Jeffrey E. Max’s research while affiliated with University of California, San Diego and other places

Introduction Suicide is a current leading cause of death in adolescents and young adults. The neurobiological underpinnings of suicide risk in youth, however, remain unclear and a brain-based model is lacking. In adult samples, current models highlight deficient serotonin release as a potential suicide biomarker, and in particular, involvement of serotonergic dysfunction in relation to the putamen and suicidal behavior. Less is known about associations among striatal regions and relative suicidal risk across development. The current study examined putamen connectivity in depressed adolescents with (AT) and without history of a suicide attempt (NAT), specifically using resting-state functional magnetic resonance imaging (fMRI) to evaluate patterns in resting-state functional connectivity (RSFC). We hypothesized the AT group would exhibit lower striatal RSFC compared to the NAT group, and lower striatal RSFC would associate with greater suicidal ideation severity and/or lethality of attempt. Methods We examined whole-brain RSFC of six putamen regions in 17 adolescents with depression and NAT (MAge [SD] = 16.4[0.3], 41% male) and 13 with AT (MAge [SD] = 16.2[0.3], 31% male). Results Only the dorsal rostral striatum showed a statistically significant bilateral between-group difference in RSFC with the superior frontal gyrus and supplementary motor area, with higher RSFC in the group without a suicide attempt compared to those with attempt history (voxel-wise p<.001, cluster-wise p<.01). No significant associations were found between any putamen RSFC patterns and suicidal ideation severity or lethality of attempts among those who had attempted. Discussion The results align with recent adult literature and have interesting theoretical and clinical implications. A possible interpretation of the results is a mismatch of the serotonin transport to putamen and to the supplementary motor area and the resulting reduced functional connectivity between the two areas in adolescents with attempt history. The obtained results can be used to enhance the diathesis-stress model and the Emotional paiN and social Disconnect (END) model of adolescent suicidality by adding the putamen. We also speculate that connectivity between putamen and the supplementary motor area may in the future be used as a valuable biomarker of treatment efficacy and possibly prediction of treatment outcome.

Adolescent traumatic brain injury (TBI) has long-term effects on brain functioning and behavior, impacting neural activity under cognitive load, especially in the reward network. Adolescent TBI is also linked to risk-taking behaviors including alcohol misuse. It remains unclear how TBI and neural functioning interact to predict alcohol experimentation during adolescence. Using Adolescent Brain Cognitive Development (ABCD) study data, this project examined if TBI at ages 9–10 predicts increased odds of alcohol sipping at ages 11–13 and if this association is moderated by neural activity during the Emotional EN-Back working memory task at ages 11–13. Logistic regression analyses showed that neural activity in regions of the fronto-basal ganglia network predicted increased odds of sipping alcohol by ages 11–13 (p < .05). TBI and left frontal pole activity interacted to predict alcohol sipping (OR = 0.507, 95% CI [0.303 - 0.846], p = .009) – increased activity predicted decreased odds of alcohol sipping for those with a TBI (OR = 0.516, 95% CI [0.314 - 0.850], p = .009), but not for those without (OR = 0.971, 95% CI [0.931 −1.012], p = .159). These findings suggest that for youth with a TBI, increased BOLD activity in the frontal pole, underlying working memory, may be uniquely protective against the early initiation of alcohol experimentation. Future work will examine TBI and alcohol misuse in the ABCD cohort across more time points and the impact of personality traits such as impulsivity on these associations.

