Genetic contributions to the outcomes of pediatric mild traumatic brain injury (mTBI) are unclear. The current study applied a genomic signature approach to characterize biological processes critical to variation in persisting symptoms after concussion (PSaC). This planned substudy used data from a prospective cohort observational study, Advancing Concussion Assessment in Pediatrics. Participants aged 8-16.99 years with mTBI or orthopedic injury (OI) were recruited from five emergency departments in Canada between September 2016 and December 2018. Parents completed the Health and Behavior Inventory at 1 week, 1 month, and 3 and 6 months postinjury. Child saliva samples were used for DNA extraction and genotyping. The final genomic dataset included 122,701 variants in 17,212 genes. A systems biology analysis identified a case set of 26,642 variants in 2299 genes likely to be related to brain injury recovery. The same analysis identified a control set of variants/genes not enriched in any of the biological processes associated with brain injury recovery. Linear models examined the interaction between group (mTBI vs. OI) and genetic variant as a predictor of cognitive and somatic PSaC severity at the four follow-up assessments. To test for a genomic signature, we compared the number of nominally significant (p < 0.05) variants associated with group differences in PSaC in the case set to the number of associations meeting the same criteria in >10,000 matched runs of the control set. When the number of nominal associations in the case genes exceeded the 95th percentile expected by chance, they were considered enriched for genes/variants associated with PSaC severity. Participants included 967 children (633 mTBI, 334 OI; median [interquartile range {IQR}] age, 12.3 [10.5-14.3] years; 562 [58.1%] male); 891 provided a saliva sample, genotyping was completed for 720 samples, and 686 (462 mTBI, 224 OI) passed quality control. The aggregate signal from the gene-case set accounted for substantial variability in group differences in somatic symptom severity and modest variability in cognitive symptom severity, especially at 1-week and 1-month postinjury. Although the specific genes varied by symptom type and time postinjury, suggesting nonidentical genomic signatures, they shared overlapping biological processes. The findings demonstrate polygenic contributions to PSaC severity after pediatric mTBI. Specific genomic signatures vary by symptom type and time postinjury but share common biological pathways and processes. A better understanding of genomic contributions to pediatric mTBI outcomes should eventually yield more individualized management approaches.

Background and Objectives:To examine the association between genetic risk of migraine and post-traumatic headache (PTH) in children. Methods:This is a secondary analysis of a cohort study that recruited children aged 8-17 years within 48 hours of concussion or orthopedic injury (OI) from 5 pediatric emergency departments and followed them for 6 months. Genetic risk of migraine was estimated through (1) family history of migraine, (2) polygenic risk scores (PRSs), and (3) forty individual single-nucleotide polymorphisms (SNPs). PTH was categorized as: no PTH (no PTH), PTH nonmigraine phenotype (PTH-NM), or PTH migraine phenotype. Ordinal regression models with cluster-adjusted standard errors and restricted cubic splines were used to estimate associations between genetic risk of migraine and increasing severity of PTH (no PTH vs PTH-NM vs PTH migraine phenotype), adjusting for injury type (concussion vs OI), age, sex, time since injury, first principal component, deprivation indices, concussion history, and preinjury headache history. Results:The sample included 646 children (median [interquartile range] age = 12.38 [10.52-14.41] years, including 436 (67.5%) with concussion. Family history of migraine was associated with increasing severity of PTH in 2/5 models (rs7684253 model: χ2 = 3.99, df = 1, p = 0.046; rs75002882 model: χ2 = 4.02, df = 1, p = 0.045), while migraine PRS was not (χ2 = 12.95, df = 12, p = 0.373). Four SNPs were associated with increasing severity of PTH (rs13078967: χ2 = 103.87, df = 6, p < 0.001; rs7684253: χ2 = 12.90, df = 6, p = 0.045; rs2160875: χ2 = 17.35, df = 6, p = 0.008; and rs75002882: χ2 = 291.79, df = 6, p < 0.001) and 2 remained significant after Bonferroni correction (rs13078967 and rs75002882). Discussion:Four migraine susceptibility genetic variants were associated with PTH, as was family history of migraine in some models, but a migraine PRS was not.

