Application of machine learning to structural connectome to predict symptom reduction in depressed adolescents with cognitive behavioral therapy (CBT).

PURPOSE: Adolescent major depressive disorder (MDD) is a highly prevalent, incapacitating and costly illness. Many depressed teens do not improve with cognitive behavioral therapy (CBT), a first-line treatment for adolescent MDD, and face devastating consequences of increased risk of suicide and many negative health outcomes. "Who will improve with CBT?" is a crucial question that remains unanswered, and treatment planning for adolescent depression remains biologically unguided. The purpose of this study was to utilize machine learning applied to patients' brain imaging data in order to help predict depressive symptom reduction with CBT. METHODS: We applied supervised machine learning to diffusion MRI-based structural connectome data in order to predict symptom reduction in 30 depressed adolescents after three months of CBT. A set of 21 attributes was chosen, including the baseline depression score, age, gender, two global network properties, and node strengths of brain regions previously implicated in depression. The practical and robust J48 pruned tree classifier was utilized with a 10-fold cross-validation. RESULTS: The classification resulted in an 83% accuracy of predicting depressive symptom reduction. The resulting tree of size seven with only three attributes highlights the role of the right thalamus in predicting depressive symptom reduction with CBT. Additional analysis showed a significant negative correlation between the change in the depressive symptoms and the node strength of the right thalamus. CONCLUSIONS: Our results demonstrate that a machine learning algorithm that exclusively uses structural connectome data and the baseline depression score can predict with a high accuracy depressive symptom reduction in adolescent MDD with CBT. This knowledge can help improve treatment planning for adolescent depression.

Increase of internalized mental health symptoms among adolescents during the last three decades.

BACKGROUND: Previous studies suggest an overall increase of adolescent mental health symptoms globally since the 1980s until today, especially an increase of internalizing symptoms in girls. Due to methodological limitations of these studies, further studies are warranted to obtain a more solid knowledgebase. METHODS: This study was cross-sectional and compared two separate but geographically identical groups of adolescents in a middle-sized industrial municipality in Northern Sweden at two time-points [(i) 1981, n = 1083, (505 girls, 577 boys), response rate 99.7%; (ii) 2014, n = 682, (338 girls, 344 boys), response rate 98.3%]. All students in their last year of compulsory school were included. The same self-report questionnaire, consisting of four sub-scales (functional somatic-, anxiety-, depressive symptoms and conduct problems), was used at both occasions. Data were analyzed with descriptive statistics, two-way ANOVA and general linear model. RESULTS: Symptoms of anxiety and depression and functional somatic symptoms, increased among both boys and girls from 1981 until 2014 (P < 0.001 for all subscales), and the increase of these symptoms was higher in girls. Conduct problems were significantly higher in boys in 1981 and decreased over time so that in 2014 there was no longer a significant difference between boys and girls regarding conduct problems (P = 0.286). CONCLUSION: In this population-based study spanning over 30 years, both girls and boys showed increasing internalizing problems, while conduct problems decreased. To halt this trend, we need a deeper understanding of the impact of the major societal changes that have occurred during the last three decades.

Test-Retest Reliability of Graph Theoretic Metrics in Adolescent Brains.

Graph theory analysis of structural brain networks derived from diffusion tensor imaging (DTI) has become a popular analytical method in neuroscience, enabling advanced investigations of neurological and psychiatric disorders. The purpose of this study was to investigate (1) the effects of edge weighting schemes and (2) the effects of varying interscan periods on graph metrics within the adolescent brain. We compared a binary (B) network definition with three weighting schemes: fractional anisotropy (FA), streamline count, and streamline count with density and length correction (SDL). Two commonly used global and two local graph metrics were examined. The analysis was conducted with two groups of adolescent volunteers who received DTI scans either 12 weeks apart (16.62 ± 1.10 years) or within the same scanning session (30 min apart) (16.65 ± 1.14 years). The intraclass correlation coefficient was used to assess test-retest reliability and the coefficient of variation (CV) was used to assess precision. On average, each edge scheme produced reliable results at both time intervals. Weighted measures outperformed binary measures, with SDL weights producing the most reliable metrics. All edge schemes except FA displayed high CV values, leaving FA as the only edge scheme that consistently showed high precision while also producing reliable results. Overall findings suggest that FA weights are more suited for DTI connectome studies in adolescents.

