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Objective: Research and clinical application of transcranial magnetic stimulation (TMS) for adolescents with major depressive disorder has advanced slowly. Significant gaps persist in understanding of optimized, age-specific protocols and dosing strategies. This study aimed to compare the clinical effects of 1-Hz vs 10-Hz TMS regimens and examine a biomarker-informed treatment approach with glutamatergic intracortical facilitation (ICF)., Method: Participants with moderate-to-severe symptoms of major depressive disorder were randomized to 30 sessions of left prefrontal 1-Hz or 10-Hz TMS, stratified by baseline ICF measures. The primary clinical outcome measure was the Children's Depression Rating Scale-Revised (CDRS-R). The CDRS-R score and ICF biomarker were collected weekly., Results: A total of 41 participants received either 1-Hz (n = 22) or 10-Hz (n = 19) TMS treatments. CDRS-R scores improved compared with baseline in both 1-Hz and 10-Hz groups. For participants with low ICF at baseline, the overall least squares means of CDRS-R scores over the 6-week trial showed that depressive symptom severity was lower for participants treated with 1-Hz TMS than for participants who received 10-Hz TMS. There were no significant changes in weekly ICF measurements across 6 weeks of TMS treatment., Conclusion: Low ICF may reflect optimal glutamatergic N-methyl-d-aspartate receptor activity that facilitates the therapeutic effect of 1-Hz TMS through long-term depression-like mechanisms on synaptic plasticity. The stability of ICF suggests that it is a tonic, traitlike measure of N-methyl-d-aspartate receptor-mediated neurotransmission, with potential utility to inform parameter selection for therapeutic TMS in adolescents with major depressive disorder., Clinical Trial Registration Information: Biomarkers in Repetitive Transcranial Magnetic Stimulation (rTMS) for Adolescent Depression; https://clinicaltrials.gov; NCT03363919., Diversity & Inclusion Statement: We worked to ensure sex and gender balance in the recruitment of human participants. We worked to ensure race, ethnic, and/or other types of diversity in the recruitment of human participants. We worked to ensure that the study questionnaires were prepared in an inclusive way. One or more of the authors of this paper self-identifies as a member of one or more historically underrepresented racial and/or ethnic groups in science. We actively worked to promote sex and gender balance in our author group. We actively worked to promote inclusion of historically underrepresented racial and/or ethnic groups in science in our author group. While citing references scientifically relevant for this work, we also actively worked to promote sex and gender balance in our reference list. While citing references scientifically relevant for this work, we also actively worked to promote inclusion of historically underrepresented racial and/or ethnic groups in science in our reference list., (Copyright © 2024 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: Suicide is a leading cause of death in adolescents worldwide. Previous research findings suggest that suicidal adolescents with depression have pathophysiological dorsolateral prefrontal cortex (DLPFC) deficits in γ-aminobutyric acid neurotransmission. Interventions with transcranial magnetic stimulation (TMS) directly address these underlying pathophysiological deficits in the prefrontal cortex. Theta burst stimulation (TBS) is newer dosing approach for TMS. Accelerated TBS (aTBS) involves administering multiple sessions of TMS daily as this dosing may be more efficient, tolerable, and rapid acting than standard TMS., Materials and Methods: This is a randomized, double-blind, sham-controlled trial of sequential bilateral aTBS in adolescents with major depressive disorder (MDD) and suicidal ideation. Three sessions are administered daily for 10 days. During each session, continuous TBS is administered first to the right DPFC, in which 1,800 pulses are delivered continuously over 120 seconds. Then intermittent TBS is applied to the left DPFC, in which 1,800 pulses are delivered in 2-second bursts and repeated every 10 seconds for 570 seconds. The TBS parameters were adopted from prior research, with 3-pulse, 50-Hz bursts given every 200 ms (at 5 Hz) with an intensity of 80% active motor threshold. The comparison group will receive 3 daily sessions of bilateral sham TBS treatment for 10 days. All participants will receive the standard of care for patients with depression and suicidal ideation including daily psychotherapeutic skill sessions. Long-interval intracortical inhibition (LICI) biomarkers will be measured before and after treatment. Exploratory measures will be collected with TMS and electroencephalography for biomarker development., Discussion: This is the first known randomized controlled trial to examine the efficacy of sequential bilateral aTBS for treating suicidal ideation in adolescents with MDD. Results from this study will also provide opportunities to further understand the neurophysiological and molecular mechanisms of suicidal ideation in adolescents., Trial Registration: Investigational device exemption (IDE) Number: G200220, ClinicalTrials.gov (ID: NCT04701840). Registered August 6, 2020. https://clinicaltrials.gov/ct2/show/NCT04502758?term=NCT04701840&draw=2&rank=1., Competing Interests: Dr Croarkin has received research grant support from Neuronetics Inc, NeoSync Inc, and Pfizer Inc. He has received in-kind support (equipment, supplies, and genotyping) for research studies from Assurex Health Inc, Neuronetics Inc, and MagVenture Inc. He has consulted for Engrail Therapeutics Inc, Myriad Neuroscience, Procter & Gamble, and Sunovion. Dr Vande Voort has received in-kind support (supplies and genotyping) from Assurex Health Inc. The other authors declare that they have no competing interests., (Copyright: © 2023 Yuruk et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Exposure to general anaesthesia in children might increase the risk of long-term behavioural problems. It is unclear if any behavioural changes in the short term after anaesthesia could be associated with long-term problems. The goal of the current study was to evaluate the short-term trajectory of parent-reported behaviour measured by the Behaviour Assessment System for Children, third edition (BASC-3) amongst children aged 2.5-6 yr who underwent general anaesthesia for elective surgery., Methods: Children who were undergoing general anaesthesia for surgery were recruited for assessment of behaviour on two occasions: preoperatively (from 1 week to 1 day before anaesthesia), and 3 months postoperatively. To assess longitudinal changes in the parent-reported behaviour measured by BASC-3, linear mixed models were built with visit number included as a categorical variable and subject-specific random intercepts., Results: Sixty-eight children (37 girls [54%]) were enrolled in the study and completed both assessments. At 3 months after anaesthesia, statistically significant improvements (decrease in T scores) in internalising problems (-2.7 [95% confidence interval -4.2 to -1.1]), anxiety (-2.5 [-4.4 to -0.5]), and somatisation (-3.0 [-5.2 to -0.9]) were found. There were no significant differences in scores between visits for other composites or scales. The pattern of results did not depend upon prior anaesthesia exposure., Conclusions: Anaesthesia for elective surgery in young children was associated with a small decrease in internalising problems but no changes in other areas of behavioural problems when assessed at 3 months postoperatively, including in children with prior exposure to anaesthesia., (Copyright © 2022 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.)

