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Abstract Machine learning (ML) techniques have gained popularity in the neuroimaging field due to their potential for classifying neuropsychiatric disorders. However, the diagnostic predictive power of the existing algorithms has been limited by small sample sizes, lack of representativeness, data leakage, and/or overfitting. Here, we overcome these limitations with the largest multi-site sample size to date (N = 5365) to provide a generalizable ML classification benchmark of major depressive disorder (MDD) using shallow linear and non-linear models. Leveraging brain measures from standardized ENIGMA analysis pipelines in FreeSurfer, we were able to classify MDD versus healthy controls (HC) with a balanced accuracy of around 62%. But after harmonizing the data, e.g., using ComBat, the balanced accuracy dropped to approximately 52%. Accuracy results close to random chance levels were also observed in stratified groups according to age of onset, antidepressant use, number of episodes and sex. Future studies incorporating higher dimensional brain imaging/phenotype features, and/or using more advanced machine and deep learning methods may yield more encouraging prospects.

Social dysfunction plays a critical role in the development and maintenance of depression in both adolescents and adults. Interpersonal psychotherapy (IPT) and interpersonal psychotherapy for depressed adolescents (IPT-A) are effective, evidence-based, and time-limited treatments for depression that aim to mitigate depressive symptoms by strengthening an individual’s interpersonal relationships and skills. Though the efficacy of IPT/IPT-A has been well established, we are just beginning to know how biological systems are implicated in its success. In this scoping review, we examine the extant literature on biological mechanisms and predictors of IPT/IPT-A treatment efficacy. Overall, seven studies were identified that consider biological processes in the context of evaluating IPT/IPTA, and the studies that were conducted are typically preliminary in nature. Notably, there is some evidence showing that the hypothalamic–pituitary–adrenal axis, various frontal and limbic brain regions, and behavioral indexes that represent brain functioning are associated with changes in IPT/IPT-A or predictive of IPT/IPT-A outcomes. We also consider consequences for treatment and future research. The hope is that a better understanding of how and for whom IPT/IPT-A works can optimize the success of the treatment in reducing an individual’s depressive symptoms.

IntroductionThe complexity of brain signals may hold clues to understand brain-based disorders. Sample entropy, an index that captures the predictability of a signal, is a promising tool to measure signal complexity. However, measurement of sample entropy from fMRI signals has its challenges, and numerous questions regarding preprocessing and parameter selection require research to advance the potential impact of this method. For one example, entropy may be highly sensitive to the effects of motion, yet standard approaches to addressing motion (e.g., scrubbing) may be unsuitable for entropy measurement. For another, the parameters used to calculate entropy need to be defined by the properties of data being analyzed, an issue that has frequently been ignored in fMRI research. The current work sought to rigorously address these issues and to create methods that could be used to advance this field.MethodsWe developed and tested a novel windowing approach to select and concatenate (ignoring connecting volumes) low-motion windows in fMRI data to reduce the impact of motion on sample entropy estimates. We created utilities (implementing autoregressive models and a grid search function) to facilitate selection of the matching length m parameter and the error tolerance r parameter. We developed an approach to apply these methods at every grayordinate of the brain, creating a whole-brain dense entropy map. These methods and tools have been integrated into a publicly available R package (“powseR”). We demonstrate these methods using data from the ABCD study. After applying the windowing procedure to allow sample entropy calculation on the lowest-motion windows from runs 1 and 2 (combined) and those from runs 3 and 4 (combined), we identified the optimal m and r parameters for these data. To confirm the impact of the windowing procedure, we compared entropy values and their relationship with motion when entropy was calculated using the full set of data vs. those calculated using the windowing procedure. We then assessed reproducibility of sample entropy calculations using the windowed procedure by calculating the intraclass correlation between the earlier and later entropy measurements at every grayordinate.ResultsWhen applying these optimized methods to the ABCD data (from the subset of individuals who had enough windows of continuous “usable” volumes), we found that the novel windowing procedure successfully mitigated the large inverse correlation between entropy values and head motion seen when using a standard approach. Furthermore, using the windowed approach, entropy values calculated early in the scan (runs 1 and 2) are largely reproducible when measured later in the scan (runs 3 and 4), although there is some regional variability in reproducibility.DiscussionWe developed an optimized approach to measuring sample entropy that addresses concerns about motion and that can be applied across datasets through user-identified adaptations that allow the method to be tailored to the dataset at hand. We offer preliminary results regarding reproducibility. We also include recommendations for fMRI data acquisition to optimize sample entropy measurement and considerations for the field.

