Smartphone App-Delivered Mindfulness-Based Intervention for Mild Traumatic Brain Injury in Adolescents: Protocol for a Feasibility Randomized Controlled Trial.

BACKGROUND: Concussion in children and adolescents is a significant public health concern, with 30% to 35% of patients at risk for prolonged emotional, cognitive, sleep, or physical symptoms. These symptoms negatively impact a child's quality of life while interfering with their participation in important neurodevelopmental activities such as schoolwork, socializing, and sports. Early psychological intervention following a concussion may improve the ability to regulate emotions and adapt to postinjury symptoms, resulting in the greater acceptance of change; reduced stress; and recovery of somatic, emotional, and cognitive symptoms. OBJECTIVE: The primary objective of this study is to assess the feasibility of conducting a parallel-group (1:1) randomized controlled trial (RCT) to evaluate a digital therapeutics (DTx) mindfulness-based intervention (MBI) in adolescents aged 12 to <18 years. The attention-matched comparator intervention (a math game also used in previous RCTs) will be delivered on the same DTx platform. Both groups will be provided with the standard of care guidelines. The secondary objective is to examine intervention trends for quality of life; resilience; self-efficacy; cognition such as attention, working memory, and executive functioning; symptom burden; and anxiety and depression scores at 4 weeks after concussion, which will inform a more definitive RCT. A subsample will be used to examine whether those randomized to the experimental intervention group have different brain-based imaging patterns compared with those randomized to the control group. METHODS: This study is a double-blind Health Canada-regulated trial. A total of 70 participants will be enrolled within 7 days of concussion and randomly assigned to receive the 4-week DTx MBI (experimental group) or comparator intervention. Feasibility will be assessed based on the recruitment rate, treatment adherence to both interventions, and retention. All outcome measures will be evaluated before the intervention (within 7 days after injury) and at 1, 2, and 4 weeks after the injury. A subset of 60 participants will undergo magnetic resonance imaging within 72 hours and at 4 weeks after recruitment to identify the neurophysiological mechanisms underlying the potential benefits from MBI training in adolescents following a concussion. RESULTS: The recruitment began in October 2022, and the data collection is expected to be completed by September 2024. Data collection and management is still in progress; therefore, data analysis is yet to be conducted. CONCLUSIONS: This trial will confirm the feasibility and resolve uncertainties to inform a future definitive multicenter efficacy RCT. If proven effective, a smartphone-based MBI has the potential to be an accessible and low-risk preventive treatment for youth at risk of experiencing prolonged postconcussion symptoms and complications. TRIAL REGISTRATION: ClinicalTrials.gov NCT05105802; https://classic.clinicaltrials.gov/ct2/show/NCT05105802. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/57226.

Results of the 2023 ISBI challenge to reduce GABA-edited MRS acquisition time.

PURPOSE: Use a conference challenge format to compare machine learning-based gamma-aminobutyric acid (GABA)-edited magnetic resonance spectroscopy (MRS) reconstruction models using one-quarter of the transients typically acquired during a complete scan. METHODS: There were three tracks: Track 1: simulated data, Track 2: identical acquisition parameters with in vivo data, and Track 3: different acquisition parameters with in vivo data. The mean squared error, signal-to-noise ratio, linewidth, and a proposed shape score metric were used to quantify model performance. Challenge organizers provided open access to a baseline model, simulated noise-free data, guides for adding synthetic noise, and in vivo data. RESULTS: Three submissions were compared. A covariance matrix convolutional neural network model was most successful for Track 1. A vision transformer model operating on a spectrogram data representation was most successful for Tracks 2 and 3. Deep learning (DL) reconstructions with 80 transients achieved equivalent or better SNR, linewidth and fit error compared to conventional 320 transient reconstructions. However, some DL models optimized linewidth and SNR without actually improving overall spectral quality, indicating a need for more robust metrics. CONCLUSION: DL-based reconstruction pipelines have the promise to reduce the number of transients required for GABA-edited MRS.