Background: Exposure to general anaesthesia in children may be related to deficits in certain areas of cognition. It is unclear if these deficits could be measured in the immediate postoperative period in young children. The goal of the current study was to evaluate the trajectory of cognitive function in the domains of processing speed, working memory, and fine motor skills amongst children aged 2.5-6 yr who underwent general anaesthesia for elective surgery., Methods: Children who were scheduled to receive general anaesthesia for surgery were recruited for assessment of cognitive function at three times: preoperatively, 1-2 weeks postoperatively, and 3 months postoperatively. Assessments included processing speed, working memory, and fine motor skills. To assess longitudinal changes in the cognitive outcomes, linear mixed models were built with visit number included as a categorical variable and subject-specific random intercepts., Results: Sixty-one children (33 girls [54%]) enrolled in the study. Twenty-three children (38%) had received general anaesthesia previously. Significant improvements in picture memory, cancellation, and the processing speed composite were found at Visit 2. The improvement in cancellation and processing speed composite remained significant at Visit 3. Statistically significant improvement in Mullen fine motor score was noticed at Visit 3 compared with Visit 1. The pattern of results did not depend upon prior anaesthesia exposure., Conclusions: General anaesthesia for elective surgery in young children was not associated with declines in working memory, processing speed, and fine motor skills in the first 3 months postoperatively, including in children with prior exposure to anaesthesia., (Copyright © 2021 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.)

