Partnering With Patients, Caregivers, and Clinicians to Determine Research Priorities for Concussion.

Importance: Identifying 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. Objective: To prioritize concussion research questions from the perspectives of patients, caregivers, and clinicians. Design, Setting, and Participants: This 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. Exposures: The 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 Measures: Top 10 concussion research questions. Results: The 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 Relevance: This 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.

Normative and Psychometric Characteristics of the Health and Behavior Inventory Among Children With Mild Orthopedic Injury Presenting to the Emergency Department: Implications for Assessing Postconcussive Symptoms Using the Child Sport Concussion Assessment Tool 5th Edition (Child SCAT5).

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.

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.

N-Acetyl-Aspartate in the Dorsolateral Prefrontal Cortex Long After Concussion in Youth.

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 (H-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.

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.

Functional brain correlates of motor response inhibition in children with developmental coordination disorder and attention deficit/hyperactivity disorder.

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.

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.

The psychiatry resident research experience.

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.

Copy-number variations are enriched for neurodevelopmental genes in children with developmental coordination disorder.

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.

Atypical within- and between-hemisphere motor network functional connections in children with developmental coordination disorder and attention-deficit/hyperactivity disorder.

Developmental coordination disorder (DCD) and attention-deficit hyperactivity disorder (ADHD) are highly comorbid neurodevelopmental disorders; however, the neural mechanisms of this comorbidity are poorly understood. Previous research has demonstrated that children with DCD and ADHD have altered brain region communication, particularly within the motor network. The structure and function of the motor network in a typically developing brain exhibits hemispheric dominance. It is plausible that functional deficits observed in children with DCD and ADHD are associated with neurodevelopmental alterations in within- and between-hemisphere motor network functional connection strength that disrupt this hemispheric dominance. We used resting-state functional magnetic resonance imaging to examine functional connections of the left and right primary and sensory motor (SM1) cortices in children with DCD, ADHD and DCD + ADHD, relative to typically developing children. Our findings revealed that children with DCD, ADHD and DCD + ADHD exhibit atypical within- and between-hemisphere functional connection strength between SM1 and regions of the basal ganglia, as well as the cerebellum. Our findings further support the assertion that development of atypical motor network connections represents common and distinct neural mechanisms underlying DCD and ADHD. In children with DCD and DCD + ADHD (but not ADHD), a significant correlation was observed between clinical assessment of motor function and the strength of functional connections between right SM1 and anterior cingulate cortex, supplementary motor area, and regions involved in visuospatial processing. This latter finding suggests that behavioral phenotypes associated with atypical motor network development differ between individuals with DCD and those with ADHD.

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.

Zac1 Regulates the Differentiation and Migration of Neocortical Neurons via Pac1.

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.

Distinct patterns of cortical thinning in concurrent motor and attention disorders.

AIM: Many neurodevelopmental disorders co-occur yet are rarely studied in terms of brain development. Developmental coordination disorder (DCD) and attention-deficit-hyperactivity disorder (ADHD) co-occur at a high frequency and are associated with functional and structural brain alterations. The objective of this study was to examine whether the effects of comorbid motor and attention problems influence cortical thickness in children and whether the pattern of changes for concurrent disorders is distinct from the alterations seen in single disorders. METHOD: A total of 34 children (19 males, 15 females, mean age 9y 9mo, range 8-17y) who met the criteria for DCD (n=14), ADHD (n=10), or DCD+ADHD (n=10) were recruited into the study. Fourteen participants with typical development (eight males, six females, mean age 11y 9mo, range 8-17y) were also recruited for comparison. Participants underwent neuropsychological assessment and magnetic resonance imaging. Cortical thickness analysis was performed to determine the patterns of cortical thinning in each disorder, which was then compared across groups. RESULTS: Children with comorbid DCD+ADHD demonstrated more widespread decreases in cortical thickness than participants with a diagnosis of DCD or ADHD alone. Cortical thinning was found to be concentrated in the frontal, parietal, and temporal lobes, and was correlated with measures of motor and attentional functioning. INTERPRETATION: The co-occurrence of DCD+ADHD was associated with a distinct global pattern of regional cortical thickness decrease, highlighting the unique neurobiology of comorbid neurodevelopmental disorders. This novel feature of concurrent DCD and ADHD may help inform diagnostic definitions and provide clues to both the shared and the isolated genetic and environmental origins of motor and attention disorders.

Corpus callosal morphology in youth with bipolar depression.

