A multi-modal assessment of self-knowledge in adolescents with non-suicidal self-injury: a research domains criteria (RDoC) study.

BACKGROUND: Adolescence is a critical period for brain development, consolidation of self-understanding, and onset of non-suicidal self-injury (NSSI). This study evaluated the RDoC (Research Domain Criteria) sub-construct of Self-Knowledge in relation to adolescent NSSI using multiple units of analysis. METHODS: One hundred and sixty-four adolescents assigned female at birth (AFAB), ages 12-16 years with and without a history of NSSI entered a study involving clinical assessment and magnetic resonance imaging (MRI), including structural, resting-state functional MRI (fMRI), and fMRI during a self-evaluation task. For imaging analyses, we used an a priori defined Self Network (anterior cingulate, orbitofrontal, and posterior cingulate cortices; precuneus). We first examined interrelationships among multi-level Self variables. We then evaluated the individual relationships between NSSI severity and multi-level Self variables (self-report, behavior, multi-modal brain Self Network measures), then conducted model testing and multiple regression to test how Self variables (together) predicted NSSI severity. RESULTS: Cross-correlations revealed key links between self-reported global self-worth and self-evaluation task behavior. Individually, greater NSSI severity correlated with lower global self-worth, more frequent and faster negative self-evaluations, lower anterior Self Network activation during self-evaluation, and lower anterior and posterior Self Network resting-state connectivity. Multiple regression analysis revealed the model including multi-level Self variables explained NSSI better than a covariate-only model; the strongest predictive variables included self-worth, self-evaluation task behavior, and resting-state connectivity. CONCLUSIONS: Disruptions in Self-Knowledge across multiple levels of analysis relate to NSSI in adolescents. Findings suggest potential neurobiological treatment targets, potentially enhancing neuroplasticity in Self systems to facilitate greater flexibility (more frequently positive) of self-views in AFAB adolescents.

Behavioral Apophenia and Dimensions of Psychoticism in Adolescents with and without Mood Disorders.

Apophenia is the tendency to falsely detect meaningful relationships and may indicate susceptibility to more extreme expressions on the psychotic spectrum. This pilot investigated the fragmented ambiguous object task (FAOT), a new measure designed to assess apophenia behaviorally in a sample of adolescents with and without mood disorders using an image recognition task. Our primary hypothesis was that increased image recognition would be associated with PID-5 psychoticism. Participants were 33 (79% female) adolescents with (n = 18) and without (n = 15) mood disorders. Consistent with predictions, increased recognition of ambiguous images correlated positively with psychoticism. There was also moderate evidence for long-term stability of FAOT apophenia scores over time (mean interval of approximately 10 months). These findings offer preliminary evidence that the FAOT may be reflective of underlying psychoticism in our target population.

Multimodal assessment of sustained threat in adolescents with nonsuicidal self-injury.

Nonsuicidal self-injury (NSSI) is a common but poorly understood phenomenon in adolescents. This study examined the Sustained Threat domain in female adolescents with a continuum of NSSI severity (N = 142). Across NSSI lifetime frequency and NSSI severity groups (No + Mild NSSI, Moderate NSSI, Severe NSSI), we examined physiological, self-reported and observed stress during the Trier Social Stress Test; amygdala volume; amygdala responses to threat stimuli; and resting-state functional connectivity (RSFC) between amygdala and medial prefrontal cortex (mPFC). Severe NSSI showed a blunted pattern of cortisol response, despite elevated reported and observed stress during TSST. Severe NSSI showed lower amygdala-mPFC RSFC; follow-up analyses suggested that this was more pronounced in those with a history of suicide attempt for both moderate and severe NSSI. Moderate NSSI showed elevated right amygdala activation to threat; multiple regressions showed that, when considered together with low amygdala-mPFC RSFC, higher right but lower left amygdala activation predicted NSSI severity. Patterns of interrelationships among Sustained Threat measures varied substantially across NSSI severity groups, and further by suicide attempt history. Study limitations include the cross-sectional design, missing data, and sampling biases. Our findings highlight the value of multilevel approaches in understanding the complexity of neurobiological mechanisms in adolescent NSSI.

