Right Superior Frontal Gyrus Cortical Thickness in Pediatric ADHD.

OBJECTIVE: We investigated the right Superior Frontal Gyrus (right-SFG) and Anterior Cingulate Cortex (ACC) in children with ADHD and their clinical relevance with Executive Function (EF) and ADHD symptom severity. METHODS: About 26 children with ADHD and 24 typically developing children (TDC; 7‒16 years) underwent Magnetic Resonance Imaging (MRI) and completed an EF assessment battery. RESULTS: Significantly thinner right-SFG in the ADHD group was found compared to the TDC group (t (48) = 2.81, p = .007, Cohen's d = 0.84). Linear regression models showed that 12.5% of inattention, 13.6% of hyperactivity, and 9.0% of EF variance was accounted for by the right-SFG thickness. CONCLUSIONS: Differences in the right-SFG thickness were found in our ADHD group and were associated with parent ratings of inattentive and hyperactive symptoms as well with EF ratings. These results replicate previous findings of thinner right-SFG and are consistent with the delayed cortical maturation theory of ADHD.

Differences in neurometabolites and transcranial magnetic stimulation motor maps in children with attention-deficit/hyperactivity disorder.

BACKGROUND: Although much is known about cognitive dysfunction in attention-deficit/hyperactivity disorder (ADHD), few studies have examined the pathophysiology of disordered motor circuitry. We explored differences in neurometabolite levels and transcranial magnetic stimulation (TMS)-derived corticomotor representations among children with ADHD and typically developing children. METHODS: We used magnetic resonance spectroscopy (MRS) protocols to measure excitatory (glutamate + glutamine [Glx]) and inhibitory (γ-aminobutyric acid [GABA]) neurometabolite levels in the dominant primary motor cortex (M1) and the supplementary motor area (SMA) in children with ADHD and typically developing children. We used robotic neuronavigated TMS to measure corticospinal excitability and create corticomotor maps. RESULTS: We collected data from 26 medication-free children with ADHD (aged 7-16 years) and 25 typically developing children (11-16 years). Children with ADHD had lower M1 Glx (p = 0.044, d = 0.6); their mean resting motor threshold was lower (p = 0.029, d = 0.8); their map area was smaller (p = 0.044, d = 0.7); and their hotspot density was higher (p = 0.008, d = 0.9). M1 GABA levels were associated with motor map area (p = 0.036).Limitations: Some TMS data were lost because the threshold of some children exceeded 100% of the machine output. The relatively large MRS voxel required to obtain sufficient signal-to-noise ratio and reliably measure GABA levels encompassed tissue beyond the M1, making this measure less anatomically specific. CONCLUSION: The neurochemistry and neurophysiology of key nodes in the motor network may be altered in children with ADHD, and the differences appear to be related to each other. These findings suggest potentially novel neuropharmacological and neuromodulatory targets for ADHD.

Targeted Interventions in Tourette's using Advanced Neuroimaging and Stimulation (TITANS): study protocol for a double-blind, randomised controlled trial of transcranial magnetic stimulation (TMS) to the supplementary motor area in children with Tourette's syndrome.

INTRODUCTION: Tourette's syndrome (TS) affects approximately 1% of children. This study will determine the efficacy and safety of paired comprehensive behavioural intervention for tics (CBIT) plus repetitive transcranial magnetic stimulation (rTMS) treatment in children with Tourette's syndrome. We hypothesise that CBIT and active rTMS to the supplementary motor area (SMA) will (1) decrease tic severity, and (2) be associated with changes indicative of enhanced neuroplasticity (eg, changes in in vivo metabolite concentrations and TMS neurophysiology measures). METHODS AND ANALYSIS: This study will recruit 50 youth with TS, aged 6-18 for a phase II, double-blind, block randomised, sham-controlled trial comparing active rTMS plus CBIT to sham rTMS plus CBIT in a 1:1 ratio. The CBIT protocol is eight sessions over 10 weeks, once a week for 6 weeks and then biweekly. The rTMS protocol is 20 sessions of functional MRI-guided, low-frequency (1 Hz) rTMS targeted to the bilateral SMA over 5 weeks (weeks 2-6). MRI, clinical and motor assessments and neurophysiological evaluations including motor mapping will be performed 1 week before CBIT start, 1 week after rTMS treatment and 1 week after CBIT completion. The primary outcome measure is Tourette's symptom change from baseline to post-CBIT treatment, as measured by the Yale Global Tic Severity Scale. Secondary outcomes include changes in imaging, neurophysiological and behavioural markers. ETHICS AND DISSEMINATION: Ethical approval by the Conjoint Health Research Ethics Board (REB18-0220). The results of this study will be published in peer-reviewed scientific journals, on ClinicalTrials.gov and shared with the Tourette and OCD Alberta Network. The results will also be disseminated through the Alberta Addictions and Mental Health Research Hub. TRIAL REGISTRATION: NCT03844919.