Linewidth-related bias in modelled concentration estimates from GABA-edited 1H-MRS.

J-difference-edited MRS is widely used to study GABA in the human brain. Editing for low-concentration target molecules (such as GABA) typically exhibits lower signal-to-noise ratio (SNR) than conventional non-edited MRS, varying with acquisition region, volume and duration. Moreover, spectral lineshape may be influenced by age-, pathology-, or brain-region-specific effects of metabolite T2, or by task-related blood-oxygen level dependent (BOLD) changes in functional MRS contexts. Differences in both SNR and lineshape may have systematic effects on concentration estimates derived from spectral modelling. The present study characterises the impact of lineshape and SNR on GABA+ estimates from different modelling algorithms: FSL-MRS, Gannet, LCModel, Osprey, spant and Tarquin. Publicly available multi-site GABA-edited data (222 healthy subjects from 20 sites; conventional MEGA-PRESS editing; TE = 68 ms) were pre-processed with a standardised pipeline, then filtered to apply controlled levels of Lorentzian and Gaussian linebroadening and SNR reduction. Increased Lorentzian linewidth was associated with a 2-5% decrease in GABA+ estimates per Hz, observed consistently (albeit to varying degrees) across datasets and most algorithms. Weaker, often opposing effects were observed for Gaussian linebroadening. Variations are likely caused by differing baseline parametrization and lineshape constraints between models. Effects of linewidth on other metabolites (e.g., Glx and tCr) varied, suggesting that a linewidth confound may persist after scaling to an internal reference. These findings indicate a potentially significant confound for studies where linewidth may differ systematically between groups or experimental conditions, e.g. due to T2 differences between brain regions, age, or pathology, or varying T2* due to BOLD-related changes. We conclude that linewidth effects need to be rigorously considered during experimental design and data processing, for example by incorporating linewidth into statistical analysis of modelling outcomes or development of appropriate lineshape matching algorithms.

Longitudinal changes in brain metabolites following pediatric concussion.

Concussion is commonly characterized by a cascade of neurometabolic changes following injury. Magnetic Resonance Spectroscopy (MRS) can be used to quantify neurometabolites non-invasively. Longitudinal changes in neurometabolites have rarely been studied in pediatric concussion, and fewer studies consider symptoms. This study examines longitudinal changes of neurometabolites in pediatric concussion and associations between neurometabolites and symptom burden. Participants who presented with concussion or orthopedic injury (OI, comparison group) were recruited. The first timepoint for MRS data collection was at a mean of 12 days post-injury (n = 545). Participants were then randomized to 3 (n = 243) or 6 (n = 215) months for MRS follow-up. Parents completed symptom questionnaires to quantify somatic and cognitive symptoms at multiple timepoints following injury. There were no significant changes in neurometabolites over time in the concussion group and neurometabolite trajectories did not differ between asymptomatic concussion, symptomatic concussion, and OI groups. Cross-sectionally, Choline was significantly lower in those with persistent somatic symptoms compared to OI controls at 3 months post-injury. Lower Choline was also significantly associated with higher somatic symptoms. Although overall neurometabolites do not change over time, choline differences that appear at 3 months and is related to somatic symptoms.

Cortical glutamate, Glx, and total N-acetylaspartate: potential biomarkers of repetitive transcranial magnetic stimulation treatment response and outcomes in major depression.