Transcendental meditation and hypothalamic-pituitary-adrenal axis functioning: a pilot, randomized controlled trial with young adults.

Transcendental meditation (TM) is effective in alleviating stress and anxiety and promoting well-being. While the underlying biological mechanisms of TM are not yet fully explored, the hypothalamic-pituitary-adrenal (HPA) axis represents an index providing important clues embodying the stress system cascade. In this pilot study, young adults were randomly assigned to TM training followed by 8 weeks of meditation practice or a wait-list control condition. TM was conducted over 8 weeks. Thirty-four young adult participants were randomized; 27 participants completed the HPA outcome assessments (41% male). To assess HPA axis functioning, salivary samples to assess cortisol awakening response (CAR) that were collected in the morning, both at baseline and at week-4. Salivary cortisol in the context of a social stressor using the Trier Social Stress Test (TSST) was collected at week-8. The results indicate that participants who were randomly assigned to TM had lower awakening salivary cortisol levels and a greater drop in CAR from baseline to week-4 than the control group. There were no significant differences in HPA axis functioning in the context of the TSST. Primary limitations of this randomized controlled trial were the small sample size, the use of a wait-list as opposed to an active control, and the limited scope of HPA axis assessments. The results of this pilot study provide tentative evidence that TM may impact biological stress system functioning and suggests that this may be a worthwhile avenue to continue to examine. It will also be useful to extend these findings to a broader array of meditative and mindful practices, particularly for those who are experiencing more distress.

Trauma Sequelae are Uniquely Associated with Components of Self-Reported Sleep Dysfunction in OEF/OIF/OND Veterans.

While the associations between psychological distress (e.g., posttraumatic stress disorder [PTSD], depression) and sleep dysfunction have been demonstrated in trauma-exposed populations, studies have not fully explored the associations between sleep dysfunction and the wide range of common physical and physiological changes that can occur after trauma exposure (e.g., pain, cardiometabolic risk factors). We aimed to clarify the unique associations of psychological and physical trauma sequelae with different aspects of self-reported sleep dysfunction. A comprehensive psychological and physical examination was administered to 283 combat-deployed trauma-exposed Operation Enduring Freedom/Operation Iraqi Freedom/Operation New Dawn (OEF/OIF/OND) veterans. The Pittsburgh Sleep Quality Index (PSQI) and PSQI Addendum for PSTD (PSQI-A) were administered along with measures of PTSD, depression, anxiety, pain, traumatic brain injury, alcohol use, nicotine dependence, and cardiometabolic symptoms. We first performed a confirmatory factor analysis of the PSQI and then conducted regressions with the separate PSQI factors as well as the PSQI-A to identify unique associations between trauma-related measures and the separate aspects of sleep. We found that the PSQI global score was composed of three factors: Sleep Efficiency (sleep efficiency/sleep duration), Perceived Sleep Quality (sleep quality/sleep latency/sleep medication) and Daily Disturbances (sleep disturbances/daytime dysfunction). Linear regressions demonstrated that PTSD symptoms were uniquely associated with the PSQI global score and all three factors, as well as the PSQI-A. For the other psychological distress variables, anxiety was independently associated with PSQI global as well as Sleep Efficiency, Perceived Sleep Quality, and PSQI-A, whereas depression was uniquely associated with Daily Disturbances and PSQI-A. Notably, cardiometabolic symptoms explained independent variance in PSQI global and Sleep Efficiency. These findings help lay the groundwork for further investigations of the mechanisms of sleep dysfunction in trauma-exposed individuals and may help in the development of more effective, individualized treatments.

Network-targeted cerebellar transcranial magnetic stimulation improves attentional control.