Importance Traumatic brain injury (TBI) is known to cause widespread neural disruption in the cerebrum. However, less is known about the association of TBI with cerebellar structure and how such changes may alter executive functioning. Objective To investigate alterations in subregional cerebellum volume and cerebral white matter microstructure after pediatric TBI and examine subsequent changes in executive function. Design, Setting, and Participants This retrospective cohort study combined 12 data sets (collected between 2006 and 2020) from 9 sites in the Enhancing Neuroimaging Genetics Through Meta-Analysis Consortium Pediatric TBI working group in a mega-analysis of cerebellar structure. Participants with TBI or healthy controls (some with orthopedic injury) were recruited from trauma centers, clinics, and institutional trauma registries, some of which were followed longitudinally over a period of 0.7 to 1.9 years. Healthy controls were recruited from the surrounding community. Data analysis occurred from October to December 2022. Exposure Accidental mild complicated-severe TBI (msTBI) for those in the TBI group. Some controls received a diagnosis of orthopedic injury. Main Outcomes and Measures Volume of 18 cerebellar lobules and vermal regions were estimated from 3-dimensional T1-weighted magnetic resonance imaging (MRI) scans. White matter organization in 28 regions of interest was assessed with diffusion tensor MRI. Executive function was measured by parent-reported scores from the Behavior Rating Inventory of Executive Functioning. Results A total of 598 children and adolescents (mean [SD] age, 14.05 [3.06] years; range, 5.45-19.70 years; 386 male participants [64.5%]; 212 female participants [35.5%]) were included in the study, with 314 participants in the msTBI group, and 284 participants in the non-TBI group (133 healthy individuals and 151 orthopedically injured individuals). Significantly smaller total cerebellum volume ( d = −0.37; 95% CI, −0.52 to −0.22; P < .001) and subregional cerebellum volumes (eg, corpus medullare; d = −0.43; 95% CI, −0.58 to −0.28; P < .001) were observed in the msTBI group. These alterations were primarily seen in participants in the chronic phase (ie, >6 months postinjury) of injury (total cerebellar volume, d = −0.55; 95% CI, −0.75 to −0.35; P < .001). Smaller cerebellum volumes were associated with higher scores on the Behavior Rating Inventory of Executive Functioning Global Executive Composite score (β = −208.9 mm ³ ; 95% CI, −319.0 to −98.0 mm ³ ; P = .008) and Metacognition Index score (β = −202.5 mm ³ ; 95% CI, −319.0 to −85.0 mm ³ ; P = .02). In a subset of 185 participants with longitudinal data, younger msTBI participants exhibited cerebellum volume reductions (β = 0.0052 mm ³ ; 95% CI, 0.0013 to 0.0090 mm ³ ; P = .01), and older participants slower growth rates. Poorer white matter organization in the first months postinjury was associated with decreases in cerebellum volume over time (β=0.52 mm ³ ; 95% CI, 0.19 to 0.84 mm ³ ; P = .005). Conclusions and Relevance In this cohort study of pediatric msTBI, our results demonstrated robust cerebellar volume alterations associated with pediatric TBI, localized to the posterior lobe. Furthermore, longitudinal cerebellum changes were associated with baseline diffusion tensor MRI metrics, suggesting secondary cerebellar atrophy. These results provide further understanding of secondary injury mechanisms and may point to new opportunities for intervention.

Introduction: Risk of suicidal ideation and suicidal behaviors greatly increases during adolescence, and rates have risen dramatically over the past two decades. However, few risk factors or biomarkers predictive of suicidal ideation or attempted suicide have been identified in adolescents. Neuroimaging correlates hold potential for early identification of adolescents at increased risk of suicidality and risk stratification for those at high risk of suicide attempt. Methods: In this systematic review, we evaluated neural regions and networks associated with suicidal ideation and suicide attempt in adolescents derived from magnetic resonance imaging (MRI) studies. A total of 28 articles were included in this review. Results: After descriptively synthesizing the literature, we propose the Emotional paiN and social Disconnect (END) model of adolescent suicidality and present two key neural circuits: (1) the emotional/mental pain circuit and (2) the social disconnect/distortion circuit. In the END model, the emotional pain circuit-consisting of the cerebellum, amygdala, and hippocampus-shows similar aberrations in adolescents with suicidal ideation as in those with a history of a suicide attempt (but to a smaller degree). The social disconnect circuit is unique to adolescent suicide attempters and includes the lateral orbitofrontal cortex (OFC), the temporal gyri, and the connections between them. Conclusion: Our proposed END brain model of suicidal behavior in youth, if confirmed by future prospective studies, can have implications for clinical goals of early detection, risk stratification, and intervention development. Treatments that target emotional pain and social disconnect may be ideal interventions for reducing suicidality in adolescents.