High levels of mitochondrial DNA are associated with adolescent brain structural hypoconnectivity and increased anxiety but not depression.

BACKGROUND: Adolescent anxiety and depression are highly prevalent psychiatric disorders that are associated with altered molecular and neurocircuit profiles. Recently, increased mitochondrial DNA copy number (mtDNA-cn) has been found to be associated with several psychopathologies in adults, especially anxiety and depression. The associations between mtDNA-cn and anxiety and depression have not, however, been investigated in adolescents. Moreover, to date there have been no studies examining associations between mtDNA-cn and brain network alterations in mood disorders in any age group. METHODS: The first aim of this study was to compare salivary mtDNA-cn between 49 depressed and/or anxious adolescents and 35 well-matched healthy controls. The second aim of this study was to identify neural correlates of mtDNA-cn derived from diffusion tensor imaging (DTI) and tractography, in the full sample of adolescents. RESULTS: There were no diagnosis-specific alterations in mtDNA-cn. However, there was a positive correlation between mtDNA-cn and levels of anxiety, but not depression, in the full sample of adolescents. A subnetwork of connections largely corresponding to the left fronto-occipital fasciculus had significantly lower fractional anisotropy (FA) values in adolescents with higher than median mtDNA-cn. LIMITATIONS: Undifferentiated analysis of free and intracellular mtDNA and use of DTI-based tractography represent this study's limitations. CONCLUSIONS: The results of this study help elucidate the relationships between clinical symptoms, molecular changes, and neurocircuitry alterations in adolescents with and without anxiety and depression, and they suggest that increased mtDNA-cn is associated both with increased anxiety symptoms and with decreased fronto-occipital structural connectivity in this population.

DTI-based connectome analysis of adolescents with major depressive disorder reveals hypoconnectivity of the right caudate.

BACKGROUND: Adolescence is a vulnerable period for the onset of major depressive disorder (MDD). While some studies have shown white matter alterations in adolescent MDD, there is still a gap in understanding how the brain is affected at a network level. METHODS: We compared diffusion tensor imaging (DTI)-based brain networks in a cohort of 57 adolescents with MDD and 41 well-matched healthy controls who completed self-reports of depression symptoms and stressful life events. Using atlas-based brain regions as network nodes and tractography streamline count or mean fractional anisotropy (FA) as edge weights, we examined weighted local and global network properties and performed Network-Based Statistic (NBS) analysis. RESULTS: While there were no significant group differences in the global network properties, the FA-weighted node strength of the right caudate was significantly lower in depressed adolescents and correlated positively with age across both groups. The NBS analysis revealed a cluster of lower FA-based connectivity in depressed subjects centered on the right caudate, including connections to frontal gyri, insula, and anterior cingulate. Within this cluster, the most robust difference between groups was the connection between the right caudate and middle frontal gyrus. This connection showed a significant diagnosis by stress interaction and a negative correlation with total stress in depressed adolescents. LIMITATIONS: Use of DTI-based tractography, one atlas-based parcellation, and FA values to characterize brain networks represent this study's limitations. CONCLUSIONS: Our results allowed us to suggest caudate-centric models of dysfunctional processes underlying adolescent depression, which might guide future studies and help better understand and treat this disorder.

Fusiform Gyrus Dysfunction is Associated with Perceptual Processing Efficiency to Emotional Faces in Adolescent Depression: A Model-Based Approach.

While the extant literature has focused on major depressive disorder (MDD) as being characterized by abnormalities in processing affective stimuli (e.g., facial expressions), little is known regarding which specific aspects of cognition influence the evaluation of affective stimuli, and what are the underlying neural correlates. To investigate these issues, we assessed 26 adolescents diagnosed with MDD and 37 well-matched healthy controls (HCL) who completed an emotion identification task of dynamically morphing faces during functional magnetic resonance imaging (fMRI). We analyzed the behavioral data using a sequential sampling model of response time (RT) commonly used to elucidate aspects of cognition in binary perceptual decision making tasks: the Linear Ballistic Accumulator (LBA) model. Using a hierarchical Bayesian estimation method, we obtained group-level and individual-level estimates of LBA parameters on the facial emotion identification task. While the MDD and HCL groups did not differ in mean RT, accuracy, or group-level estimates of perceptual processing efficiency (i.e., drift rate parameter of the LBA), the MDD group showed significantly reduced responses in left fusiform gyrus compared to the HCL group during the facial emotion identification task. Furthermore, within the MDD group, fMRI signal in the left fusiform gyrus during affective face processing was significantly associated with greater individual-level estimates of perceptual processing efficiency. Our results therefore suggest that affective processing biases in adolescents with MDD are characterized by greater perceptual processing efficiency of affective visual information in sensory brain regions responsible for the early processing of visual information. The theoretical, methodological, and clinical implications of our results are discussed.