Developing non-invasive brain stimulation interventions to improve attentional control is extremely relevant to a variety of neurological and psychiatric populations, yet few studies have identified reliable biomarkers that can be readily modified to improve attentional control. One potential biomarker of attention is functional connectivity in the core cortical network supporting attention - the dorsal attention network (DAN). We used a network-targeted cerebellar transcranial magnetic stimulation (TMS) procedure, intended to enhance cortical functional connectivity in the DAN. Specifically, in healthy young adults we administered intermittent theta burst TMS (iTBS) to the midline cerebellar node of the DAN and, as a control, the right cerebellar node of the default mode network (DMN). These cerebellar targets were localized using individual resting-state fMRI scans. Participants completed assessments of both sustained (gradual onset continuous performance task, gradCPT) and transient attentional control (attentional blink) immediately before and after stimulation, in two sessions (cerebellar DAN and DMN). Following cerebellar DAN stimulation, participants had significantly fewer attentional lapses (lower commission error rates) on the gradCPT. In contrast, stimulation to the cerebellar DMN did not affect gradCPT performance. Further, in the DAN condition, individuals with worse baseline gradCPT performance showed the greatest enhancement in gradCPT performance. These results suggest that temporarily increasing functional connectivity in the DAN via network-targeted cerebellar stimulation can enhance sustained attention, particularly in those with poor baseline performance. With regard to transient attention, TMS stimulation improved attentional blink performance across both stimulation sites, suggesting increasing functional connectivity in both networks can enhance this aspect of attention. These findings have important implications for intervention applications of TMS and theoretical models of functional connectivity.

Cortisol Awakening Response, Internalizing Symptoms, and Life Satisfaction in Emerging Adults.

The cortisol awakening response (CAR) has been associated with depression and a broader range of internalizing problems. Emerging adulthood is characterized by numerous stressful transitional life events. Furthermore, the functioning of the neurobiological stress system changes across development. These considerations underscore the importance of evaluating the physiological stress system in emerging adults in identifying the extent to which cortisol levels vary with risk and protective factors for mental health. The present study evaluated the association between internalizing symptoms and perceived life satisfaction with CAR in 32 young adults. Three saliva samples were collected to measure cortisol levels upon awakening and participants completed the Depression Anxiety Stress Scale (DASS) and Satisfaction with Life Scale (SWLS). Results show a significant positive correlation between area under the curve for CAR with internalizing symptoms (DASS total) and the DASS-depression subscale, but not with life satisfaction. Study limitations, implications, and future directions for these finding were discussed.

Frontal eye field involvement in sustaining visual attention: evidence from transcranial magnetic stimulation.

The frontal eye field (FEF), particularly the right FEF, is broadly implicated in top-down control of transient acts of attention, but less is known about its involvement in sustained attention. Although neuroimaging studies of sustained attention tasks commonly find FEF activation, it is unclear how this region contributes to moment-to-moment fluctuations in sustained performance. We sought to determine if the FEF plays a critical role in sustained attention, and if that role differs between periods of worse performance (out-of-the-zone) and periods of better performance (in-the-zone). We used offline 1 Hz repetitive transcranial magnetic stimulation (TMS) to temporarily attenuate either right or left FEF excitability while participants performed a go/no-go sustained attention task (the gradual onset continuous performance task). The results demonstrate that following TMS to the right FEF, sustained attention during in-the-zone periods significantly worsened both in terms of lower accuracy and increased reaction time variability. In contrast, applying TMS to the left FEF did not significantly affect accuracy or variability. These results demonstrate that the right FEF plays a crucial role in supporting optimal sustained attention.

Superiority of pictorial versus verbal presentation and initial exposure in the P300-based, complex trial protocol for concealed memory detection.