An extensive library of symptom inventories has been developed over time to measure clinical symptoms, but this variety has led to several long standing issues. Most notably, results drawn from different settings and studies are not comparable, which limits reproducibility. Here, we present an artificial intelligence (AI) approach using semantic textual similarity (STS) to link symptoms and scores across previously incongruous symptom inventories. We tested the ability of four pre-trained STS models to screen thousands of symptom description pairs for related content - a challenging task typically requiring expert panels. Models were tasked to predict symptom severity across four different inventories for 6,607 participants drawn from 16 international data sources. The STS approach achieved 74.8% accuracy across five tasks, outperforming other models tested. This work suggests that incorporating contextual, semantic information can assist expert decision-making processes, yielding gains for both general and disease-specific clinical assessment.

Objective: The authors sought to identify predictive factors of new-onset or novel oppositional defiant disorder or conduct disorder assessed 24 months after traumatic brain injury (TBI). Methods: Children ages 5 to 14 years who had experienced TBI were recruited from consecutive hospital admissions. Soon after injury, participants were assessed for preinjury characteristics, including psychiatric disorders, socioeconomic status (SES), psychosocial adversity, and family function, and the presence and location of lesions were documented by MRI. Psychiatric outcomes, including novel oppositional defiant disorder or conduct disorder, were assessed 24 months after injury. Results: Of the children without preinjury oppositional defiant disorder, conduct disorder, or disruptive behavior disorder not otherwise specified who were recruited in this study, 165 were included in this sample; 95 of these children returned for the 24-month assessment. Multiple imputation was used to address attrition. The prevalence of novel oppositional defiant disorder or conduct disorder was 23.7 out of 165 (14%). In univariable analyses, novel oppositional defiant disorder or conduct disorder was significantly associated with psychosocial adversity (p=0.049) and frontal white matter lesions (p=0.016) and was marginally but not significantly associated with SES. In the final multipredictor model, frontal white matter lesions were significantly associated with novel oppositional defiant disorder or conduct disorder (p=0.021), and psychosocial adversity score was marginally but not significantly associated with the outcome. The odds ratio of novel oppositional defiant disorder or conduct disorder among the children with versus those without novel depressive disorder was significantly higher for girls than boys (p=0.025), and the odds ratio of novel oppositional defiant disorder or conduct disorder among the children with versus those without novel attention-deficit hyperactivity disorder (ADHD) was significantly higher for boys than girls (p=0.006). Conclusion: Approximately 14% of children with TBI developed oppositional defiant disorder or conduct disorder. The risk for novel oppositional defiant disorder or conduct disorder can be understood from a biopsychosocial perspective. Sex differences were evident for comorbid novel depressive disorder and comorbid novel ADHD.

The objectives of this machine-learning (ML) resting-state magnetoencephalography (rs-MEG) study involving children with mild traumatic brain injury (mTBI) and orthopedic injury (OI) controls were to define a neural injury signature of mTBI and to delineate the pattern/s of neural injury that determine behavioral recovery. Children aged 8-15 years with mTBI (n=59) and OI (n=39) from consecutive admissions to an emergency department were studied prospectively for parent-rated post-concussion symptoms (PCS) at 1) baseline (average of 3 weeks postinjury) to measure preinjury symptoms and also concurrent symptoms, and 2) at 3-months postinjury. rs-MEG was conducted at the baseline assessment. The ML algorithm predicted cases of mTBI versus OI with sensitivity of 95.5 ± 1.6% and specificity of 90.2 ± 2.7% at 3-weeks postinjury for the combined delta-gamma frequencies. The sensitivity and specificity were significantly better (p<0.0001) for the combined delta-gamma frequencies compared with the delta-only, and gamma-only frequencies. There were spatial differences in rs-MEG activity between mTBI and OI groups in both delta and gamma bands in frontal and temporal lobe as well as more widely in the brain. The ML algorithm accounted for 84.5% of the variance in predicting recovery measured by PCS changes between 3-week and 3-month postinjury in the mTBI group, and this was significantly lower (p < 10-4) in the OI group (65.6%). Frontal lobe pole (higher) gamma activity was significantly (p<0.001) associated with (worse) PCS recovery exclusively in the mTBI group. These findings demonstrate a neural injury signature of pediatric mTBI and patterns of mTBI-induced neural injury related to behavioral recovery.

