehavioral measures of interest as the outcome variables, the group as a fixed effect, and the subject as a random effect.P-values were corrected for multiple comparisons with false discovery rate (q-values <0.1 49 ).Secondary analyses were conducted to evaluate group difference between the VPT group after MBI and the FT group on neurobehavioral measures.
3 Association between reliable changes in neurobehavioral outcomes and reliable changes in temporal properties of iCAPs (i.e.before and after the MBI) a Calculation of the reliable change index (RCI) For each neurobehavioral measure and each temporal property of iCAPs (i.e.duration, coupling, and anticoupling), the RCI was calculated for each participant. 50The RCI is a commonly applied approach to quantify a clinically significant change.It allows assessment of whether a patient's change over time on a given outcome measure cannot be attributable to error.A negative RCI signifies a decrease in scores between two time points, while a positive RCI indicates an increase in scores between two time points.The formula for the RCI is: RCI score = d i /SEM d ; where d i is an individual-level difference score (i.e. after MBI À before MBI) and SEM d is the standard error of measurement, i.e. of the difference between the two test scores.
b Partial least-square correlation Partial least-square correlation analyses (PLSC) were performed to evaluate multivariate patterns of correlation between: (i) clinical measures, including RCI in neurobehavioral measures as well as gestational age at birth and age at testing; and (ii) RCI in iCAPs' temporal properties.PLSC, a data-driven multivariate technique, enhances the covariance between two matrices by identifying latent components (LCs) that represent linear combinations of the two matrices. 43,51,52o implement this, a publicly accessible MATLAB PLSC implementation was used: https://github.com/danizoeller/myPLS 43,52(see Supplementary Methods for detailed description of the PLSC applied).
In an initial PLSC, we investigated associations between clinical measures (32 Â 7 matrix [X]) and reliable changes in the total duration of each iCAP (32 Â 8 matrix [Y]).Subsequently, in a second PLSC, we delved into the relationships between clinical measures (X) and reliable changes in the occurrences of each pair of iCAPs (Y).In a third and fourth PLSC, associations between clinical measures (32 Â 7 matrix denoted X) and reliable changes in the coupling and anticoupling of each pair of iCAPs (32 Â 28 matrix denoted Y) were explored.

Clinical Neurosciences
Mindfulness intervention in preterms

Participant characteristics
The final sample included 32 VPT and 24 FT young adolescents aged between 10 to 14 years.Neonatal and demographic characteristics can be found in Table 2.In this final sample, parents reported neurodevelopmental disorders in 12.5% of young adolescents (n = 4), including 9.4% with dyslexia (n = 3) and 3.1% with dyspraxia (n = 1).Socioeconomic status (SES) of the parents was estimated using the Largo scale. 63Higher Largo scores reflect lower SES of the parents.The Wechsler Intelligence Scale for Children, 5th Edition (WISC-V 37 ), was used to evaluate the General Ability Index (GAI) as a measure of general intellectual functioning (M = 100, SD = 15).BPD, bronchopulmonary dysplasia; cPVL, cystic periventricular leukomalacia; FT, full-term; IVH, intraventricular hemorrhage.Neurobehavioral measures indicating significant group differences between the very preterm (VPT; before the mindfulness-based intervention) and the full-term (FT) groups using linear regression models (false discovery rate, q-values <0.1).Dark blue = VPT; yellow = FT; group means are represented by a black dot; ***q < 0.001, **q < 0.01, *q < 0. Comparison between the VPT and FT groups on neurobehavioral measures The VPT group showed higher scores on the Behavior Rating Inventory of Executive Function, parent version (BRIEF) for the Global Executive Composite (BRIEF GEC; q < 0.001), Metacognition index (BRIEF MI; q < 0.001), Behavioral Regulation Index (BRIEF BRI; q < 0.01), and on the total score of the Strengths and Difficulties Questionnaire, parent version (SDQ total score; q < 0.01), reflecting increased executive and behavioral difficulties in daily life compared with the FT group.Moreover, the self-compassion score was significantly reduced in the VPT group compared with the FT group (q < 0.1) (Figure 1).Other neurobehavioral measures were comparable between the VPT and FT groups (Supplementary Tables S3 and  S4).Secondary analyses including the GAI as covariate showed comparable results (Supplementary Table S4).