Two mock guilty groups had either pictorial or verbal initial exposure to crime items (probes) on which they were told they would later be tested. Then each subject was tested in two sessions on two successive days with both verbal and pictorial presentation, one test modality per session/day. The three dependent variables analyzed were three different estimates of the same basic measurement: the difference between P300s evoked by key (probe) and irrelevant stimuli. All three indexes were significantly increased more by both initial pictorial exposure, as well as by pictorial presentation modality, than by verbal exposure and presentation. We saw no main effect of exposure-presentation modality congruence, as congruence interacted with exposure: The largest probe-irrelevant differences were evoked by congruent pictorial exposure and presentation modality, and the smallest by congruent verbal exposure and presentation modality.

Neural and behavioral markers of inhibitory control predict symptom improvement during internet-delivered cognitive behavioral therapy for depression.

Poor inhibitory control contributes to deficits in emotion regulation, which are often targeted by treatments for major depressive disorder (MDD), including cognitive behavioral therapy (CBT). Brain regions that contribute to inhibitory control and emotion regulation overlap; thus, inhibitory control might relate to response to CBT. In this study, we examined whether baseline inhibitory control and resting state functional connectivity (rsFC) within overlapping emotion regulation-inhibitory control regions predicted treatment response to internet-based CBT (iCBT). Participants with MDD were randomly assigned to iCBT (N = 30) or a monitored attention control (MAC) condition (N = 30). Elastic net regression was used to predict post-treatment Patient Health Questionnaire-9 (PHQ-9) scores from baseline variables, including demographic variables, PHQ-9 scores, Flanker effects (interference, sequential dependency, post-error slowing), and rsFC between the dorsal anterior cingulate cortex, bilateral anterior insula (AI), and right temporoparietal junction (TPJ). Essential prognostic predictor variables retained in the elastic net regression included treatment group, gender, Flanker interference response time (RT), right AI-TPJ rsFC, and left AI-right AI rsFC. Prescriptive predictor variables retained included interactions between treatment group and baseline PHQ-9 scores, age, gender, Flanker RT, sequential dependency effects on accuracy, post-error accuracy, right AI-TPJ rsFC, and left AI-right AI rsFC. Inhibitory control and rsFC within inhibitory control-emotion regulation regions predicted reduced symptom severity following iCBT, and these effects were stronger in the iCBT group than in the MAC group. These findings contribute to a growing literature indicating that stronger inhibitory control at baseline predicts better outcomes to psychotherapy, including iCBT.

Deep transcranial magnetic stimulation for adolescents with treatment-resistant depression: A preliminary dose-finding study exploring safety and clinical effectiveness.

BACKGROUND: Transcranial magnetic stimulation (TMS) is an intervention for treatment-resistant depression (TRD) that modulates neural activity. Deep TMS (dTMS) can target not only cortical but also deeper limbic structures implicated in depression. Although TMS has demonstrated safety in adolescents, dTMS has yet to be applied to adolescent TRD. OBJECTIVE/HYPOTHESIS: This pilot study evaluated the safety, tolerability, and clinical effects of dTMS in adolescents with TRD. We hypothesized dTMS would be safe, tolerable, and efficacious for adolescent TRD. METHODS: 15 adolescents with TRD (Age, years: M = 16.4, SD = 1.42) completed a six-week daily dTMS protocol targeting the left dorsolateral prefrontal cortex (BrainsWay H1 coil, 30 sessions, 10 Hz, 3.6 s train duration, 20s inter-train interval, 55 trains; 1980 total pulses per session, 80 % to 120 % of motor threshold). Participants completed clinical, safety, and neurocognitive assessments before and after treatment. The primary outcome was depression symptom severity measured by the Children's Depression Rating Scale-Revised (CDRS-R). RESULTS: 14 out of 15 participants completed the dTMS treatments. One participant experienced a convulsive syncope; the other participants only experienced mild side effects (e.g., headaches). There were no serious adverse events and minimal to no change in cognitive performance. Depression symptom severity significantly improved pre- to post-treatment and decreased to a clinically significant degree after 10 treatment sessions. Six participants met criteria for treatment response. LIMITATIONS: Main limitations include a small sample size and open-label design. CONCLUSIONS: These findings provide preliminary evidence that dTMS may be tolerable and associated with clinical improvement in adolescent TRD.