Background: Childhood adversity is a global health problem affecting 25-50% of children worldwide. Few prior studies have examined the underlying neurochemistry of adversity in adolescents. This cross-sectional study examined spectroscopic markers of trauma in a cohort of adolescents with major depressive disorder (MDD) and healthy controls. We hypothesized that historical adversity would have a negative relationship with spectroscopic measures of glutamate metabolites in anterior cingulate cortex., Methods: Adolescent participants (aged 13-21) underwent a semi-structured diagnostic interview and clinical assessment, which included the self-report Childhood Trauma Questionnaire (CTQ), a 28-item assessment of childhood adversity. Proton magnetic resonance spectroscopy ( 1 H-MRS) scans at 3 Tesla of an anterior cingulate cortex (ACC) voxel (8 cm 3 ) encompassing both hemispheres were collected using a 2-dimensional J -averaged sequence to assess N -acetylaspartate (NAA), Glx (glutamate+glutamine) and [NAA]/[Glx] concentrations. Generalized linear models assessed the relationships between CTQ scores and metabolite levels in ACC., Results: Thirty-nine participants (17 healthy controls, 22 depressed participants) underwent 1 H-MRS and completed the CTQ measures. There were decrements in [NAA]/[Glx] ratio in the ACC of participants with childhood adversity while no significant relationship between CTQ total score and any of the ACC metabolites was found in the combined sample. Exploratory results revealed a positive association between Glx levels and CTQ scores in depressed participants. Conversely the [NAA]/[Glx] ratio had a negative association with total CTQ scores in the depressed participants. Emotional Abuse Scale showed a significant negative relationship with [NAA]/[Glx] ratio in the combined sample when adjusted for depression severity., Conclusions: Our findings suggest that childhood adversity may impact brain neurochemical profiles. Further longitudinal studies should examine neurochemical correlates of childhood adversity throughout development and in populations with other psychiatric disorders., Competing Interests: Statement of Interest Dr. Lewis. received grant support from the Brain & Behavior Research Foundation as the Alan G. Ross Memorial Investigator. He has been a site investigator for multicenter trials funded by Neuronetics, Inc. and NeoSync, Inc. Dr. Port has served as an imaging consultant for Takeda Pharmaceutical Company, Ltd., Biomedical Systems Corp., and Neuronetics, Inc. Dr. Choi is a scientific advisory board member for Peptron Inc. Dr Croarkin has received research grant support from Pfizer, Inc; equipment support from Neuronetics, Inc; equipment support from MagVenture, Inc; and supplies and genotyping services from Assurex Health, Inc for investigator-initiated studies. He was the primary investigator for a multicenter study funded by Neuronetics, Inc and a site primary investigator for a study funded by NeoSync, Inc. Dr Croarkin has served as a consultant for Engrail Therapeutics, Myriad Neuroscience, Procter & Gamble Companyand Sunovion. The other authors report no financial relationships with commercial interests.

Background: Children's exposure to anaesthesia has been associated with risk of developing attention-deficit/hyperactivity disorder (ADHD). The goal of this study was to determine if selected patient characteristics moderate the association between exposure to anaesthesia and ADHD., Methods: In a cohort of children born in between 2006 and 2012, exposure to anaesthesia before the age of 5 yr was categorised into unexposed, singly, or multiply exposed. Weighted proportional hazard regression was performed to evaluate the hazard ratios (HRs) of ADHD diagnosis related to anaesthesia exposure. Interaction analyses were performed to evaluate potential moderators., Results: Among 185 002 children in the cohort, 9179 were diagnosed with ADHD. Compared with unexposed children, a single exposure to anaesthesia was associated with a HR of 1.39, (95% confidence interval [CI], 1.32-1.47) for ADHD. Multiple exposures were associated with a HR of 1.75 (95% CI, 1.62-1.87). In the analyses evaluating moderators of the association between exposure and ADHD, only the interaction for race was statistically significant (P=0.006); exposure increased the incidence of ADHD to a greater extent in non-White compared with White children. Among children with a single exposure, the age at exposure did not affect the relationship between exposure and incidence of ADHD (P=0.78)., Conclusions: Exposure of young children to anaesthesia and surgery is associated with an increased incidence of ADHD, with more exposures associated with greater risk. Compared with White children, non-White children are at greater risk for reasons that are unknown but need to be further explored., (Copyright © 2021 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.)