Purpose: The childhood-to-adolescence transition is a notable period of change including pubertal development, neurodevelopment, and psychopathology onset, that occurs in divergent patterns between sexes. This study examined the effects of sex and puberty on cortical thickness (CT) in children and explored whether CT changes over time related to emergence of psychopathology in early adolescence. Methods: We used longitudinal data (baseline ages 9–10 and Year 2 [Y2] ages 11–12) from the ABCD Study (n = 9985). Linear and penalized function-on-function regressions modeled the impact of puberty, as it interacts with sex, on CT. Focusing on regions that showed sex differences, linear and logistic regressions modeled associations between change in CT and internalizing problems and suicide ideation. Results: We identified significant sex differences in the inverse relation between puberty and CT in fifteen primarily posterior brain regions. Nonlinear pubertal effects across age were identified in the fusiform, isthmus cingulate, paracentral, and precuneus. All effects were stronger for females relative to males during this developmental window. We did not identify associations between CT change and early adolescent clinical outcomes. Conclusion: During this age range, puberty is most strongly associated with regional changes in CT in females, which may have implications for the later emergence of psychopathology.

Background: The COVID-19 pandemic presents a unique context in which to study the impact of protective and risk factors for non-suicidal self-injury (NSSI) in adolescents under circumstances of heightened stress. Methods: Female participants (N = 91, aged 12–16) enrolled in an ongoing study of NSSI completed self-report questionnaires that assessed NSSI recency, internalizing symptoms (anxiety, depressive), stress perception (stress, family conflict, loneliness), and coping resources (emotion regulation, friend and family support). Parents reported on experiences during the pandemic (family's financial status, health, and schooling). We compared protective and risk factors among three groups of adolescents: those with no history of NSSI (Never), those who did not continue to engage in NSSI in the early months of the COVID-19 pandemic (Desist), and those with a history of NSSI who did (Persist). Results: Participants in the Persist group reported higher levels of perceived stress and loneliness and lower family support than those in the Desist group. A larger set of coping resources (emotion regulation difficulties, friend support) also differed between the Persist and Never NSSI groups. These findings largely remained significant when controlling for possible contributing factors. Limitations: A strength is the longitudinal study design. Limitations include the inability to assess changes in rate of NSSI engagement, small sample size, inclusion of only female participants, reliance primarily on self-report, and a design not suitable for making causal inferences. Conclusions: In the context of the COVID-19 pandemic, factors such as family support may protect against NSSI engagement and offer avenues for treatment.

Treatment-resistant depression (TRD) is a serious problem in adolescents. Development and optimization of novel interventions for these youth will require a deeper knowledge of the neurobiology of depression. A well-established phenomenon of depression is an attention bias toward negativity and away from positivity that is evidenced behaviorally and neurally, but it is unclear how symptom reduction is related to changes to this bias. Neurobiological research using a treatment probe has promise to help discover the neural changes that accompany symptom improvement. Ketamine has utility for such research because of its known rapid and strong antidepressant effects in the context of TRD. Our previous study of six open-label ketamine infusions in 11 adolescents with TRD showed variable response, ranging from full remission, partial response, non-response, or clinical worsening. In this study, we examined the performance of these participants on Word Face Stroop (WFS) fMRI task where they indicated the valence of affective words superimposed onto either congruent or incongruent emotional faces before and after the ketamine infusions. Participants also completed a clinical assessment (including measurement of depression symptomology and anhedonia/pleasure) before and after the ketamine infusions. Following ketamine treatment, better WFS performance correlated with self-reported decreased depressive symptoms and increased pleasure. Analyses of corticolimbic, corticostriatal and default mode (DMN) networks showed that across networks, decreased activation during all conditions (congruent negative, congruent positive, incongruent negative, and incongruent positive) correlated with decreases in depressive symptoms and with increases in pleasure. These findings suggest that in adolescents with TRD, clinical improvement may require an attenuation of the negativity bias and re-tuning of these three critical neural networks to attenuate DMN and limbic regions activation and allow more efficient recruitment of the reward network. Lower activation across conditions may facilitate shifting across different salient emotional stimuli rather than getting trapped in downward negative spirals.