Mitochondrial health, NLRP3 inflammasome activation, and white matter integrity in adolescent mood disorders: A pilot study.

Adolescence is a particularly important period for brain development and is also when mood disorders typically emerge. Several psychiatric illnesses exhibit mitochondrial dysfunction, elevated inflammation, and impaired white matter integrity. This study explored the intersection of mitochondrial health, NLRP3 inflammasome activation, and white matter integrity in a small cohort of 29 adolescent patients with mood disorders (bipolar disorder (BD): n = 11, major depressive disorder (MDD): n = 19) and 19 healthy controls. In this sample, adolescents with mood disorders showed lower fractional anisotropy of the ventral cingulum bundle than healthy controls. Across all adolescents, we demonstrated a significant relationship between mitochondrial electron transport chain gene expression, and NLRP3 inflammasome gene expression and activation. Furthermore, circulating cell free mitochondrial DNA was associated with lower white matter integrity in the anterior thalamic radiation. Exploratory subgroup analyses revealed that adolescents with bipolar disorder exhibited lower levels of mitochondrial gene expression and volume, along with increased sensitivity to NLRP3 inflammasome activation compared to adolescents with unipolar depression. Overall, our results reveal relationships between peripherally-measured endpoints of mitochondrial health and NLRP3 inflammasome activation, and centrally measured endpoints of white matter integrity in adolescents. Together with subtle patterns of aberrant neural and biological structure and function in association with mood disorder diagnoses, these results may shed light on the pathophysiology of disease in this early phase of illness.

A Multilevel Examination of Cognitive Control in Adolescents With Nonsuicidal Self-injury.

Background: Nonsuicidal self-injury (NSSI), a transdiagnostic behavior, often emerges during adolescence. This study used the Research Domain Criteria approach to examine cognitive control (CC) with a focus on response inhibition and urgency relative to NSSI severity in adolescents. Methods: One hundred thirty-eight adolescents, assigned female sex at birth, with a continuum of NSSI severity completed negative and positive urgency measurements (self-report), an emotional Go/NoGo task within negative and positive contexts (behavioral), and structural and functional imaging during resting state and task (brain metrics). Cortical thickness, subcortical volume, resting-state functional connectivity, and task activation focused on an a priori-defined CC network. Eighty-four participants had all these main measures. Correlations and stepwise model selection followed by multiple regression were used to examine the association between NSSI severity and multiunit CC measurements. Results: Higher NSSI severity correlated with higher negative urgency and lower accuracy during positive no-inhibition (Go). Brain NSSI severity correlates varied across modalities and valence. For right medial prefrontal cortex and right caudate, higher NSSI severity correlated with greater negative but lower positive inhibition (NoGo) activation. The opposite pattern was observed for the right dorsolateral prefrontal cortex. Higher NSSI severity correlated with lower left dorsal anterior cingulate cortex (ACC) negative inhibition activation and thicker left dorsal ACC, yet it was correlated with higher right rostral ACC positive inhibition activation and thinner right rostral ACC, as well as lower CC network resting-state functional connectivity. Conclusions: Findings revealed multifaceted signatures of NSSI severity across CC units of analysis, confirming the relevance of this domain in adolescent NSSI and illustrating how multimodal approaches can shed light on psychopathology.

Adolescent stress experience-expression-physiology correspondence: Links to depression, self-injurious thoughts and behaviors, and frontolimbic neural circuity.