ImportanceIdentifying research priorities of patients with concussion, their caregivers, and their clinicians is important to ensure future concussion research reflects the needs of those who will benefit from the research. ObjectiveTo prioritize concussion research questions from the perspectives of patients, caregivers, and clinicians. Design, Setting, and ParticipantsThis cross-sectional survey study used the standardized James Lind Alliance priority-setting partnership methods (2 online cross-sectional surveys and 1 virtual consensus workshop using modified Delphi and nominal group techniques). Data were collected between October 1, 2020, and May 26, 2022, from people with lived concussion experience (patients and caregivers) and clinicians who treat concussion throughout Canada. ExposuresThe first survey collected unanswered questions about concussion that were compiled into summary questions and checked against research evidence to ensure they were unanswered. A second priority-setting survey generated a short list of questions, and 24 participants attended a final priority-setting workshop to decide on the top 10 research questions. Main Outcomes and MeasuresTop 10 concussion research questions. ResultsThe first survey had 249 respondents (159 [64%] who identified as female; mean [SD] age, 45.1 [16.3] years), including 145 with lived experience and 104 clinicians. A total of 1761 concussion research questions and comments were collected and 1515 (86%) were considered in scope. These were combined into 88 summary questions, of which 5 were considered answered following evidence review, 14 were further combined to form new summary questions, and 10 were removed for being submitted by only 1 or 2 respondents. The 59 unanswered questions were circulated in a second survey, which had 989 respondents (764 [77%] who identified as female; mean [SD] age, 43.0 [4.2] years), including 654 people who identified as having lived experience and 327 who identified as clinicians (excluding 8 who did not record type of participant). This resulted in 17 questions short-listed for the final workshop. The top 10 concussion research questions were decided by consensus at the workshop. The main research question themes focused on early and accurate concussion diagnosis, effective symptom management, and prediction of poor outcomes. Conclusions and RelevanceThis priority-setting partnership identified the top 10 patient-oriented research questions in concussion. These questions can be used to provide direction to the concussion research community and help prioritize funding for research that matters most to patients living with concussion and those who care for them.

Objective: The study sought to present normative and psychometric data and reliable change formulas for the Health and Behavior Inventory (HBI), a postconcussive symptom rating scale embedded in the Child Sport Concussion Assessment Tool 5th edition (Child SCAT5). Design: Prospective cohort study with longitudinal follow-up. Setting: Pediatric emergency departments (EDs). Participants: As part of 3 studies conducted in the United States and Canada between 2001 and 2019, 450 children aged 8 to 16 years with mild orthopedic injuries were recruited during ED visits and assessed postacutely (M = 9.38 days, SD = 3.31) and 1 month and 3 months postinjury. Independent variables were rater (child vs parent), sex, and age at injury. Main Outcome Measure: HBI ratings. Methods: Children and parents rated children's symptoms at each time point; parents also rated children's preinjury symptoms retrospectively. Normative data (mean, SD, skewness, kurtosis, and percentiles) were computed for child and parent ratings. Internal consistency was assessed using Cronbach alpha (α), and test–retest reliability and interrater agreement were assessed with intraclass correlations (ICCs). Reliable change formulas were computed using linear regression and mixed models. Results: HBI ratings were positively skewed. Mean ratings and percentiles were stable over time. Child and parent ratings demonstrated good-to-excellent internal consistency (α 0.76-0.94) and moderate-to-good test–retest reliability (ICC 0.51-0.76 between adjacent assessments). However, parent–child agreement was poor to moderate (ICC 0.31-0.69). Conclusions: The HBI demonstrates acceptable normative and psychometric characteristics. Modest parent–child agreement highlights the importance of multiple informants when assessing postconcussive symptoms. The results will facilitate the use of the HBI in research and clinical practice.