Repetitive transcranial magnetic stimulation (rTMS) is an effective treatment for individuals with major depressive disorder (MDD) who have not improved with standard therapies. However, only 30-45% of patients respond to rTMS. Predicting response to rTMS will benefit both patients and providers in terms of prescribing and targeting treatment for maximum efficacy and directing resources, as individuals with lower likelihood of response could be redirected to more suitable treatment alternatives. In this exploratory study, our goal was to use proton magnetic resonance spectroscopy to examine how glutamate (Glu), Glx, and total N-acetylaspartate (tNAA) predict post-rTMS changes in overall MDD severity and symptoms, and treatment response. Metabolites were measured in a right dorsal anterior cingulate cortex voxel prior to a standard course of 10 Hz rTMS to the left DLPFC in 25 individuals with MDD. MDD severity and symptoms were evaluated via the Inventory of Depression Symptomatology Self-Report (IDS-SR). rTMS response was defined as ≥50% change in full-scale IDS-SR scores post treatment. Percent change in IDS-SR symptom domains were evaluated using principal component analysis and established subscales. Generalized linear and logistic regression models were used to evaluate the relationship between baseline Glu, Glx, and tNAA and outcomes while controlling for age and sex. Participants with baseline Glu and Glx levels in the lower range had greater percent change in full scale IDS-SR scores post-treatment (p < 0.001), as did tNAA (p = 0.007). Low glutamatergic metabolite levels also predicted greater percent change in mood/cognition symptoms (p ≤ 0.001). Low-range Glu, Glx, and tNAA were associated with greater improvement on the immuno-metabolic subscale (p ≤ 0.003). Baseline Glu predicted rTMS responder status (p = 0.025) and had an area under the receiving operating characteristic curve of 0.81 (p = 0.009), demonstrating excellent discriminative ability. Baseline Glu, Glx, and tNAA significantly predicted MDD improvement after rTMS; preliminary evidence also demonstrates metabolite association with symptom subdomain improvement post-rTMS. This work provides feasibility for a personalized medicine approach to rTMS treatment selection, with individuals with Glu levels in the lower range potentially being the best candidates.

Brain Glutamate Dynamics Predict Positive Agency in Healthy Women: Insights from Combined Application of Pharmacological Challenge, Comprehensive Affective Assessment, and Magnetic Resonance Spectroscopy.

Contributions of brain glutamate (Glu) to conscious emotion are not well understood. Here, we evaluate the relationship of experimentally induced change in neocortical Glu (ΔGlu) and subjective states in well individuals, using combined application of pharmacological challenge, magnetic resonance spectroscopy (MRS), and comprehensive affective assessment. Drug challenge with d-amphetamine (AMP) (20 mg oral), methamphetamine (MA) (Desoxyn, 20 mg oral), and placebo (PBO) was conducted on three separate test days in a within-subjects double blind design. Proton MRS quantified neurometabolites in the right dorsal anterior cingulate cortex 140-150 min post-drug and PBO. Subjective states were assessed at half hour intervals over 5.5 h on each session, yielding 3792 responses per participant (91,008 responses overall, N = 24 participants), with self-reports reduced by principal components analysis (PCA). PCA produced a primary factor score of AMP- and MA-induced positive agency (ΔPA). MRS indicated drug-induced ΔGlu related positively to ΔPA (ΔGluMA r = +0.44, p < 0.05, N = 21), with large effects in females (ΔGluMA r = +0.52, p < 0.05; ΔGluAMP r = +0.61, p < 0.05, N = 11). Subjective states related to ΔGlu included rise in subjective stimulation, vigor, friendliness, elation, positive mood, positive affect (r's = +0.51 to +0.74, p < 0.05), and alleviation of anxiety in females (r = -0.61, p < 0.05, N = 11). These self-reports correlated with ΔGlu to the extent they loaded on ΔPA (r = 0.95 AMP, p = 5 × 10-10; r = 0.63 MA, p = 0.0015, N = 11), indicating the coherence of ΔGlu effects on emotional states. Timing data indicated Glu shaped positive emotion both concurrently and prospectively, with no relationship with pre-MRS emotion (ΔGluAMP r = +0.59 to +0.65, p's < 0.05; ΔGluMA r = +0.53, p < 0.05, N = 11). Together these findings indicate substantive, mechanistic contributions of neocortical Glu to positive agentic states in healthy individuals, which are most readily observed in women. The findings illustrate the promise of combined application of pharmacological challenge, comprehensive affective assessment, and MRS neuroimaging techniques in basic and clinical studies.

Brain Glutamate Dynamics Predict Positive Agency in Healthy Women.