Effect of MBI on neurobehavioral measures significantly affected by preterm birth
For measures showing significant differences between VPT and FT, significant score reductions were noted after MBI in the following: BRIEF GEC (q < 0.001), BRIEF MI (q < 0.01), BRIEF BRI (q < 0.01), and SDQ total score (q < 0.01).This indicates significantly less executive and behavioral difficulties in daily life following MBI.There was also a significant difference between selfcompassion scores before and after MBI, with increased selfcompassion scores after MBI in young VPT adolescents (q < 0.1) (Figure 2 and Supplementary Table S5).Secondary analyses comparing the VPT group after MBI and FT young adolescents showed no significant group difference that survived multiple comparison correction (Supplementary Table S6).
Association between reliable changes in neurobehavioral outcomes and reliable changes in temporal properties of iCAPs (i.e., before and after the MBI) Only the first PLSC analysis applied on clinical measures (i.e., RCI in neurobehavioral measures as well as gestational age and age at testing) and reliable changes in the total duration of each iCAP gave a significant LC: LC 1 (P = 0.012).The three other PLSC applied on clinical measures and reliable changes in occurrences of each iCAP and in coupling and anticoupling of each pair of iCAPs did not show any significant associations.To reiterate, a negative RCI signifies a decrease in scores between the two time points, while a positive RCI indicates an increase in scores between them.
Latent component 1 (P = 0.012) was observed in the context of the association between clinical measures (i.e., RCI BRIEF GEC,

Mindfulness intervention in preterms
RCI BRIEF MI, RCI BRIEF BRI, RCI SDQ total, RCI Selfcompassion, gestational age, and age at assessment before MBI) and reliable changes in the total duration of each iCAP.Bootstrapestimated mean saliences, along with their bootstrap-estimated SDs for clinical measures and reliable changes in the total duration of each iCAP, are detailed in Supplementary Table S8.Latent component 1 displayed a broad pattern of association between decreased RCI in BRIEF GEC, RCI BRIEF MI, and RCI BRIEF BRI with increased RCI in the total duration of iCAP1, iCAP2, iCAP3, and iCAP4, as illustrated in Figure 4a and 4b.In other words, a reduction in scores of the BRIEF after MBI, reflecting better executive abilities in daily life, was associated with an increase in the total duration of the frontolimbic (iCAP1), dorsolateral prefrontal (iCAP2), amygdalahippocampus (iCAP3), and visual (iCAP4) networks.