Aim To explore the feasibility and possible effects of low‐frequency repetitive transcranial magnetic stimulation (rTMS) delivered to the supplementary motor area (SMA) on tic severity and motor system neurophysiology in children with Tourette syndrome. Method Ten children with Tourette syndrome (eight males, two females; 9–15y) participated in this open‐label, phase 1 clinical trial. Treatment consisted of 1800 low‐frequency (1Hz) neuronavigated robotic rTMS (100% resting motor threshold) to the SMA, bilaterally for 15 sessions. The primary outcome was a change in Yale Global Tic Severity Scale (YGTSS) total score from baseline to posttreatment. Secondary outcome measures included changes in magnetic resonance spectroscopy metabolite concentrations, TMS neurophysiology measures, TMS motor maps, and clinical assessments (anxiety, depression) from baseline to the end of treatment. Results The YGTSS score decreased from baseline after treatment ( p <0.001; Cohen's d =2.9). All procedures were well‐tolerated. Interpretation Robot‐driven, neuronavigated bilateral rTMS of the SMA is feasible in children with Tourette syndrome and appears to reduce tic severity. What this paper adds Repetitive transcranial magnetic stimulation (rTMS) is feasible to use in children with Tourette syndrome. rTMS is tolerated by children with Tourette syndrome. Precise targeting of the supplementary motor area using functional magnetic resonance imaging is also feasible in these children.

Objective: Despite increasing interest in the neurobiological effects of concussion in youth, a paucity of information is available regarding outcomes long after injury. The objective of this study was to determine the association between a history of concussion and the putative neuronal marker N-acetyl-aspartate (NAA) in the dorsolateral prefrontal cortex (DLPFC) in youth. Setting: Outpatient clinic in a children's hospital. Participants: Youth with concussion (N = 35, mean = 2.63, SD = 1.07 years postinjury) and youth with a nonconcussive orthopedic injury (N = 17) participated. Design: A cross-sectional proton magnetic resonance spectroscopy (1H-MRS) study. Main Measures: The primary outcome measure was NAA concentration in the right and left DLPFCs. Results: We observed lower levels of NAA in the right DLPFC in youth with past concussion (F = 3.31, df = 4,51, P = .018) than in orthopedic controls but not in the left DLPFC (F = 2.04, df = 4,51, P = .105). The effect of lower NAA concentrations in the right DLPFC was primarily driven by youth with a single prior concussion versus those with multiple concussions. NAA in the left DLPFC, but not in right DLPFC, was associated with worse emotional symptoms in youth with concussion. Conclusion: The presence of lower levels of DLPFC NAA suggests potential association of concussion in youth, although further investigation is needed, given that the result is driven by those with a single (and not multiple) concussion. Exploration of applying MRS in other brain regions is also warranted.

Background: Major depressive disorder (MDD) is common in youth and treatment options are limited. We evaluated the effectiveness and safety of repetitive transcranial magnetic stimulation (rTMS) in adolescents and transitional aged youth with treatment resistant MDD.Methods: Thirty-two outpatients with moderate to severe, treatment-resistant MDD, aged 13–21 years underwent a three-week, open-label, single center trial of rTMS (ClinicalTrials.gov identifier NCT01731678). rTMS was applied to the left dorsolateral prefrontal cortex (DLPFC) using neuronavigation and administered for 15 consecutive week days (120% rest motor threshold; 40 pulses over 4 s [10 Hz]; inter-train interval, 26 s; 75 trains; 3,000 pulses). The primary outcome measure was change in the Hamilton Depression Rating Scale (Ham-D). Treatment response was defined as a >50% reduction in Ham-D scores. Safety and tolerability were also examined.Results: rTMS was effective in reducing MDD symptom severity (t = 8.94, df = 31, p < 0.00001). We observed 18 (56%) responders (≥ 50% reduction in Ham-D score) and 14 non-responders to rTMS. Fourteen subjects (44%) achieved remission (Ham-D score ≤ 7 post-rTMS). There were no serious adverse events (i.e., seizures). Mild to moderate, self-limiting headaches (19%) and mild neck pain (16%) were reported. Participants ranked rTMS as highly tolerable. The retention rate was 91% and compliance rate (completing all study events) was 99%.Conclusions: Our single center, open trial suggests that rTMS is a safe and effective treatment for youth with treatment resistant MDD. Larger randomized controlled trials are needed.Clinical Trial Registration:www.ClinicalTrials.gov, identifier: NCT01731678