Background: Two prior population-based (children born in Olmsted County, MN), retrospective cohort studies both found that multiple exposures to anesthesia before age 3 were associated with a significant increase in the frequency of attention-deficit hyperactivity disorder (ADHD) and learning disabilities (LD) later in life. The primary purpose of this secondary analysis of these data was to test the hypothesis that a single exposure to anesthesia before age 3 was associated with an increased risk of ADHD. We also examined the association of single exposures with LD and the need for individualized educational plans as secondary outcomes., Methods: This analysis includes 5339 children who were unexposed to general anesthesia before age 3 (4876 born from 1976 to 1982 and 463 born from 1996 to 2000), and 1054 children who had a single exposure to anesthesia before age 3 (481 born from 1976 to 1982 and 573 born from 1996 to 2000). The primary outcome of interest was ADHD. Secondary outcomes included LD (reading, mathematics, and written language) and the need for individualized educational programs (speech/language and emotion/behavior). To compare the incidence of each outcome between those who were unexposed and singly exposed to anesthesia before the age of 3 years, an inverse probability of treatment weighted proportional hazards model was used., Results: For children not exposed to anesthesia, the estimated cumulative frequency (95% confidence interval [CI]) of ADHD at age 18 was 7.3% (95% CI, 6.5-8.1) and 13.0% (95% CI, 10.1-16.8) for the 1976-1982 and 1996-2000 cohorts, respectively. For children exposed to a single anesthetic before age 3, the cumulative frequency of ADHD was 8.1% (95% CI, 5.3-12.4) and 17.6% (95% CI, 14.0-21.9) for the 1976-1982 and 1996-2000 cohorts, respectively. In weighted analyses, single exposures were not significantly associated with an increased frequency of ADHD (hazard ratio [HR], 1.21; 95% CI, 0.91-1.60; P = .184). Single exposures were also not associated with an increased frequency of any LD (HR, 0.98; 95% CI, 0.78-1.23), or the need for individualized education plans., Conclusions: This analysis did not find evidence that single exposures to procedures requiring general anesthesia, before age 3, are associated with an increased risk of developing ADHD, LD, or the need for individualized educational plans in later life., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2020 International Anesthesia Research Society.)

Importance: There are limited data on the racial disparities in the incidence of attention-deficit/hyperactivity disorder (ADHD) diagnosis in children at the national level., Objective: To explore differences in rates of diagnosis of ADHD and use of treatment among children by race and ethnicity., Design, Setting, and Participants: This retrospective cohort study assessed insurance claims data of children born in the US between January 1, 2006, and December 31, 2012, who had continuous insurance coverage for at least 4 years. The last date of follow-up included in the cohort was June 30, 2019. Race/ethnicity designations were based on self-report and included non-Hispanic White, Black, Hispanic, and Asian. Data were analyzed between October 2019 and December 2020., Exposures: Race and ethnicity., Main Outcomes and Measures: ADHD diagnosis as defined by International Classification of Diseases codes (ninth or tenth editions) and treatment within 1 year of diagnosis, including medication and behavior therapy as defined by billing codes. Data on ADHD diagnosis and treatment were adjusted for sex, region, and household income in a multivariate Cox regression model., Results: Among 238 011 children in the cohort (116 093 [48.8%] girls; 15 183 [6.7%] Asian, 14 792 [6.2%] Black, 23 358 [9.8%] Hispanic, and 173 082 [72.7%] White children), 11 401 (4.8%) were diagnosed with ADHD. The cumulative incidence at age 12 was 13.12% (95% CI, 12.79%-13.46%). In multivariate Cox regression adjusting for sex, region, and household income, the hazard ratio for Asian children was 0.48 (95% CI, 0.43-0.53); Black children, 0.83 (95% CI, 0.77-0.90); and Hispanic children, 0.77 (95% CI, 0.72, 0.82) compared with White children. In the first year after diagnosis, 516 preschool children (19.4%) received behavioral therapy only, 860 (32.4%) had medications only, 505 (19.0%) had both, and 774 (29.2%) had no claims associated with either option. A higher percentage of school-aged children (2904 [65.6%]) were prescribed medications, and fewer had therapy only (639 [14.4%]) or no treatment at all (884 [20.0%]). Compared with other groups, White children were more likely to receive some kind of treatment. Asian children had the highest odds of receiving no treatment (odds ratio compared with White children, 0.54; 95% CI, 0.42-0.70)., Conclusions and Relevance: Racial and ethnic disparities in the diagnosis and treatment of ADHD are evident. Future study is needed to elucidate the mechanism behind these disparities, with special attention to Asian children. Clinicians should provide racially sensitive care in the evaluation and treatment of ADHD.