Discussion
This study explored the benefit of an 8-week MBI on executive, behavioral, and socioemotional abilities in VPT young adolescents and its association with reliable changes in the temporal dynamics of large-scale brain networks.VPT young adolescents showed specific executive, behavioral, and socioemotional difficulties in everyday life compared with FT controls; these difficulties were significantly reduced after MBI in the VPT group.Our findings show that the enhancement observed in executive abilities after MBI, previously observed in a gold-standard randomized controlled trial, is associated with reliable changes in temporal characteristics of large-scale brain networks.More specifically, increased executive functioning in everyday life was associated with: (i) longer activation in frontolimbic and amygdala-hippocampus networks known to be related with self-regulation; (ii) longer activation in the dorsolateral prefrontal network known to be associated with attentional control; and (iii) longer activation in visual networks that have been related to attentional awareness of relevant sensory stimuli.
In the current sample, VPT young adolescents exhibited significant executive, behavioral, and socioemotional difficulties in everyday life in comparison to FT peers, as measured by parent-reported and self-reported questionnaires.The vulnerability of VPT children and adolescents for executive, behavioral, and socioemotional abilities has been well-described in previous studies, and corresponds to the 'preterm behavioral phenotype' proposed in the literature. 2 After an 8-week MBI specifically designed for this age range, i.e. 10 to 14 years, we observed a significant reduction of executive, behavioral, and socioemotional difficulties in everyday life as well as a significant increase in self-compassion.Furthermore, the significant difficulties in executive and socioemotional measures observed before the MBI in the VPT group compared with FT young adolescents no longer showed group differences after MBI.These findings are in line with the randomized controlled trial completed in a larger cohort of VPT young adolescents. 28This suggests that the improvement observed in executive, behavioral, and socioemotional measures following MBI in our study population is likely to be unrelated to a test-retest effect and is not only specific to the current sample of VPT young adolescents.Moreover, the beneficial impact of MBI on these abilities is consistent with previous studies conducted not only in typically developing adolescents but also in different clinical populations. 20,21onsidering the beneficial impact of MBI on vulnerable abilities in VPT young adolescents, we explored potential associations of behavioral benefits with temporal dynamics of large-scale brain networks.For this purpose, a whole-brain data-driven approach was employed to unravel the transient activity of coordinated brain networks from spontaneous rs-fMRI measurements.This approach aimed to extract dynamic features of FC across the entire brain. 33The findings showed a significant association between the improvement in executive abilities in everyday life after MBI with a longer activation of frontolimbic, dorsolateral prefrontal, amygdala-hippocampus, and visual networks.These findings are coherent with previous studies conducted in adolescents as well as in adults both in healthy and clinical populations.Mindfulness-mediated FC changes have been largely observed in frontolimbic as well as amygdala-hippocampus networks. 53,54These changes have been related to behavioral selfregulation, including emotion regulation, as well as in the monitoring of social cognition. 22,55Hippocampal activity has also largely been associated with mindfulness meditation and meditation expertise. 55,56lso in line with previous studies, we observed an association between the improvement in executive functioning with a longer activation of the dorsolateral prefrontal network after MBI. 24,53The changes in the recruitment of the dorsolateral prefrontal network have been associated with attentional control and the online processing of events and action. 22Increased activity within this region, as part of the executive network involved in controlling attentional resources to deal with immediate or future demands, has been associated with greater meditation experience. 57Additionally, the results showed that executive enhancement was associated with longer activation of the visual network involving the cuneus and precuneus, as well as superior and middle occipital regions.Mindfulness-mediated FC changes in the visual networks have been consistently observed in the literature. 22,24,53Previous studies suggest that changes in visual connectivity could play a role in internally directed attention. 58,59Within this concept, it has been hypothesized that mindfulness-related processes could allow an increase in attentional awareness of relevant sensory stimuli normally suppressed. 22,60Another proposed hypothesis is linked to the role of visual networks in a relaxation effect following mindfulness meditation as it has been shown that FC of the visual cortex is increased during light sleep, sedation, and alcohol consumption. 55,61Finally, there was no association between the gain observed after MBI on any of the neurobehavioral measures with reliable changes in the occurrence, nor in the coupling or anticoupling of the different networks extracted.
A recent study on the same cohort exploring white-matter microstructural changes associated with neurobehavioral changes after MBI corroborate these findings. 62This prior study demonstrated that enhanced executive functions in daily life were associated with increased structural connectivity using a tractography-based approach characterized by increased fractional anisotropy and reduced axonal dispersion.Remarkably, this previous study exhibited high regional overlaps with the current study, reflected by changes both in the microstructural properties of white-matter tracts and in dynamic FC.Specifically, longer activation in the frontolimbic and amygdalahippocampus networks might correspond to increased structural connectivity in the cingula, anterior thalamic radiations, and other thalamic tracts observed in the prior study.Longer activation in the dorsolateral prefrontal network might coincide to increase in structural connectivity in the genu of the corpus callosum as well as in other tracts involving the dorsolateral prefrontal cortex (e.g., arcuate fascicles and inferior occipitofrontal fascicule).Finally, longer activation in visual networks might correspond to increase structural connectivity in the optic radiations and other occipital tracts.Altogether, enhancements in everyday executive functioning following MBI appear to be associated with concurrent structural and functional changes in overlapping brain regions.
Of note, the presence of neurodevelopmental disorders, specifically dyslexia and dyspraxia, within our sample may not exert a substantial influence on our findings for several compelling reasons.First, the analyses are centered on examining intraindividual changes rather than making direct comparisons with an external group.Second, we would expect MBI to have an impact on attention-deficit/ hyperactivity disorder, which was not reported in our current sample.
Our study has limitations that require mentioning.Although embedded within a broader randomized controlled trial, 28,35 this study employed a pre-post intervention design exclusively within the VPT group, which completed the MBI as the MRI scan was only completed before and after MBI.Consequently, a notable limitation of this study is the absence of an active control condition or a placebo condition.It is imperative to underscore that comparing the effects of the MBI against an engaging active control condition is indispensable for