BACKGROUND:Growing evidence suggests an endophenotype for suicidality, including brain morphometric features, could provide an improved platform for suicide risk assessment. Reduced right superior temporal gyrus (rSTG) volumes have been implicated in suicidality across psychiatric disorders. Treatment-resistant depression (TRD) has unique neurobiology and adolescents with TRD are at increased suicide risk. Here, we investigated whether reduced rSTG volume was present in adolescents with TRD and history of suicide attempt.METHODS:45 adolescents - 14 with history of suicide attempt and TRD, 14 without a suicide attempt history and TRD, and 17 healthy controls - underwent magnetic resonance imaging and reconstructed rSTG volumes were compared. Depressive and anxious symptoms were assessed with Hamilton depression and anxiety rating scales, and differences between attempters and non-attempters were explored.RESULTS:Adolescents with TRD and history of suicide attempt showed reduced rSTG volume compared to healthy controls. Exploratory analyses revealed greater diurnal variation in depressive symptoms in the suicide attempt group compared to non-attempters.LIMITATIONS:Sample size and temporal separation between suicide attempt date and data collection limits interpretation of findings.CONCLUSIONS:Reduced rSTG volume may serve as a marker of suicide attempt in adolescence and specific symptom features may have a role in suicide risk assessment. Presently, risk assessment is limited by patient self-report and clinical judgement. A biological model of suicidality will be key to improve risk assessment and could lead to novel treatment approaches. Our findings extend previous results and contribute to our neurobiological understanding of suicidality.

Motor impairment is associated with developmental coordination disorder (DCD), and to a lesser extent with attention-deficit/hyperactivity disorder (ADHD). Previous functional imaging studies investigated children with DCD or ADHD only; however, these two disorders co-occur in up to 50% of cases, suggesting that similar neural correlates are associated with these disorders. This study compared functional brain activation in children and adolescents (age range 8-17, M = 11.73, SD = 2.88) with DCD (n = 9), ADHD (n = 20), co-occurring DCD and ADHD (n = 18) and typically developing (TD) controls (n = 20). When compared to TD controls, children with co-occurring DCD/ADHD showed decreased activation during response inhibition in primary motor and sensory cortices. These findings suggest that children with co-occurring DCD and ADHD display significant functional changes in brain activation that could interfere with inhibition of erroneous motor responses. In contrast to previous studies, significant alterations in brain activation relative to TD controls, were not found in children with isolated DCD or ADHD. These findings highlight the importance of considering co-occurring disorders when investigating brain function in children with neurodevelopmental disorders.

Growing evidence suggests an endophenotype for suicidality, including brain morphometric features, could provide an improved platform for suicide risk assessment. Reduced right superior temporal gyrus (rSTG) volumes have been implicated in suicidality across psychiatric disorders.