OBJECTIVES: Recent evidence has demonstrated that corpus callosum maturation follows a similar developmental timeline to cognitive processes. Bipolar disorder (BD) has been associated with disruptions in error processing, response inhibition, and motor functioning, which are mediated by underlying white matter structures, including the corpus callosum. Disruptions in white matter integrity have been demonstrated in BD. However, it is unknown whether alterations in the developmental trajectory of the corpus callosum may contribute to cognitive impairments in the disorder. METHODS: We assessed the area of the corpus callosum and its subregions (the genu, rostral body, anterior and posterior bodies, isthmus, and splenium) in 14 treatment-naïve adolescents with BD (<21 years of age and in the depressed phase) and 18 healthy adolescent controls. RESULTS: In comparison with healthy controls, participants with BD demonstrated a significantly reduced overall corpus callosum area. We also noted smaller areas in the anterior and posterior mid-body of the corpus callosum in adolescents with BD. CONCLUSIONS: Our results suggest that commissural fibers of the corpus callosum are disrupted in early-onset BD. Specific decreases in the anterior and posterior mid-body callosal aspects may contribute to motor organization and inhibition deficits seen in BD. These findings are consistent with the involvement of inter-hemispheric tracts in early-onset BD, which may reflect an early deviation in white matter development.

Functional connectivity of neural motor networks is disrupted in children with developmental coordination disorder and attention-deficit/hyperactivity disorder.

Developmental coordination disorder (DCD) and attention deficit/hyperactivity disorder (ADHD) are prevalent childhood disorders that frequently co-occur. Evidence from neuroimaging research suggests that children with these disorders exhibit disruptions in motor circuitry, which could account for the high rate of co-occurrence. The primary objective of this study was to investigate the functional connections of the motor network in children with DCD and/or ADHD compared to typically developing controls, with the aim of identifying common neurophysiological substrates. Resting-state fMRI was performed on seven children with DCD, 21 with ADHD, 18 with DCD + ADHD and 23 controls. Resting-state connectivity of the primary motor cortex was compared between each group and controls, using age as a co-factor. Relative to controls, children with DCD and/or ADHD exhibited similar reductions in functional connectivity between the primary motor cortex and the bilateral inferior frontal gyri, right supramarginal gyrus, angular gyri, insular cortices, amygdala, putamen, and pallidum. In addition, children with DCD and/or ADHD exhibited different age-related patterns of connectivity, compared to controls. These findings suggest that children with DCD and/or ADHD exhibit disruptions in motor circuitry, which may contribute to problems with motor functioning and attention. Our results support the existence of common neurophysiological substrates underlying both motor and attention problems.

Glutamate alterations associated with transcranial magnetic stimulation in youth depression: a case series.

OBJECTIVE: We hypothesized an increase in dorsolateral prefrontal cortex (DLPFC) glutamate levels would occur after 3 weeks of repetitive transcranial magnetic stimulation (rTMS) treatment and a decrease in major depressive disorder (MDD) symptoms. METHODS: We report 6 patients (4 females) 15 to 21 years of age with treatment-resistant MDD. Participants had a mean (SD) age of 18.7 (1.95) years and a mean (SD) IQ of 102.3 (3.39). Short echo proton magnetic resonance spectroscopy (¹H-MRS) was used to quantify glutamate levels in the left DLPFC (4.5 cc) before and after rTMS treatment. Repetitive transcranial magnetic stimulation was localized to the left DLPFC and applied for 15 consecutive weekdays (120% resting motor threshold; 40 pulses over 4 seconds [10 Hz]; intertrain interval, 26 seconds; 75 trains; 3000 pulses). Treatment response was defined as a greater than 50% reduction in Hamilton Depression Rating Scale scores. Short echo proton magnetic resonance spectroscopy data were analyzed with LCModel to determine glutamate concentration. RESULTS: After rTMS, treatment responders (n = 4) showed an increase (relative to baseline) in left DLPFC glutamate levels (11%), which corresponded to an improvement in depressive symptom severity (68% Hamilton Depression Rating Scale score reduction). Treatment nonresponders (n = 2) had elevated baseline glutamate levels compared to responders in that same region, which decreased with rTMS (-10%). Procedures were generally well tolerated with no adverse events. CONCLUSIONS: Repetitive transcranial magnetic stimulation is feasible and possibly efficacious in adolescents with MDD. In responders, rTMS may act by induced elevations in elevating DFPLC glutamate levels in the left DLPFC, thereby leading to symptom improvement.

Cortical thickness in youth with major depressive disorder.