BACKGROUND: Dysregulated stress responsivity is implicated in adolescent risk for depression and self-injurious thoughts and behaviors (STBs). However, studies often examine levels of the stress response in isolation, precluding understanding of how coordinated disturbance across systems confers risk. The current study utilized a novel person-centered approach to identify stress correspondence profiles and linked them to depressive symptoms, STBs, and neural indices of self-regulatory capacity. METHOD: Adolescents with and without a major depressive disorder diagnosis (N = 162, Mage = 16.54, SD = 1.96, 72.8% White, 66.5% female) completed the Trier Social Stress Test (TSST), questionnaires, and clinical interviews. Stress experience (self-report), expression (observed), and physiology (salivary cortisol) were assessed during the experimental protocol. Adolescents also underwent a magnetic resonance imaging scan. RESULTS: Multitrajectory modeling revealed four profiles. High Experience-High Expression-Low Physiology (i.e., lower stress correspondence) adolescents were more likely to report depressive symptoms, lifetime nonsuicidal self-injury, and suicidal ideation relative to all other subgroups reflecting higher stress correspondence: Low Experience-Low Expression-Low Physiology, Moderate Experience-Moderate Expression-Moderate Physiology, High Experience-High Expression-High Physiology. High Experience-High Expression-Low Physiology adolescents also exhibited less positive amygdala-ventromedial prefrontal cortex resting state functional connectivity relative to Moderate Experience-Moderate Expression-Moderate Physiology. LIMITATIONS: Data were cross-sectional, precluding inference about our profiles as etiological risk factors or mechanisms of risk. CONCLUSIONS: Findings illustrate meaningful heterogeneity in adolescent stress correspondence with implications for multimodal, multilevel assessment and outcome monitoring in depression prevention and intervention efforts.

Editorial: The Ups and Downs of Mind-Wandering in Adolescents.

The human brain is always active; it wanders freely during rest as well as when we lose focus during tasks. Mind-wandering encompasses spontaneous thinking, such as processing recent experiences, problem solving, and achieving insights. Understanding this unconstrained brain activity may lead to clues about the neural mechanisms of mental health problems. Brain networks implicated in mind-wandering include the default mode network (DMN), the salience network, and task-positive networks including the frontoparietal control network and dorsal attention network.1 Given that these networks mature during adolescence, coinciding with a time notable for the emergence of mental health problems, quantifying and examining the neural correlates of mind-wandering in adolescents with psychopathology may shed light on how the healthy and pathological brain functions and point to possible methods of intervening.

Coordination between frontolimbic resting state connectivity and hypothalamic-pituitary-adrenal axis functioning in adolescents with and without depression.

Depression is associated with abnormalities in Hypothalamic-Pituitary-Adrenal (HPA) axis functioning and neural circuitry that underlie the stress response. Resting-state functional connectivity (RSFC) between frontolimbic brain regions captures intrinsic connections that may set the stage for the rallying and regulating of the HPA axis system. This study examined the association between cortisol stress response and frontolimbic (amygdala and ventral and dorsal medial prefrontal cortex [vmPFC and dmPFC respectively]) RSFC in 88 (Age: M = 15.95, SD = 2.04; 71.60% female) adolescents with (N = 55) and without (N = 33) major depressive disorder (MDD). We collected salivary cortisol in the context of a modified Trier Social Stress Test (TSST) paradigm. Key findings were that adolescents with depression and healthy controls showed different patterns of association between amygdala and vmPFC RSFC and HPA functioning: while healthy controls showed a positive relationship between frontolimbic connectivity and cortisol levels that may indicate coordination across neural and neuroendocrine systems, adolescents with depression showed a minimal or inverse relationship, suggesting poor coordination of these systems. Results were similar when examining non-suicidal self-injury subgroups within the MDD sample. These findings suggest that the intrinsic quality of this frontolimbic connection may be related to HPA axis functioning. In MDD, inverse associations may represent a compensatory response in one system in response to dysfunction in the other. Longitudinal multilevel research, however, is needed to disentangle how stress system coordination develops in normal and pathological contexts and how these systems recover with treatment.

Adolescent cortisol and DHEA responses to stress as prospective predictors of emotional and behavioral difficulties: A person-centered approach.