Background: Smaller hippocampal volumes, as assessed by magnetic resonance imaging (MRI), and proton magnetic resonance spectroscopy (H-1-MRS) indexed alterations in brain metabolites have been identified in adults with major depressive disorder (MDD). Our group has found similar effects in MDD youth. However, this has not been studied in youth with treatment resistant MDD (TRD), nor has the interaction between regional N-acetyl-aspartate and volume deficits. N-acetyl-aspartate is an amino acid in the synthesis pathway of glutamate and serves a marker of neuronal viability/number.Methods: Fifteen typically developing youth (16-22 years of age; 7 males, 8 females) and eighteen youth with TRD (14-22 years of age; 8 males, 10 females) underwent H-1-MRS and MRI on a 3 T scanner. A short echo PRESS protocol was used with voxels in the right and left hippocampi (6 mL each). Hippocampal volume war evaluated using FreeSurfer.Results: Compared with the typically developing group, youth with TRD had lower concentrations of N-acetylaspartate in the left hippocampus (p=0.004), and a trend for smaller left hippocampal volume (p=0.067). In TRD subjects, hippocampal N-acetyl-aspartate was inversely correlated with left (r=-0.68, p=0.003) but not right hippocampal volume. Right hippocampal glutamate+glutamine was greater in TRD youth compared to typically developing controls (p=0.007).Conclusions: These results suggest a neurochemical and structural deficit in the hippocampi of youth with TRD These findings fit with the role of N-acetyl-aspartate in glutamate neurotransmission and the effect of glutamate on brain morphology.

Current treatment options for major depressive disorder (MDD) in youth are limited. Repetitive transcranial magnetic stimulation (rTMS) is an emerging intervention for treatment resistant major depressive disorder (MDD) in youth. We hypothesize that the target site for rTMS, the dorsolateral prefrontal cortex (DLPFC), will differ in cortical thickness between responders and non-responders to treatment.

Background Developmental coordination disorder is a common neurodevelopment disorder that frequently co-occurs with other neurodevelopmental disorders including attention-deficit hyperactivity disorder (ADHD). Copy-number variations (CNVs) have been implicated in a number of neurodevelopmental and psychiatric disorders; however, the proportion of heritability in developmental coordination disorder (DCD) attributed to CNVs has not been explored. Objective This study aims to investigate how CNVs may contribute to the genetic architecture of DCD. Methods CNV analysis was performed on 82 extensively phenotyped Canadian children with DCD, with or without co-occurring ADHD and/or reading disorder, and 2988 healthy European controls using identical genome-wide SNP microarrays and CNV calling algorithms. Results An increased rate of large and rare genic CNVs (p=0.009) was detected, and there was an enrichment of duplications spanning brain-expressed genes (p=0.039) and genes previously implicated in other neurodevelopmental disorders (p=0.043). Genes and loci of particular interest in this group included: GAP43, RBFOX1, PTPRN2, SHANK3, 16p11.2 and distal 22q11.2. Although no recurrent CNVs were identified, 26% of DCD cases, where sample availability permitted segregation analysis, were found to have a de novo rare CNV. Of the inherited CNVs, 64% were from a parent who also had a neurodevelopmental disorder. Conclusions These findings suggest that there may be shared susceptibility genes for DCD and other neurodevelopmental disorders and highlight the need for thorough phenotyping when investigating the genetics of neurodevelopmental disorders. Furthermore, these data provide compelling evidence supporting a genetic basis for DCD, and further implicate rare CNVs in the aetiology of neurodevelopmental disorders.

AimStructural, functional, and metabolic changes in the dorsolateral prefrontal cortex (DLPFC) are implicated in the pathogenesis of major depressive disorder (MDD). We used proton magnetic resonance spectroscopy ((1) H-MRS) to examine the metabolite choline (glycerophosphocholine plus phosphocholine), which is used as an index of membrane integrity in the left DLPFC, in adolescents and young adults with MDD who were treatment-resistant and had a positive family history compared to healthy controls. Differences in the choline resonance indicate an imbalance between synthesis and degradation activity of neuronal and glia membrane phospholipids.MethodsSeventeen adolescents with MDD and 11 healthy controls underwent (1) H-MRS. A short echo point-resolved spectroscopy (echo time = 30 ms, repetition time = 2000 ms) protocol was used with a voxel (4.5cm(3), 128 averages) placed within the left DLPFC.ResultsThere were significantly increased choline (P = 0.04) and creatine concentrations (P = 0.005) in the left DLPFC of the MDD group compared to controls. In MDD participants, choline concentration correlated with scores on the Beck Depression Inventory (r = 0.41, P = 0.03).ConclusionIncreased left DLPFC choline and creatine levels in depressed adolescents may be biomarkers for the disorder. The increased choline levels may indicate abnormalities in neuronal membrane integrity, and the increased creatine could be reflective of altered energy demands and metabolism.