BackgroundNon-suicidal self-injury (NSSI) is a growing public health concern that commonly begins in adolescence, and can persist into young adulthood. A promising approach for advancing our understanding of NSSI in youth is to examine white matter microstructure using diffusion magnetic resonance imaging (dMRI).MethodThe present study examined whole-brain group differences in structural connectivity (as measured by generalized fractional anisotropy [GFA]) between 28 female adolescents and young adults ages 13–21 years with NSSI and 22 age-matched healthy controls (HC). We also explored the association between clinical characteristics including NSSI severity and duration, impulsivity, emotion regulation and personality traits within the NSSI group and GFA of the uncinate fasciculus and cingulum.ResultsCompared to the HC group, participants with NSSI had lower GFA in several white matter tracts, including the uncinate fasciculus, cingulum, bilateral superior and inferior longitudinal fasciculi, anterior thalamic radiation, callosal body, and corticospinal tract. When controlling for depressive symptoms, the NSSI group showed an association between NSSI duration (time since initiating NSSI behavior) and lower GFA in the left cingulum. Higher levels of attentional impulsivity were related to lower GFA in the left uncinate fasciculus within the NSSI group.ConclusionsWe found evidence suggesting widespread white matter microstructure deficits in adolescents and young adults with NSSI versus HC. We also report inverse associations between white matter integrity and clinical characteristics (duration of NSSI and attentional impulsivity). These white matter microstructural deficits may represent a possible neurobiologically-based vulnerability to developing maladaptive coping mechanisms, such as NSSI. Additionally, results suggest that this white matter disorganization may either worsen with prolonged engagement in NSSI or predict persistent NSSI; thereby highlighting the importance of early intervention targeting this behavior.

Understanding the context of suicidal behaviors is critical for effective suicide prevention strategies. Although suicide is an important topic for Asian Americans, there is limited information about what Asian Americans’ attitudes are towards suicide and their perceptions about the effectiveness of prevention efforts. These questions are critical to examine to provide foundational knowledge for determining how best to intervene. In this study, Asian American (n = 87) and White (n = 87) participants completed self-report indexes on their knowledge of depression and suicide (e.g., estimates of suicide rates), coping attitudes (e.g., help-seeking) and suicide prevention attitudes (e.g., usefulness of PSAs). The results indicate that in comparison to Whites, Asian Americans perceived suicidal behavior to be more common, perceived a stronger link between depression and suicide, less frequently endorsed help-seeking strategies, and reported more concern or distress after viewing a suicide prevention PSA. These preliminary results also suggest the possibility of cultural differences in perceptions of suicide prevention messages. The implications of these findings are discussed with a focus on providing recommendations for exploring suicide prevention efforts for Asian Americans.

Abstract Suicide continues to be one of the most serious public health challenges. Public service announcements are frequently used to address this challenge, but are rarely sufficiently evaluated to determine if they meet the intended goals, or are associated with potential iatrogenic effects. Although it is challenging to assess the relative impact of different PSA modalities, our group previously noted that one billboard message failed to show the same benefits as one TV ad (e.g., Klimes-Dougan & Lee, 2010). The purpose of this study was to extend these findings to test critical aspects of suicide prevention billboard messaging. Although both simulated billboard messages presented had identical supporting messages, we predicted that the more personal billboard message, focused on saving one’s life, would cause more favorable help-seeking attitudes than the message focused on suicide. Young adult university students (N = 785) were randomly assigned to one of three conditions; one of two billboard simulations or a TV ad simulation. Help-seeking attitudes, maladaptive coping and reports of concern and distress were evaluated. The results of this study suggest some relative benefits in endorsement of favorable help-seeking attitudes for one of the billboard conditions - Stop depression from taking another life. Although further research is needed to determine what methods will alter the risk for suicide in the population, the results of this study provide a useful first step showing that some billboard messaging may favorably influence help-seeking attitudes.

Impaired intellectual functioning is an important risk factor for the emergence of severe mental illness. Unlike many other forms of mental disorder however, the association between bipolar disorder and intellectual deficits is unclear. In this narrative review, we examine the current evidence on intellectual functioning in children and adolescents at risk for developing bipolar disorder. The results are based on 18 independent, peer-reviewed publications from 1980 to 2017 that met criteria for this study. The findings yielded no consistent evidence of lower or higher intellectual quotient (IQ) in offspring of parents diagnosed with bipolar disorder. Some tentative evidence was found for lower performance IQ in offspring of bipolar parents as compared to controls. It is recommended that future research examine variability in intellectual functioning and potential moderators. These findings demonstrate the need to examine how intellectual functioning unfolds across development given the potential role of IQ as a marker of vulnerability or resilience in youth at high risk for affective disorders.