BACKGROUND: Studies in adults with major depressive disorder (MDD) have implicated dysregulation of frontal-limbic circuits in the symptomology of this disorder. We hypothesized that the middle frontal gyrus (MFG; a core portion of the dorsolateral prefrontal cortex or DLPFC) and the anterior cingulate (caudal), regions implicated in emotive and cognitive control, would display a reduced cortical thickness in youth with MDD as compared to healthy, non-depressed adolescents. METHODS: Sixteen healthy control adolescents (17.19 ± 1.87 years; 7 males, 9 females) and thirty MDD participants (16.89 ± 2.01 years; 9 males, 21 females) underwent magnetic resonance imaging (MRI). Cortical thickness analysis was carried out using FreeSurfer software. RESULTS: Counter to our hypothesis, we observed thicker right and left rostral MFG in MDD adolescents as compared to controls (p = 0.004 and p = 0.005, respectively). Furthermore, the left caudal anterior cingulate cortex was thicker in MDD subjects as compared to controls (p = 0.009). In MDD subjects, there was a significant inverse correlation between age and left MFG thickness (r = -0.45, p = 0.001). CONCLUSIONS: These results have implications for the developmental trajectory of the frontal lobe in adolescent MDD. The MFG is implicated in the frontal-limbic circuits underlying executive functioning and their interaction with affective processing. Alterations in this region are likely involved with the symptoms of MDD. Limitations include a small sample size and cross sectional design.

Common white matter microstructure alterations in pediatric motor and attention disorders.

OBJECTIVE: To characterize white matter alterations in children with isolated or concurrent developmental coordination disorder and/or attention-deficit/hyperactivity disorder (ADHD) compared with typically-developing controls, and to determine whether group differences on motor and attention tasks could be explained by differences in diffusion tensor imaging (DTI) measures. STUDY DESIGN: In a cohort of children (n = 85) with developmental coordination disorder, ADHD, or combined developmental coordination disorder+ADHD, we examined 3 major white matter tracts involved in attention and motor processes. Using DTI, the corpus callosum, superior longitudinal fasciculus, and cingulum were analyzed with respect to measures of white matter integrity. Differences in fractional anisotropy (FA), mean diffusivity, radial diffusivity, and axial diffusivity were analyzed using ANOVA. Motor and attentional functioning was assessed using standardized tests, and correlated to DTI measures. RESULTS: FA reductions were noted in the frontal regions of the corpus callosum for children with ADHD (P = .039), whereas children with developmental coordination disorder displayed similar reductions in regions of the corpus callosum underlying parietal brain regions (P = .040), as well as the left superior longitudinal fasciculus (P = .026). White matter integrity was impacted in both frontal and parietal regions for children with comorbid developmental coordination disorder+ADHD (P = .029; .046). FA was positively correlated with scores on both motor and attentional assessments in a region-specific manner. CONCLUSION: Our findings suggest that alterations in the corpus callosum underlie difficulties in motor and attention functioning. These changes are functionally and regionally distinct and could reflect a neurobiological basis for motor and attention disorders in children.

Disorder-specific volumetric brain difference in adolescent major depressive disorder and bipolar depression.

Structural abnormalities in frontal, limbic and subcortical regions have been noted in adults with both major depressive disorder (MDD) and bipolar disorder (BD). In the current study, we examined regional brain morphology in youth with MDD and BD as compared to controls. Regional brain volumes were measured in 32 MDD subjects (15.7 ± 2.1 years), 14 BD subjects (16.0 ± 2.4 years) and 22 healthy controls (16.0 ± 2.8 years) using magnetic resonance imaging (MRI). Regions of interest included the hippocampus, dorsolateral prefrontal cortex (DLPFC), anterior cingulate cortex (ACC), caudate, putamen and thalamus. Volumetric differences between groups were significant (F26,80 = 1.80, p = 0.02). Post-hoc analyses indicated that individuals with MDD showed reduced left hippocampus volumes (p = 0.048) as well as right ACC white and gray matter volumes (p = 0.003; p = 0.01) compared to controls. BD participants also displayed reduced left hippocampal and right/left putamen volumes compared to controls (p < 0.001; p = 0.015; p = 0.046 respectively). Interestingly, right and left ACC white matter volumes were smaller in MDD than in BD participants (p = 0.019; p = 0.045 respectively). No volumetric group differences were observed for the DLPFC and thalamus. Discriminant analysis was able to correctly classify 81.0 % of subjects as having BD or as MDD based on imaging data. Confirmation and extension of our findings requires larger sample sizes. Our findings provide new evidence of distinct, specific regional brain volumetric differences between MDD and BD that may be used to distinguish the two disorders.