Feasibility and Preliminary Efficacy of a Novel RDoC-Based Treatment Program for Adolescent Depression: "Training for Awareness Resilience and Action" (TARA)-A Pilot Study.

BACKGROUND: The novel group treatment program Training for Awareness, Resilience, and Action (TARA) was developed to target specific mechanisms based on neuroscience findings in adolescent depression and framed within the National Institute of Mental Health Research Domain Criteria. TARA contains training of autonomic and emotional self-regulation, interoceptive awareness, relational skills, and value-based committed action. METHODS: We performed a single-arm trial to test the feasibility and preliminary efficacy of TARA in reducing depression and anxiety levels and assessed whether the specific targeted domains of function reflected the hypothesized symptom change. Twenty-six adolescents (14-18 years old, 7 males and 19 females) participated in the 12-week group program. Assessment was performed before (T0), immediately after (T1), and 3 months after the end of TARA (T2). RESULTS: Significant improvement was seen in depression symptoms (Reynolds Adolescent Depression Scale Second Edition) between T0-T1 (t-value = -3.56, p = 0.002, CI = -6.64, -1.77) and T0-T2 (t-value = -4.17, p < 0.001, CI = -11.20, -3.75) and anxiety symptoms (Multidimensional Anxiety Scale for Children) between T0-T1 (t-value = -2.26, p = 0.033, CI = -4.61, -0.21) and T0-T2 (t-value = -3.06, p = 0.006, 95% confidence interval = -9.02, -1.73). Significant improvements in psychological flexibility, sleep, and mindfulness skills were also found between T0 and T2. LIMITATIONS: The sample size was small without a control condition. The pilot design did not allow for testing the hypothesized brain changes and effect of TARA on relevant systemic biomarkers. CONCLUSION: TARA is feasible in a sample of clinically depressed and/or anxious adolescents and preliminary efficacy was demonstrated by reduced depression and anxiety symptoms. The specific symptom and behavioral outcomes corresponded well with the hypothesized mechanisms of change.

The neuroscience and context of adolescent depression.

UNLABELLED: Adolescent depression is a growing public health concern with an increased risk of negative health outcomes, including suicide. The use of antidepressants and psychotherapy has not halted its increasing prevalence, and there is a critical need for effective prevention and treatment. We reviewed the neuroscience of adolescent depression, with a focus on the neurocircuitry of sustained threat and summarised contextual factors that have an impact on brain development and the pathophysiology of depression. We also reviewed novel treatment models. CONCLUSION: Attention to the relevant neurocircuitry and contextual factors implicated in adolescent depression is necessary to advance prevention and treatment development.

Neurophysiological and neurocognitive mechanisms underlying the effects of yoga-based practices: towards a comprehensive theoretical framework.

During recent decades numerous yoga-based practices (YBP) have emerged in the West, with their aims ranging from fitness gains to therapeutic benefits and spiritual development. Yoga is also beginning to spark growing interest within the scientific community, and yoga-based interventions have been associated with measureable changes in physiological parameters, perceived emotional states, and cognitive functioning. YBP typically involve a combination of postures or movement sequences, conscious regulation of the breath, and various techniques to improve attentional focus. However, so far little if any research has attempted to deconstruct the role of these different component parts in order to better understand their respective contribution to the effects of YBP. A clear operational definition of yoga-based therapeutic interventions for scientific purposes, as well as a comprehensive theoretical framework from which testable hypotheses can be formulated, is therefore needed. Here we propose such a framework, and outline the bottom-up neurophysiological and top-down neurocognitive mechanisms hypothesized to be at play in YBP.

Altered insular activation and increased insular functional connectivity during sad and happy face processing in adolescent major depressive disorder.