BACKGROUND:Research activity is especially critical in the field of psychiatry as it is evolving rapidly thanks to advances in neuroscience.RESULTS:We administered a 34-item survey regarding research experiences targeted at psychiatry residents and postgraduate residency program directors in Canada. One hundred and nineteen participants answered the survey (16 program directors, 103 residents) allowing for a margin of error of 8.4% at a 95% confidence interval. Research was rated as important in informing clinical practice (87.0% yes, 13.0% no), but only 28.7% of respondents reported that it was taught well at their home institution (33.0% no, 38.3% neutral). Only a small proportion was enthusiastic or very enthusiastic about participating in research (21.7%).CONCLUSIONS:While the importance of research is recognized, there is little consensus with respect to whether a standardized research practicum component is included in the resident curriculum.

Imprinted genes are dosage sensitive, and their dysregulated expression is linked to disorders of growth and proliferation, including fetal and postnatal growth restriction. Common sequelae of growth disorders include neurodevelopmental defects, some of which are indirectly related to placental insufficiency. However, several growth-associated imprinted genes are also expressed in the embryonic CNS, in which their aberrant expression may more directly affect neurodevelopment. To test whether growth-associated genes influence neural lineage progression, we focused on the maternally imprinted gene Zac1. In humans, either loss or gain of ZAC1 expression is associated with reduced growth rates and intellectual disability. To test whether increased Zac1 expression directly perturbs neurodevelopment, we misexpressed Zac1 in murine neocortical progenitors. The effects were striking: Zac1 delayed the transition of apical radial glial cells to basal intermediate neuronal progenitors and postponed their subsequent differentiation into neurons. Zac1 misexpression also blocked neuronal migration, with Zac1 -overexpressing neurons pausing more frequently and forming fewer neurite branches during the period when locomoting neurons undergo dynamic morphological transitions. Similar, albeit less striking, neuronal migration and morphological defects were observed on Zac1 knockdown, indicating that Zac1 levels must be regulated precisely. Finally, Zac1 controlled neuronal migration by regulating Pac1 transcription, a receptor for the neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP). Pac1 and Zac1 loss- and gain-of-function presented as phenocopies, and overexpression of Pac1 rescued the Zac1 knockdown neuronal migration phenotype. Thus, dysregulated Zac1 expression has striking consequences on neocortical development, suggesting that misexpression of this transcription factor in the brain in certain growth disorders may contribute to neurocognitive deficits. SIGNIFICANCE STATEMENT Altered expression of imprinted genes is linked to cognitive dysfunction and neuropsychological disorders, such as Angelman and Prader–Willi syndromes, and autism spectrum disorder. Mouse models have also revealed the importance of imprinting for brain development, with chimeras generated with parthenogenetic (two maternal chromosomes) or androgenetic (two paternal chromosomes) cells displaying altered brain sizes and cellular defects. Despite these striking phenotypes, only a handful of imprinted genes are known or suspected to regulate brain development (e.g., Dlk1 , Peg3 , Ube3a , necdin , and Grb10 ). Herein we show that the maternally imprinted gene Zac1 is a critical regulator of neocortical development. Our studies are relevant because loss of 6q24 maternal imprinting in humans results in elevated ZAC1 expression, which has been associated with neurocognitive defects.