Background: The potential adverse effects of exposures to general anesthesia on the developing human brain remain controversial. It has been hypothesized that hypotension accompanying anesthesia could be contributory. We hypothesized that among children exposed to multiple anesthetics prior to age 3, children developing adverse neurodevelopmental outcomes would be more likely to have intraoperative hypotension., Methods: Two previously published study cohorts were utilized for analysis: the retrospective and prospective Mayo Anesthesia Safety in Kids cohorts. The two lowest consecutive systolic blood pressure measurements were abstracted and standardized by calculating a z-score for noninvasive blood pressure reference ranges for children. The lowest systolic blood pressure z-score (continuous variable) and intraoperative hypotension (lowest systolic blood pressure z-score <-1.0) were used to assess the association of intraoperative hypotension with the incidence of learning disabilities or attention-deficit/hyperactivity disorder(retrospective cohort) and factor scores/cluster membership (prospective cohort)., Results: One hunderd and sixteen and 206 children with multiple exposures to general anesthesia were analyzed in the retrospective and prospective cohorts with mean lowest systolic blood pressure z-scores -0.26 (SD 1.02) and -0.62 (SD 1.10), respectively. There was no overall association of the lowest z-score or hypotension with learning disabilities or attention-deficit/hyperactivity disorder in the retrospective cohort. In the prospective cohort, there was no overall association of the lowest systolic blood pressure or hypotension with factor scores or cluster membership., Conclusions: We did not find evidence to support the hypothesis that, among children exposed to multiple anesthetics prior to age 3, children developing adverse neurodevelopmental outcomes would be more likely to have intraoperative hypotension compared with those who did not., (© 2020 John Wiley & Sons Ltd.)

Background: Whether exposure to a single general anaesthetic (GA) in early childhood causes long-term neurodevelopmental problems remains unclear., Methods: PubMed/MEDLINE, Embase, CINAHL, Web of Science, and the Cochrane Library were searched from inception to October 2019. Studies evaluating neurodevelopmental outcomes and prospectively enrolling children exposed to a single GA procedure compared with unexposed children were identified. Outcomes common to at least three studies were evaluated using random-effects meta-analyses., Results: Full-scale intelligence quotient (FSIQ); the parentally reported Child Behavior Checklist (CBCL) total, externalising, and internalising problems scores; and Behavior Rating Inventory of Executive Function (BRIEF) scores were assessed. Of 1644 children identified, 841 who had a single exposure to GA were evaluated. The CBCL problem scores were significantly higher (i.e. worse) in exposed children: mean score difference (CBCL total: 2.3 [95% confidence interval {CI}: 1.0-3.7], P=0.001; CBCL externalising: 1.9 [95% CI: 0.7-3.1], P=0.003; and CBCL internalising problems: 2.2 [95% CI: 0.9-3.5], P=0.001). Differences in BRIEF were not significant after multiple comparison adjustment. Full-scale intelligence quotient was not affected by GA exposure. Secondary analyses evaluating the risk of these scores exceeding predetermined clinical thresholds found that GA exposure was associated with increased risk of CBCL internalising behavioural deficit (risk ratio [RR]: 1.47; 95% CI: 1.08-2.02; P=0.016) and impaired BRIEF executive function (RR: 1.68; 95% CI: 1.23-2.30; P=0.001)., Conclusions: Combining results of studies utilising prospectively collected outcomes showed that a single GA exposure was associated with statistically significant increases in parent reports of behavioural problems with no difference in general intelligence., (Copyright © 2020 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.)

Background: To develop and evaluate machine learning algorithms to ascertain attention-deficit/hyperactivity (ADHD) and learning disability (LD) using diagnostic codes in the medical record., Method: Diagnoses of ADHD and LD were confirmed in cohorts of children in Olmsted County of Minnesota based on validated research criteria. Models to predict ADHD and LD were developed using ICD-9 codes in a derivation cohort of 1057 children before evaluated in a validation cohort of 536 children., Results: The ENET-MIN model using selected ICD-9 codes at prior probability of 0.25 has a sensitivity of 0.76, PPV of 0.85, specificity of 0.98, and NPV of 0.97 in the validation cohort. However, it does not offer significant advantage over a model using a single ICD-9 code of 314.X, which shows sensitivity of 0.81, PPV of 0.83, specificity of 0.98, and NPV of 0.97. None of the models developed for LD performed well in the validation cohort., Conclusions: It is feasible to utilize diagnostic codes to ascertain cases of ADHD in a population of children. Machine learning approaches do not have advantage compared with simply using a single family of diagnostic codes for ADHD. The use of medical record diagnostic codes is not feasible to ascertain LD.