BACKGROUND: Well-orchestrated cortisol and DHEA stress responsivity is thought to support efficacious stressor management (i.e., coping) and reduce risk for psychopathology during adolescence. Evidence of these relations, however, is lacking empirically. This longitudinal investigation had three aims: 1) to identify within-adolescent profiles of joint cortisol-DHEA responsivity, 2) examine profiles as prospective predictors of adolescents' later emotional and behavioral difficulties, and 3) examine whether distraction coping helped buffer such prospective risk in each profile. METHOD: At Time 1, boys (n = 110) and girls (n = 105) between 11 and 16 years of age with varied levels of risk for psychopathology completed a lab-based socio-evaluative stressor and questionnaires (e.g., coping, internalizing and externalizing problems). Emotional and behavioral adjustment was assessed again at Time 2 (2 years later). RESULTS: Multi-trajectory modeling of adolescents' cortisol and DHEA within the context of the stressor revealed three groups: Normative (n = 107; 49.8%), Hyperresponsive (n = 64; 29.8%), Hyporesponsive (n = 44; 20.5%). Relative to Normative, Hyperresponsive and Hyporesponsive adolescents were more and less advanced in pubertal status, respectively. Hyperresponsive adolescents, but not Hyporesponsive, reported greater emotional and behavioral problems at Time 2, relative to Normative adolescents. Links between distraction coping and Time 2 adjustment varied across the groups. Specifically, distraction coping was associated with fewer Time 2 emotional and behavioral problems for Normative adolescents. However, the converse was true for Hyporesponsive adolescents, with distraction associated with greater Time 2 emotional and behavioral problems. Distraction was not associated with Time 2 emotional and behavioral problems for Hyperresponsive adolescents (i.e., elevated levels irrespective of distraction coping utilization). CONCLUSION: Our results strengthen inference about the role neuroendocrine coordination plays in risk for psychopathology. Findings also help to clarify inconsistent distraction coping-psychopathology linkages, illustrating different patterns of cortisol-DHEA responsivity that support as well as thwart the use of this potentially efficacious strategy.

Brain entropy and neurotrophic molecular markers accompanying clinical improvement after ketamine: Preliminary evidence in adolescents with treatment-resistant depression.

BACKGROUND: Current theory suggests that treatment-resistant depression (TRD) involves impaired neuroplasticity resulting in cognitive and neural rigidity, and that clinical improvement may require increasing brain flexibility and adaptability. AIMS: In this hypothesis-generating study, we sought to identify preliminary evidence of brain flexibility correlates of clinical change within the context of an open-label ketamine trial in adolescents with TRD, focusing on two promising candidate markers of neural flexibility: (a) entropy of resting-state functional magnetic resonance imaging (fMRI) signals; and (b) insulin-stimulated phosphorylation of mammalian target of rapamycin (mTOR) and glycogen synthase-3-beta (GSK3ß) in peripheral blood mononuclear cells. METHODS: We collected resting-state functional magnetic resonance imaging data and blood samples from 13 adolescents with TRD before and after a series of six ketamine infusions over 2 weeks. Usable pre/post ketamine data were available from 11 adolescents for imaging and from 10 adolescents for molecular signaling. We examined correlations between treatment response and changes in the central and peripheral flexibility markers. RESULTS: Depression reduction correlated with increased nucleus accumbens entropy. Follow-up analyses suggested that physiological changes were associated with treatment response. In contrast to treatment non-responders (n=6), responders (n=5) showed greater increase in nucleus accumbens entropy after ketamine, together with greater post-treatment insulin/mTOR/GSK3ß signaling. CONCLUSIONS: These data provide preliminary evidence that changes in neural flexibility may underlie symptom relief in adolescents with TRD following ketamine. Future research with adequately powered samples is needed to confirm resting-state entropy and insulin-stimulated mTOR and GSK3ß as brain flexibility markers and candidate targets for future clinical trials. CLINICAL TRIAL NAME: Ketamine in adolescents with treatment-resistant depressionURL: https://clinicaltrials.gov/ct2/show/NCT02078817Registration number: NCT02078817.

Neural and Behavioral Correlates of Clinical Improvement to Ketamine in Adolescents With Treatment Resistant Depression.

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.