Impact of COVID-19 on lifestyle habits and mental health symptoms in children with attention-deficit/hyperactivity disorder in Canada.

OBJECTIVES: The COVID-19 pandemic created an environment of restricted access to health and recreation services. Lifestyle habits including sleep, eating, exercise, and screen use were modified, potentially exacerbating adverse mental health outcomes. This study investigates the impact of COVID-19 on lifestyle habits and mental health symptoms in paediatric attention-deficit/hyperactivity disorder (ADHD) in Canada. METHODS: An online survey was distributed across Canada to caregivers of children with ADHD (children aged 5 to 18 years) assessing depression (PHQ-9), anxiety (GAD-7), ADHD (SNAP-IV), and lifestyle behaviours. Data were analyzed by gender (male/female) and age category (5 to 8, 9 to 12, and 13 to 18 years). Spearman's correlations between lifestyle habits and mental health outcomes were conducted. RESULTS: A total of 587 surveys were completed. Mean child age was 10.14 years (SD 3.06), including 166 females (28.3%). The PHQ-9 and GAD-7 indicated that 17.4% and 14.1% of children met criteria for moderately severe to severe depression and anxiety symptoms respectively. Children met SNAP-IV cut-off scores for inattention (73.7%), hyperactivity/impulsivity (66.8%), and oppositional defiant disorder (38.6%) behaviours. Caregivers reported changes in sleep (77.5%), eating (58.9%), exercise (83.7%), and screen use (92.9%) in their ADHD child, greatly impacting youth. Sleeping fewer hours/night, eating more processed foods, and watching TV/playing videogames >3.5 hours/day correlated with greater depression, anxiety and ADHD symptoms, and exercising <1 hour/day further correlated with depression symptoms (P<0.01). CONCLUSIONS: The COVID-19 pandemic has resulted in less healthy lifestyle habits and increased mental health symptoms in Canadian children with ADHD. Longitudinal studies to better understand the relationship between these factors are recommended.

Bilateral transcranial magnetic stimulation of the supplementary motor area in children with Tourette syndrome.

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.

Body mass index and variability in hippocampal volume in youth with major depressive disorder.

BACKGROUND: The hippocampus has been implicated in major depressive disorder (MDD), in both adults and youth. However, possible sources of variability for the hippocampus have not been well delineated. Here, we explored the relationship between body mass index (BMI) and hippocampal volume in youth with MDD. METHODS: Twenty-two controls (9 male, 13 female, 12-24 years), 24 youth with MDD and normal BMI (12 male, 12 female, 14-24 years), and 20 youth with MDD and high BMI (14 male, 6 female, 13-22 years) underwent magnetic resonance (MR) imaging and spectroscopy (1H-MRS). Hippocampal volume was determined through manual tracing of high-resolution anatomical T1 scans, and LCModel quantified neurochemical concentrations. Intracranial volume was used as a covariate in analysis to control for effects of brain volume on hippocampus. RESULTS: In youth with MDD and normal BMI, right hippocampal volume was reduced (p = 0.006, Bonferroni) and a trend for reduced left hippocampal volume was noted when compared to healthy controls (p = 0.054, Bonferroni). Left hippocampal volumes were negatively associated with BMI in youth with MDD and high BMI group (r = -0.593, p = 0.006). No associations were found between the right hippocampus and BMI and there were no group differences for metabolite concentrations. LIMITATIONS: Larger sample sizes would enable researchers to explore overweight vs obese groups and effect of sex in MDD-BMI groups. CONCLUSIONS: BMI may account for some of the variability observed in previous studies of hippocampal volume in MDD, and therefore BMI impacts should be considered in future analyses.