Contributions of brain glutamate to conscious emotion are not well understood. Here we evaluate the relationship of experimentally-induced change in neocortical glutamate (ΔGlu) and subjective states in well individuals. Drug challenge with d-amphetamine (AMP; 20 mg oral), methamphetamine (MA; Desoxyn®, 20 mg oral), and placebo (PBO) was conducted on three separate test days in a within-subjects double blind design. Proton magnetic resonance spectroscopy (MRS) quantified neurometabolites in the right dorsal anterior cingulate cortex (dACC) 140-150 m post-drug and PBO. Subjective states were assessed at half hour intervals over 5.5-hours on each session, yielding 3,792 responses per participant (91,008 responses overall, N=24 participants). Self-reports were reduced by principal components analysis to a single factor score of AMP- and MA-induced Positive Agency (ΔPA) in each participant. We found drug-induced ΔGlu related positively with ΔPA (ΔGluMA r=+.44, p<.05, N=21), with large effects in females (ΔGluMA r=+.52, p<.05; ΔGluAMP r=+.61, p<.05, N=11). States related to ΔGlu in females included rise in subjective stimulation, vigor, friendliness, elation, positive mood, positive affect (r's=+.51 to +.74, p<.05), and alleviation of anxiety (r=-.61, p<.05, N=11). Self-reports correlated with DGlu to the extent they loaded on ΔPA (r=.95 AMP, p=5×10-10; r=.63 MA, p=.0015, N=11), indicating coherence of ΔGlu effects. Timing data indicated Glu shaped emotion both concurrently and prospectively, with no relationship to pre-MRS emotion (ΔGluAMP r=+.59 to +.65, p's<.05; ΔGluMA r=+.53, p<.05, N=11). Together these findings indicate substantive, mechanistic contributions of neocortical Glu to positive agentic states in healthy individuals, most readily observed in women.

Comparison of different approaches to manage multi-site magnetic resonance spectroscopy clinical data analysis.

Introduction: The effects caused by differences in data acquisition can be substantial and may impact data interpretation in multi-site/scanner studies using magnetic resonance spectroscopy (MRS). Given the increasing use of multi-site studies, a better understanding of how to account for different scanners is needed. Using data from a concussion population, we compare ComBat harmonization with different statistical methods in controlling for site, vendor, and scanner as covariates to determine how to best control for multi-site data. Methods: The data for the current study included 545 MRS datasets to measure tNAA, tCr, tCho, Glx, and mI to study the pediatric concussion acquired across five sites, six scanners, and two different MRI vendors. For each metabolite, the site and vendor were accounted for in seven different models of general linear models (GLM) or mixed-effects models while testing for group differences between the concussion and orthopedic injury. Models 1 and 2 controlled for vendor and site. Models 3 and 4 controlled for scanner. Models 5 and 6 controlled for site applied to data harmonized by vendor using ComBat. Model 7 controlled for scanner applied to data harmonized by scanner using ComBat. All the models controlled for age and sex as covariates. Results: Models 1 and 2, controlling for site and vendor, showed no significant group effect in any metabolites, but the vendor and site were significant factors in the GLM. Model 3, which included a scanner, showed a significant group effect for tNAA and tCho, and the scanner was a significant factor. Model 4, controlling for the scanner, did not show a group effect in the mixed model. The data harmonized by the vendor using ComBat (Models 5 and 6) had no significant group effect in both the GLM and mixed models. Lastly, the data harmonized by the scanner using ComBat (Model 7) showed no significant group effect. The individual site data suggest there were no group differences. Conclusion: Using data from a large clinical concussion population, different analysis techniques to control for site, vendor, and scanner in MRS data yielded different results. The findings support the use of ComBat harmonization for clinical MRS data, as it removes the site and vendor effects.

Changes in brain metabolite levels across childhood.