Background: We hypothesised that exposure to multiple, but not single, procedures requiring general anaesthesia before age 3 yr is associated with a specific pattern of deficits in processing speed and fine motor skills., Methods: A secondary analysis (using factor and cluster analyses) of data from the Mayo Anesthesia Safety in Kids study was conducted, in which unexposed, singly exposed, and multiply exposed children born in Olmsted County, MN, USA from 1994 to 2007 were sampled using a propensity-guided approach and underwent neuropsychological testing at ages 8-12 or 15-20 yr., Results: In the factor analysis, the data were well fit to a five factor model. For subjects multiply (but not singly) exposed to anaesthesia, a factor reflecting motor skills, visual-motor integration, and processing speed was significantly lower [standardised difference of -0.35 (95% confidence interval {CI} -0.57 to -0.13)] compared with unexposed subjects. No other factor was associated with exposure. Three groups were identified in the cluster analysis, with 106 subjects (10.6%) in Cluster A (lowest performance in most tests), 557 (55.9%) in Cluster B, and 334 (33.5%) in Cluster C (highest performance in most tests). The odds of multiply exposed children belonging to Cluster A was 2.83 (95% CI: 1.49-5.35; P=0.001) compared with belonging to Cluster B; there was no other significant association between exposure status and cluster membership., Conclusions: Multiple, but not single, exposures to procedures requiring general anaesthesia before age 3 yr are associated with a specific pattern of deficits in neuropsychological tests. Factors predicting which children develop the most pronounced deficits remain unknown., (Copyright © 2019 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.)

Background: It is not known whether the neurotoxicity produced by anaesthetics administered to young animals can also occur in children. Exposure of infant macaques to ketamine impairs performance in selected domains of the Operant Test Battery (OTB), which can also be administered to children. This study determined whether a similar pattern of results on the OTB is found in children exposed to procedures requiring general anaesthesia before age 3 yr., Methods: We analysed data from the Mayo Anesthesia Safety in Kids (MASK) study, in which unexposed, singly-exposed, and multiply-exposed children born in Olmsted County, MN, USA, from 1994 to 2007 were sampled using a propensity-guided approach and prospectively underwent OTB testing at ages 8-12 or 15-20 yr, using five tasks that generated 15 OTB test scores., Results: In primary analysis, none of the OTB test scores depended upon anaesthesia exposure status when corrected for multiple comparisons. Cluster analysis identified four clusters of subjects, with cluster membership determined by relative performance on the OTB tasks. There was no evidence of association between exposure status and cluster membership. Exploratory factor analysis showed that the OTB scores loaded onto four factors. The score for one factor was significantly less in multiply-exposed children (mean standardised difference -0.28 [95% confidence interval, -0.55 to -0.01; P=0.04]), but significance did not survive a sensitivity analysis accounting for outlying values., Conclusions: These findings provide little evidence to support the hypothesis that children exposed to procedures requiring anaesthesia show deficits on OTB tasks that are similar to those observed in non-human primates., (Copyright © 2019 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.)

Background: Few studies of how exposure of children to anesthesia may affect neurodevelopment employ comprehensive neuropsychological assessments. This study tested the hypothesis that exposure to multiple, but not single, procedures requiring anesthesia before age 3 yr is associated with adverse neurodevelopmental outcomes., Methods: Unexposed, singly exposed, and multiply exposed children born in Olmsted County, Minnesota, from 1994 to 2007 were sampled using a propensity-guided approach and underwent neuropsychological testing at ages 8 to 12 or 15 to 20 yr. The primary outcome was the Full-Scale intelligence quotient standard score of the Wechsler Abbreviated Scale of Intelligence. Secondary outcomes included individual domains from a comprehensive neuropsychological assessment and parent reports., Results: In total, 997 children completed testing (411, 380, and 206 unexposed, singly exposed, and multiply exposed, respectively). The primary outcome of intelligence quotient did not differ significantly according to exposure status; multiply exposed and singly exposed children scoring 1.3 points (95% CI, -3.8 to 1.2; P = 0.32) and 0.5 points (95% CI, -2.8 to 1.9; P = 0.70) lower than unexposed children, respectively. For secondary outcomes, processing speed and fine motor abilities were decreased in multiply but not singly exposed children; other domains did not differ. The parents of multiply exposed children reported increased problems related to executive function, behavior, and reading., Conclusions: Anesthesia exposure before age 3 yr was not associated with deficits in the primary outcome of general intelligence. Although secondary outcomes must be interpreted cautiously, they suggest the hypothesis that multiple, but not single, exposures are associated with a pattern of changes in specific neuropsychological domains that is associated with behavioral and learning difficulties.