BACKGROUND: Major depressive disorder (MDD) is a leading cause of disability worldwide and occurs commonly first during adolescence. The insular cortex (IC) plays an important role in integrating emotion processing with interoception and has been implicated recently in the pathophysiology of adult and adolescent MDD. However, no studies have yet specifically examined the IC in adolescent MDD during processing of faces in the sad-happy continuum. Thus, the aim of the present study is to investigate the IC during sad and happy face processing in adolescents with MDD compared to healthy controls (HCL). METHODS: Thirty-one adolescents (22 female) with MDD and 36 (23 female) HCL underwent a well-validated emotional processing fMRI paradigm that included sad and happy face stimuli. RESULTS: The MDD group showed significantly less differential activation of the anterior/middle insular cortex (AMIC) in response to sad versus happy faces compared to the HCL group. AMIC also showed greater functional connectivity with right fusiform gyrus, left middle frontal gyrus, and right amygdala/parahippocampal gyrus in the MDD compared to HCL group. Moreover, differential activation to sad and happy faces in AMIC correlated negatively with depression severity within the MDD group. LIMITATIONS: Small age-range and cross-sectional nature precluded assessment of development of the AMIC in adolescent depression. CONCLUSIONS: Given the role of the IC in integrating bodily stimuli with conscious cognitive and emotional processes, our findings of aberrant AMIC function in adolescent MDD provide a neuroscientific rationale for targeting the AMIC in the development of new treatment modalities.

Emotion-Dependent Functional Connectivity of the Default Mode Network in Adolescent Depression.

BACKGROUND: Functional magnetic resonance imaging research suggests that major depressive disorder (MDD) in both adults and adolescents is marked by aberrant connectivity of the default mode network (DMN) during resting state. However, emotional dysregulation is also a key feature of MDD. No studies to date have examined emotion-related DMN pathology in adolescent depression. Comprehensively understanding the dynamics of DMN connectivity across brain states in individuals with depression with short disease histories could provide insight into the etiology of MDD. METHODS: We collected functional magnetic resonance imaging data during an emotion identification task and during resting state from 26 medication-free adolescents (13-17 years old) with MDD and 37 well-matched healthy control subjects. We examined between-group differences in blood oxygenation level-dependent task responses and emotion-dependent and resting-state functional connectivity of the two primary nodes of the DMN: medial prefrontal cortex and posterior cingulate cortex (PCC). Additionally, we examined between-group differences in DMN functional connectivity and its relationship to depression severity and onset. RESULTS: Relative to healthy control subjects, unmedicated adolescents with MDD demonstrated reduced medial prefrontal cortex and PCC emotion-related deactivation and greater medial prefrontal cortex and PCC emotion-dependent functional connectivity with precuneus, cingulate gyrus, and striatum/subcallosal cingulate gyrus. The PCC-subcallosal cingulate connectivity remained inflexibly elevated in the subjects with MDD versus healthy control subjects during resting state. Stronger PCC emotion-dependent functional connectivity was associated with greater depression severity and an earlier age of depression onset. CONCLUSIONS: Adolescent depression is associated with inflexibly elevated DMN connections. Given more recent evidence of DMN maturation throughout adolescence, our findings suggest that early-onset depression adversely affects normal development of functional brain networks.

The development of an RDoC-based treatment program for adolescent depression: "Training for Awareness, Resilience, and Action" (TARA).

Major depressive disorder (MDD) is one of the current leading causes of disability worldwide. Adolescence is a vulnerable period for the onset of depression, with MDD affecting 8-20% of all youth. Traditional treatment methods have not been sufficiently effective to slow the increasing prevalence of adolescent depression. We therefore propose a new model for the treatment of adolescent depression - Training for Awareness, Resilience, and Action (TARA) - that is based on current understanding of developmental and depression neurobiology. The TARA model is aligned with the Research Domain Criteria (RDoC) of the National Institute of Mental Health. In this article, we first address the relevance of RDoC to adolescent depression. Second, we identify the major RDoC domains of function involved in adolescent depression and organize them in a way that gives priority to domains thought to be driving the psychopathology. Third, we select therapeutic training strategies for TARA based on current scientific evidence of efficacy for the prioritized domains of function in a manner that maximizes time, resources, and feasibility. The TARA model takes into consideration the developmental limitation in top-down cognitive control in adolescence and promotes bottom-up strategies such as vagal afference to decrease limbic hyperactivation and its secondary effects. The program has been informed by mindfulness-based therapy and yoga, as well as modern psychotherapeutic techniques. The treatment program is semi-manualized, progressive, and applied in a module-based approach designed for a group setting that is to be conducted one session per week for 12 weeks. We hope that this work may form the basis for a novel and more effective treatment strategy for adolescent depression, as well as broaden the discussion on how to address this challenge.