Neurochemical Correlates of Executive Function in Children with Attention-Deficit/Hyperactivity Disorder.

OBJECTIVES: Attention-Deficit/Hyperactivity Disorder (ADHD) is a prevalent neurodevelopmental disorder with no known biomarkers. The objectives of this study were 1) to investigate spectroscopic biomarkers in the right prefrontal cortex (R-PFC) and left striatum; 2) to evaluate Executive Function (EF) performance; and, 3) to examine the clinical relevance of glutamate in EF tasks. METHODS: A total of 21 children with ADHD (M = 10.41 years, SD = 1.41) and 15 controls without ADHD (M = 9.90 years, SD = 1.54 years) were enrolled. Short echo proton magnetic resonance spectroscopy (1H-MRS; TE = 30ms) was used to study the changes in the R-PFC and left striatum. Both groups completed an EF assessment battery, including working memory, inhibition, cognitive flexibility and verbal fluency tasks. RESULTS: In the R-PFC, independent t-tests found decreased concentration of glutamate (p = 0.009), NAA (p = 0.029) and choline (p = 0.016) in ADHD participants compared to controls. No significant differences were seen in the left striatum. Multivariate analysis of variance did not indicate overall EF challenges in the ADHD sample (p < .05). Positive correlations with glutamate concentration and EF performance in the control group were observed, however, no such correlations were reported in the ADHD group. CONCLUSIONS: The results indicated a subgroup of children with ADHD who presented with hypo-glutamatergic signalling in the R-PFC. Additionally, findings suggested a decoupling effect of glutamate in EF related tasks in children with ADHD compared to controls. Thus, glutamate concentration may be a possible ADHD biomarker and novel treatments target.

OBJECTIFS: Le trouble de déficit de l'attention avec hyperactivité (TDAH) est un trouble neurodéveloppemental prévalent sans biomarqueurs connus. Les objectifs de la présente étude étaient 1) de rechercher les biomarqueurs spectroscopiques du cortex préfrontal droit (CPF-D) et du striatum gauche; 2) d'évaluer le rendement de la fonction exécutive (FE); et 3) d'examiner la pertinence clinique du glutamate dans les tâches de la FE. MÉTHODES: Au total, 21 enfants souffrant du TDAH (M = 10,41 ans, ET = 1,41) et 15 témoins sans TDAH (M = 9,90 ans, ET = 1,54 an) ont été inscrits. La spectroscopie par résonance magnétique protonique à bref temps d'écho (1H-SRM; TE = 30 ms) a servi à étudier les changements dans le CPF-D et le striatum gauche. Les deux groupes ont passé une batterie de tests d'évaluation de la FE, dont les tâches de la mémoire de travail, l'inhibition, la flexibilité cognitive et la fluidité verbale. RÉSULTATS: Dans le CPF-D, les t-tests indépendants ont constaté une concentration réduite de glutamate (p = 0,009), de NAA (p = 0,029) et de choline (p = 0,016) chez les participants du TDAH comparés aux témoins. Aucune différence significative n'a été observée dans le striatum gauche. Des analyses multivariées de la variance n'ont pas indiqué de problèmes généraux pour la FE dans l'échantillon TDAH (p < 0,05). Des corrélations positives avec la concentration de glutamate et le rendement de la FE dans le groupe témoin ont été observées, toutefois, ces corrélations n'ont pas été observées dans le groupe du TDAH. CONCLUSIONS: Les résultats indiquaient un sous-groupe d'enfants souffrant du TDAH qui présentait un signal hypo-glutamatergique dans le CPF-D. En outre, les résultats suggéraient un effet de découplage du glutamate dans les tâches liées à la FE chez les enfants souffrant du TDAH comparés aux témoins. Ainsi, la concentration de glutamate peut être un biomarqueur du TDAH et une nouvelle cible de traitement.

National Analysis of Risk Assessment Content in Prenatal Records Across Canada.