Objective: Despite ample research documenting deficits in executive functioning for adults with chronic pain, the literature on pediatric patients with chronic pain is limited and provides mixed results. The current study sought to further investigate the nature of executive dysfunction in this population and also examine the relationships between pain intensity, duration, and catastrophizing with sustained attention, working memory, and self- and parent-report of executive functioning., Settings: Pediatric pain clinic and rehabilitation program., Participants: Forty adolescents with chronic pain and their parents participated in this study., Methods: Participants completed neuropsychological measures and standardized self-report questionnaires during a 45- to 60-minute testing session., Results: Fifty percent of this sample of adolescents with chronic pain demonstrated significant difficulties on at least one measure, with nine participants indicating difficulties on multiple measures. Pain significantly increased during the testing session. Pain variables of intensity, duration, and catastrophizing are related to sustained attention and working memory., Conclusions: This study adds support to previous findings suggesting subclinical struggles with executive functioning for adolescents with chronic pain. One-half of the sample indicated difficulties in either sustained attention and/or working memory. Future studies that would more thoroughly examine more complex executive functioning skills in this population would be helpful to further guide multidisciplinary treatment of these patients, particularly regarding whether or not school accommodations are warranted., (© 2017 American Academy of Pain Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com)

Background: Exposure of young animals to general anesthesia causes neurodegeneration and lasting behavioral abnormalities; whether these findings translate to children remains unclear. This study used a population-based birth cohort to test the hypothesis that multiple, but not single, exposures to procedures requiring general anesthesia before age 3 yr are associated with adverse neurodevelopmental outcomes., Methods: A retrospective study cohort was assembled from children born in Olmsted County, Minnesota, from 1996 to 2000 (inclusive). Propensity matching selected children exposed and not exposed to general anesthesia before age 3 yr. Outcomes ascertained via medical and school records included learning disabilities, attention-deficit/hyperactivity disorder, and group-administered ability and achievement tests. Analysis methods included proportional hazard regression models and mixed linear models., Results: For the 116 multiply exposed, 457 singly exposed, and 463 unexposed children analyzed, multiple, but not single, exposures were associated with an increased frequency of both learning disabilities and attention-deficit/hyperactivity disorder (hazard ratio for learning disabilities = 2.17 [95% CI, 1.32 to 3.59], unexposed as reference). Multiple exposures were associated with decreases in both cognitive ability and academic achievement. Single exposures were associated with modest decreases in reading and language achievement but not cognitive ability., Conclusions: These findings in children anesthetized with modern techniques largely confirm those found in an older birth cohort and provide additional evidence that children with multiple exposures are more likely to develop adverse outcomes related to learning and attention. Although a robust association was observed, these data do not determine whether anesthesia per se is causal.

Cognitive and behavioural comorbidities are often seen in children with epilepsy, and are more common and severe in refractory epilepsy. These comorbidities are associated with worse quality of life, increased behavioural and language problems and worse social skills, all of which adversely affect long-term psychosocial functioning. To enable early intervention and therapy, children and teens with epilepsy should be periodically screened for cognitive comorbidities. The location of the epileptic focus can, to a certain degree, predict the type(s) of comorbidity; however, the spectrum of disability is often broad, presumably because focal perturbations can cause network dysfunction. Comorbidities often result from underlying structural or functional pathology that has led to seizures. In selected cases, therapy targeting the underlying cause, such as the ketogenic diet for GLUT1 deficiency syndromes, may be remarkably effective in ameliorating both seizures and cognitive concerns. In many cases, however, cognitive impairment persists despite seizure control. In epileptic encephalopathies, frequent seizures and/or interictal epileptiform abnormalities exacerbate neurocognitive dysfunction, owing to synaptic reorganization or impaired neurogenesis, or to other effects on developing neural circuits, and prompt initiation of effective antiepileptic therapy is essential to limit cognitive comorbidities.