Adolescent girls with emotional disorders have a lower end-tidal CO2 and increased respiratory rate compared with healthy controls.

Hyperventilation has been linked to emotional distress in adults. This study investigates end-tidal carbon dioxide (ETCO2 ), respiratory rate (RR), and heart rate variability (HRV) in adolescent girls with emotional disorders and healthy controls. ETCO2 , RR, HRV, and ratings of emotional symptom severity were collected in adolescent female psychiatric patients with emotional disorders (n = 63) and healthy controls (n = 62). ETCO2 and RR differed significantly between patients and controls. ETCO2, HR, and HRV were significant independent predictors of group status, that is, clinical or healthy, while RR was not. ETCO2 and RR were significantly related to emotional symptom severity and to HRV in the total group. ETCO2 and RR were not affected by use of selective serotonin reuptake inhibitors. It is concluded that emotional dysregulation is related to hyperventilation in adolescent girls. Respiratory-based treatments may be relevant to investigate in future research.

Functional connectivity of negative emotional processing in adolescent depression.

BACKGROUND: The subgenual anterior cingulate cortex (sgACC) and its connected circuitry have been heavily implicated in emotional functioning in adolescent-onset major depressive disorder (MDD). While several recent studies have examined sgACC functional connectivity (FC) in depressed youth at rest, no studies to date have investigated sgACC FC in adolescent depression during negative emotional processing. METHODS: Nineteen medication-naïve adolescents with MDD and 19 matched healthy controls (HCL) performed an implicit fear facial affect recognition task during functional magnetic resonance imaging (fMRI). We defined seeds in bilateral sgACC and assessed FC using the psychophysiological interaction method. We also applied cognitive behavioral modeling to estimate group differences in perceptual sensitivity in this task. Finally, we correlated connectivity strength with clinical data and perceptual sensitivity. RESULTS: Depressed adolescents showed increased sgACC-amygdala FC and decreased sgACC-fusiform gyrus, sgACC-precuneus, sgACC-insula, and sgACC-middle frontal gyrus FC compared to HCL (p<0.05, corrected). Among the MDD, sgACC-precuneus FC negatively correlated with depression severity (p<0.05, corrected). Lastly, MDD adolescents exhibited poorer perceptual sensitivity in the task than HCL, and individual differences in perceptual sensitivity significantly correlated with sgACC FC and depression scores (p<0.05, corrected). LIMITATIONS: Subjects were clinically homogenous, possibly limiting generalizability of the findings. CONCLUSIONS: Adolescent depression is associated with biased processing of negative stimuli that may be driven by sgACC dysregulation and may possibly lead to an imbalance among intrinsic functional brain networks. This work also establishes the use of combining neuroimaging and cognitive behavioral modeling methods to investigate cognitive and neural differences between psychiatric and healthy populations.

Pro-inflammatory cytokines are elevated in adolescent females with emotional disorders not treated with SSRIs.

BACKGROUND: Adults with major depressive disorder (MDD) show elevated levels of IL-6 and TNF-alpha. Studies of adolescents with MDD or anxiety disorders (AD) are few and present conflicting results. METHODS: We studied plasma cytokines in a clinical sample of adolescent females with MDD and/or clinical AD (n=60, mean age 16.8 years), compared to healthy controls (n=44; mean age 16.5 years). RESULTS: The clinical sample showed significantly higher values of IL-2 (Z=-4.09, p>0.0001), IL1-beta (Z=-2.40, p<0.05) and IL-10 (Z=-2.38, p<0.05) as compared to controls. The subgroup of the clinical sample not treated with SSRIs had a significant difference of IL-6 (Z=-2.26, p<0.05) in addition to the difference of IL-2 and IL1-beta, but showed no difference of IL-10 as compared to the controls. SSRI treatment was related to IL-6, explaining 26% of the variance in the clinical sample after controlling for BMI and symptom severity. In the clinical sample, levels of IL-6 and IFN-gamma were positively correlated with self-assessed symptoms of anxiety and/or depression (corr.coeff 0.35 resp 0.40 at p<0.05). LIMITATIONS: The cross-sectional design does not allow for conclusions on causality. The sample sizes were relatively small and a large drop-out in the clinical sample may have influenced the representativity. DISCUSSION: The study suggests that pro-inflammatory cytokines are part of the pathophysiology of emotional disorders in adolescent females and that SSRIs have anti-inflammatory properties. The findings prompt further studies on the specific mechanisms involved and may contribute to the development of more effective treatment and prevention.