Each Canadian province/territory has a distinct prenatal record form to guide maternity health care. Because there is no national oversight of these forms, little is known about how they compare regarding content on risk assessment for adverse perinatal outcomes. We cataloged and compared the risk factors that are captured on prenatal record forms across Canada. Nine out of 12 records included risk sections, with an average of 35 risk items. We identified 100 prenatal risk factors and categorized them as medical (73%), lifestyle (11%), psychosocial (11%), or personal (5%). Where present, clinical definitions for risk factors often varied. The substantial differences in risk assessment content in the prenatal record forms may contribute to differences in health care quality among provinces. The development of standardized national guidelines for prenatal risk assessment may be a valuable goal.

Repetitive Transcranial Magnetic Stimulation in Youth With Treatment Resistant Major Depression.

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.

History of suicide attempt and right superior temporal gyrus volume in youth with treatment-resistant major depressive disorder.

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.

Academic Productivity in Psychiatry: Benchmarks for the H-Index.

OBJECTIVE: Bibliometrics play an increasingly critical role in the assessment of faculty for promotion and merit increases. Bibliometrics is the statistical analysis of publications, aimed at evaluating their impact. The objective of this study is to describe h-index and citation benchmarks in academic psychiatry. METHODS: Faculty lists were acquired from online resources for all academic departments of psychiatry listed as having residency training programs in Canada (as of June 2016). Potential authors were then searched on Web of Science (Thomson Reuters) for their corresponding h-index and total number of citations. RESULTS: The sample included 1683 faculty members in academic psychiatry departments. Restricted to those with a rank of assistant, associate, or full professor resulted in 1601 faculty members (assistant = 911, associate = 387, full = 303). h-index and total citations differed significantly by academic rank. Both were highest in the full professor rank, followed by associate, then assistant. The range in each, however, was large. CONCLUSIONS: This study provides the initial benchmarks for the h-index and total citations in academic psychiatry. Regardless of any controversies or criticisms of bibliometrics, they are increasingly influencing promotion, merit increases, and grant support. As such, benchmarking by specialties is needed in order to provide needed context.

A pilot study of hippocampal N-acetyl-aspartate in youth with treatment resistant major depression.

BACKGROUND: Smaller hippocampal volumes, as assessed by magnetic resonance imaging (MRI), and proton magnetic resonance spectroscopy (1H-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 1H-MRS and MRI on a 3T scanner. A short echo PRESS protocol was used with voxels in the right and left hippocampi (6mL each). Hippocampal volume was evaluated using FreeSurfer. RESULTS: Compared with the typically developing group, youth with TRD had lower concentrations of N-acetyl-aspartate 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.

Proton spectroscopy study of the dorsolateral prefrontal cortex in youth with familial depression.

AIM: Structural, 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. METHODS: Seventeen 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. RESULTS: There 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). CONCLUSION: Increased 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.

Pannexin 1 regulates postnatal neural stem and progenitor cell proliferation.

BACKGROUND: Pannexin 1 forms ion and metabolite permeable hexameric channels and is abundantly expressed in the brain. After discovering pannexin 1 expression in postnatal neural stem and progenitor cells we sought to elucidate its functional role in neuronal development. RESULTS: We detected pannexin 1 in neural stem and progenitor cells in vitro and in vivo. We manipulated pannexin 1 expression and activity in Neuro2a neuroblastoma cells and primary postnatal neurosphere cultures to demonstrate that pannexin 1 regulates neural stem and progenitor cell proliferation likely through the release of adenosine triphosphate (ATP). CONCLUSIONS: Permeable to ATP, a potent autocrine/paracine signaling metabolite, pannexin 1 channels are ideally suited to influence the behavior of neural stem and progenitor cells. Here we demonstrate they play a robust role in the regulation of neural stem and progenitor cell proliferation. Endogenous postnatal neural stem and progenitor cells are crucial for normal brain health, and their numbers decline with age. Furthermore, these special cells are highly responsive to neurological injury and disease, and are gaining attention as putative targets for brain repair. Therefore, understanding the fundamental role of pannexin 1 channels in neural stem and progenitor cells is of critical importance for brain health and disease.