While traditionally ignored as a region purely responsible for motor function, the cerebellum is increasingly being appreciated for its contributions to higher-order functions through cerebro-cerebellar networks. Traumatic brain injury (TBI) research generally focuses on the cerebrum, in part because of the frequency of acute pathology. Acute pathology is an important predictor of outcome, but neural disruption evolves over time in ways that influence daily-life functioning. We examine these changes in a multi-modal, multi-cohort study. Combining 12 datasets from the Enhancing NeuroImaging Genetics through Meta-Analysis (ENIGMA) Pediatric msTBI (moderate-severe TBI) working group, we measured volume of the total cerebellum and 17 subregions using a state-of-the-art, deep learning-based approach for automated parcellation in 598 children and adolescents with or without TBI (msTBI; n = 314 | non-TBI; n = 284; age M = 14.0 +/- 3.1 years). Further, we investigated brain-behavior relations between cerebellar volumes and a measure of executive functioning (Behavioral Rating Inventory of Executive Function). In a subsample with longitudinal data (n = 80), we assessed associations between late changes in cerebellar volume and early white matter (WM) microstructure using diffusion tensor imaging (DTI). Significantly smaller total cerebellar volume was observed in the msTBI group (Cohens d = -0.37). In addition, smaller volume was found in posterior lobe regions including crus II, lobule VIIB and VIIIB, and vermis VII and IX (Cohens d range = -0.22 to -0.43). These alterations were primarily driven by participants in the chronic phase of injury (> 6 months). Smaller cerebellum volumes were associated with more parent-reported executive function problems. In a subset of participants with longitudinal data, we found evidence of altered growth in total cerebellum volume, with younger msTBI participants showing secondary degeneration (volume reductions), and older participants showing disrupted development (slower growth rates). Changes in total cerebellum volume over time were also associated with WM microstructure in the first months post-injury, such that poorer WM organization in the first months post-injury was associated with decreases in volume longitudinally. Pediatric msTBI was characterized by smaller cerebellar volumes, primarily in the posterior lobe and vermis. The course of these alterations, along with group differences in longitudinal volume changes and injury-specific associations between DTI measures and volume changes, suggests secondary cerebellar atrophy, possibly related to supratentorial lesions, and/or disruption in cerebellar structural and functional circuits. Moreover, evidence for brain-behavior relationships underscore the potential cognitive and behavioral consequences of cerebellar disruption during a critical period of brain development.

Introduction Childhood trauma is known to have dramatic effects on the risks for developing psychiatric disorders and increased suicidality. We conducted a meta-analysis of whole brain voxel-based morphometry (VBM) correlates of childhood trauma in adolescents exposed to childhood maltreatment ( N = 379) and unexposed controls ( N = 348). Methods Anisotropic effect size-signed differential mapping (AES-SDM) was utilized to synthesize the studies. Results We observed increased volume amongst adolescents with a history of childhood trauma in regions that are involved in motor functions and language production: left precentral gyrus, including part of the left inferior frontal gyrus, left fibers of the body of corpus callosum, and left postcentral gyrus. We observed decreased volume amongst adolescents with a history of childhood trauma in regions that are involved in language processing and/or sensory processing: bilateral cerebellum, bilateral middle temporal gyrus, left rostrum of corpus callosum, and bilateral supramarginal gyrus. Discussion We suggest that these morphometric differences may be reflective of impaired motor development and increased sensory sensitivity and hypervigilance in adolescents with experiences of childhood trauma. Our results differ from meta-analytical findings in adults with history of childhood trauma and may contribute to a better understanding of neural mechanisms of childhood trauma, prediction of neurodevelopmental outcomes, and development of more effective and personalized therapies.