Low Sense of Coherence (SOC) is a mirror of general anxiety and persistent depressive symptoms in adolescent girls - a cross-sectional study of a clinical and a non-clinical cohort.

BACKGROUND: The Sense of Coherence (SOC) scale is assumed to measure a distinct salutogenic construct separated from measures of anxiety and depression. Our aim was to challenge this concept. METHODS: The SOC-scale, Beck's Depression Inventory (BDI), Beck's Anxiety Inventory (BAI) , the emotional subscale of the Strengths and Difficulties Questionnaire (SDQ-em) and self-assessed health-related and physiological parameters were collected from a sample of non-clinical adolescent females (n = 66, mean age 16.5 years with a range of 15.9-17.7 years) and from female psychiatric patients (n = 73), mean age 16.8 years with a range of 14.5-18.4 years), with diagnoses of major depressive disorders (MDD) and anxiety disorders. RESULTS: The SOC scores showed high inverse correlations to BDI, BAI and SDQ-em. In the non-clinical sample the correlation coefficient was -0.86 to -0.73 and in the clinical samples -0.74 to -0.53 (p < 0.001). Multiple regression models showed that BDI was the strongest predictor of SOC in the non-clinical (beta coefficient -0.47) and clinical sample (beta coefficient -0.52). The total degree of explanation of self assessed anxiety and depression on the SOC variance estimated by multiple R2 = 0.74, adjusted R2 = 0.73 in the non-clinical sample and multiple R2 = 0.66, adjusted R2 = 0.65 in the clinical sample.Multivariate analyses failed to isolate SOC as a separate construct and the SOC-scale, BDI, BAI and SDQ-em showed similar patterns of correlations to self-reported and physiological health parameters in both samples. The SOC-scale was the most stable measure over six months. CONCLUSIONS: The SOC-scale did not appear to be a measure of a distinct salutogenic construct, but an inverse measure of persistent depressive symptoms and generalized social anxiety similar to the diagnostic criteria for major depressive disorder (MDD), dysthymic disorder, generalized anxiety disorder (GAD) or generalized social anxiety disorder (SAD) according to DSM-IV. These symptoms were better captured with SOC than by the specialized scales for anxiety and depression. Self-assessment scales that adequately identify MDD, dysthymic disorder, GAD and SAD need to be implemented. Comorbidity of these disorders is common in adolescent females and corresponds to a more severe symptomatology and impaired global function.

Heart rate variability is related to self-reported physical activity in a healthy adolescent population.

This study investigated whether there is a relationship between heart rate variability (HRV) versus lifestyle and risk factors for cardiovascular disease in a population of healthy adolescents. HRV is as an index of tonic autonomic activity and in adults HRV is related to lifestyle and risk factors for cardiovascular disease, but it is not known if this is the case in adolescents. HRV was registered for 4 min in sitting position in 99 healthy adolescents (age range 15 years 11 months-17 years 7 months) and repeated after 6 months. On both occasions there were significant correlations (P < 0.05) between physical activity and HRV, with respective r values: high frequency (HF) 0.26, 0.30; low frequency power (LF) 0.35, 0.29 and the standard deviation of inter-beat intervals (SDNN) 0.28, 0.37. There was no significant interaction between first and second measurements. In contrast, there were no correlations to sleeping patterns, eating habits and smoking. Risk factors for cardiovascular disease [body mass index (BMI = weight (kg)/length in m(2)), systolic blood pressure and p-glucose] did not show any repeatable significant correlations to HRV. Multiple regression models showed that physical activity was a predictor for HF, LF and SDNN in both measurements. In conclusion HF, LF and SDNN were reproducible after 6 months and were related to physical activity on both occasions.