Exposure to general anesthesia at an early age has been associated with adverse neurodevelopmental outcomes in both animal and human studies, but some of these studies employed anesthetic agents that are no longer in clinical use. In this manuscript, we describe the methods used to construct a new population-based study cohort to study the association between early anesthetic exposure and subsequent neurodevelopmental outcomes. A birth cohort of all children born in Olmsted County, MN from January 1, 1996 to December 31, 2000 was identified. For each, school enrollment status in the Independent School District (ISD) 535 at age 5 or 6 and all episodes of anesthetic exposure before age 3 were identified. A study cohort was created by matching children enrolled in ISD 535 based on the propensity of receiving general anesthesia. Three analyses were performed to characterize the study cohort by comparing the birth and parental information, comorbidities, and socioeconomic status. The first analysis compared the characteristics of birth cohort children who were and were not enrolled in ISD 535. The second analysis evaluated the success of the propensity matching schemes in creating groups of children that were similar in measured characteristics except for anesthesia exposure. The third analysis compared the characteristics of children with anesthesia exposures who were and were not included in the final cohort based on propensity matching. Results of these analyses demonstrate only slight differences among the comparison groups, and therefore these are unlikely to compromise our future analysis of anesthetic exposure and neurodevelopmental outcomes.

There is increasing evidence that exposure of developing brains in animals, including nonhuman primates, to commonly-utilized anesthetic agents may cause adverse effects on cognition and behavior. In this paper, we summarize our methodology for a population-based, propensity-matched study to evaluate possible anesthesia-related sequelae in preschool children when evaluated in elementary or high school. A cohort of all children born in Olmsted County, Minnesota between the years 1994 and 2007 who are currently local residents has been identified. Existing medical records are being used to identify all episodes of exposure to general anesthesia prior to the age of 3 years (i.e., prior to their 3rd birthday). Children with multiple, single, and no anesthesia exposure are sampled for testing between the ages of 8 and 12 years or 15 and 19 years during the period 2012-2016. To match children in different exposure groups as closely as possible, sampling is guided by propensity-matching for the likelihood of receiving anesthesia. Selected children are invited to participate in a single 4-hour session of neuropsychological testing, including the National Center for Toxicological Research-Operant Test Battery, which has been used to study anesthetic neurotoxicity in nonhuman primates. The results of this testing will be compared among children with different anesthetic exposure histories. The expected products of this research will be a detailed phenotype of possible anesthetic-associated neurotoxicity in humans, utilizing a robust patient database and neuropsychological testing battery, and the first comparison of effects of anesthetic exposure in children and nonhuman primates performing nearly identical behavioral tasks., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Objectives: The objective of this post-hoc exploratory analysis was to examine the relationship between age and measures of cortical excitability and inhibition., Methods: Forty-six participants (24 with major depressive disorder and 22 healthy controls) completed MT, SICI, ICF, and CSP testing in a cross-sectional protocol. Of these 46 participants, 33 completed LICI testing. Multiple linear robust regression and Spearman partial correlation coefficient were used to examine the relationship between age and the TMS measures., Results: In the overall sample of 46 participants, age had a significant negative relationship with motor threshold (MT) in both the right (r s = -0.49, adjusted p = 0.007; β = -0.08, adjusted p = 0.001) and left (r s = -0.42, adjusted p = 0.029; β = -0.05, adjusted p = 0.004) hemispheres. This significant negative relationship of age with MT was also observed in the sample of depressed youth in both the right (r s = -0.70, adjusted p = 0.002; β = -0.09, adjusted p = 0.001) and left (r s = -0.54, adjusted p = 0.034; β = -0.05, adjusted p = 0.017) hemispheres, but not in healthy controls. In the sample of the 33 participants who completed LICI testing, age had a significant negative relationship with LICI (200 ms interval) in both the right (r s = -0.48, adjusted p = 0.05; β = -0.24, adjusted p = 0.007) and left (r s = -0.64, adjusted p = 0.002; β = -0.23, adjusted p = 0.001) hemispheres. This negative relationship between age and LICI (200 ms interval) was also observed in depressed youth in both the right (r s = -0.76, adjusted p = 0.034; β = -0.35, adjusted p = 0.004) and left (r s = -0.92, adjusted p = 0.002; β = -0.25, adjusted p = 0.001) hemispheres., Conclusion: These findings suggest that younger children have higher MTs. This is more pronounced in depressed youth than healthy controls. LICI inhibition may also increase with age in youth.