Clinical Neurosciences
Mindfulness intervention in preterms ensuring a robust evaluation of the impact on neurobehavioral measures and the related changes in FC dynamics among VPT young adolescents.Second, the group difference observed as well as the beneficial effect of MBI was only observed via self-and parentreported questionnaires.The subjective aspect of these tools is well-documented. 63The completion of questionnaires by multiple informants from different settings (e.g., parents and teachers) could be considered in future studies to give a more objective view of the changes occurring after MBI. 64,65In addition, it is possible that neurobehavioral tests employed in this study may not have effectively captured the everyday life challenges faced by these young adolescents. 66While our findings are promising, a well-designed active control condition or placebo condition are needed to further investigate the neural signature of positive clinical changes after MBI.Moreover, in the context of a mindfulness study, specifically targeting a given mindful practice during a functional MRI sequence (e.g.grounding meditation) 35 and instructing participants accordingly could bring further insight into the underlying process of a specific practice with neurobiological underpinning and associated neurobehavioral changes. 67 Neuropsychological testsAffect recognition (NEPSY-II45 ) Evaluates the ability to recognize facial emotional expressions.Standardized scores were used (M = 10; SD = 3).Higher scores reflect better affect recognition skills Affect recognition Theory of Mind (NEPSY-II45 ) Evaluates the ability of mental functions and other people's perspectives.The total raw score was used.Higher scores reflect better theory of mind skillsTheory of mindPsychiatry and Clinical Neurosciences 78: 416-425, 2024Mindfulness intervention in pretermsPCN Psychiatry and Clinical Neurosciencestheir eyes closed, try not to think about anything specific, and engage in mind wandering.

Fig. 1
Fig.1Neurobehavioral measures indicating significant group differences between the very preterm (VPT; before the mindfulness-based intervention) and the full-term (FT) groups using linear regression models (false discovery rate, q-values <0.1).Dark blue = VPT; yellow = FT; group means are represented by a black dot; ***q < 0.001, **q < 0.01, *q < 0.1.BRIEF GEC, Behavior Rating Inventory of Executive Function, parent version (BRIEF) for the Global Executive Composite; BRIEF BRI, Behavioral Regulation Index; BRIEF MI, Metacognition Index; SDQ, Strengths and Difficulties Questionnaire, parent version.

Fig. 2
Fig.2Neurobehavioral measures showing significant differences for the very preterm (VPT) group between before the mindfulness-based intervention (MBI) and after the MBI using linear regression models (false discovery rate, q-values <0.1).Dark blue = before MBI, light blue = after MBI.Means for before MBI and after MBI are represented by a black dot; ***q < 0.001, **q < 0.01, *q < 0.1.BRIEF GEC, Behavior Rating Inventory of Executive Function, parent version (BRIEF) for the Global Executive Composite; BRIEF BRI, Behavioral Regulation Index; BRIEF MI, Metacognition Index.

Fig. 3 Fig. 4
Fig. 3 Spatial patterns of the eight innovation-driven coactivation patterns (iCAPs) retrieved in very preterm (VPT) young adolescents before and after the mindfulnessbased intervention (MBI).Locations denote displayed slices in MNI Average Brain coordinates.

Table 1 .
Neurobehavioral outcome measures and scores (MI).Standardized T scores were used (M = 50; SD = 10).Higher scores reflect increased difficulties in executive functioning BRIEF GEC BRIEF BRI BRIEF MI Neuropsychological tests Letter-Number Sequencing (WISC-V 37 ) Evaluates working memory.Standardized scores were used (M = 10; SD = 3).Higher standardized scores reflect higher working memory skills Letter-number sequencing Tempo Test Rekenen 38 Evaluates arithmetic.The total raw score was used.Higher total scores reflect higher arithmetic skills Tempo test Neurocognitive computerized tasks Flanker Visual Filtering Task 39 Evaluates attentional control and information processing speed Higher mean reaction times in the congruent condition reflect slower processing speed.Higher inhibition scores reflect increased difficulties in attentional control 40 Evaluates reality filtering.The Temporal Context Confusion index was used as a reality filtering score.Higher TCC score indicate increased reality filtering difficulties Reality filtering TCC Behavior and socioemotional abilities Parent-reported questionnaires Strengths and Difficulties Questionnaire, parent version (SDQ 41 )

Table 2 .
Neonatal and demographic characteristics of VPT and FT participants