Metabolites play important roles in brain development and their levels change rapidly in the prenatal period and during infancy. Metabolite levels are thought to stabilize during childhood, but the development of neurochemistry across early-middle childhood remains understudied. We examined the developmental changes of key metabolites (total N-acetylaspartate, tNAA; total choline, tCho; total creatine, tCr; glutamate+glutamine, Glx; and myo-inositol, mI) using short echo-time magnetic resonance spectroscopy (MRS) in the anterior cingulate cortex (ACC) and the left temporo-parietal cortex (LTP) using a mixed cross-sectional/longitudinal design in children aged 2-11 years (ACC: N = 101 children, 112 observations; LTP: N = 95 children, 318 observations). We found that tNAA increased with age in both regions, while tCho decreased with age in both regions. tCr increased with age in the LTP only. Glx did not show linear age effects in either region, but a follow-up analysis in participants with ≥3 datapoints in the LTP revealed a quadratic effect of age following an inverted U-shape. These substantial changes in neurochemistry throughout childhood likely underlie various processes of structural and functional brain development.

Changes in Brain GABA and Glutamate and Improvements in Physical Functioning Following Intensive Pain Rehabilitation in Youth With Chronic Pain.

Intensive interdisciplinary pain treatments (IIPT) have been developed to treat youth with unmanaged chronic pain and functional disability. Dysregulation of metabolites gamma-aminobutyric acid (GABA) and glutamate are thought to play a role in the chronification of pain due to imbalances in inhibition and excitation in adults. Using magnetic resonance spectroscopy (MRS), we investigated the effect of IIPT on GABA and Glx (glutamate + glutamine) in 2 pain-related brain regions: the left posterior insula (LPI) and the anterior cingulate cortex (ACC). Data were collected in 23 youth (mean age = 16.09 ± 1.40, 19 female) at entry and discharge from a hospital-based outpatient IIPT. GABA and Glx were measured using GABA-edited MEGA-PRESS and analyzed using Gannet. Physical measures including a 6-minute walk test were recorded, and patients completed the PLAYSelf Physical Literacy Questionnaire, PROMIS Pain Interference Questionnaire, and Functional Disability Inventory. LPI GABA (P < .05) significantly decreased, but not ACC GABA (P > .05), following IIPT. There were no significant Glx changes (P > .05). The decrease in LPI GABA was associated with increased distance in the 6-minute walk test (P < .001). IIPT may decrease GABAergic inhibitory tone within the LPI, thereby promoting plasticity and contributing to improvements in physical outcomes with IIPT. PERSPECTIVE: Regional GABA changes are associated with a reduction in pain interference and improvement in physical function in youth following intensive pain rehabilitation. GABA may serve as a possible biomarker for IIPT; and may also further aid in the development of IIPT, and other treatments for chronic pain in youth.

Functional Changes in GABA and Glutamate during Motor Learning.

Functional magnetic resonance spectroscopy (fMRS) of GABA at 3 T poses additional challenges compared with fMRS of other metabolites because of the difficulties of measuring GABA levels; GABA is present in the brain at relatively low concentrations, and its signal is overlapped by higher concentration metabolites. Using 7 T fMRS, GABA levels have been shown to decrease specifically during motor learning (and not during a control task). Though the use of 7 T is appealing, access is limited. For GABA fMRS to be widely accessible, it is essential to develop this method at 3 T. Nine healthy right-handed participants completed a motor learning and a control button-pressing task. fMRS data were acquired from the left sensorimotor cortex during the task using a continuous GABA-edited MEGA-PRESS acquisition at 3 T. We found no significant changes in GABA+/tCr, Glx/tCr, or Glu/tCr levels in either task; however, we show a positive relationship between motor learning and glutamate levels both at rest and at the start of the task. Though further refinement and validation of this method is needed, this study represents a further step in using fMRS at 3 T to probe GABA levels in both healthy cognition and clinical disorders.

Consistency of frontal cortex metabolites quantified by magnetic resonance spectroscopy within overlapping small and large voxels.

Single voxel magnetic resonance spectroscopy (MRS) quantifies metabolites within a specified volume of interest. MRS voxels are constrained to rectangular prism shapes. Therefore, they must define a small voxel contained within the anatomy of interest or include not of interest neighbouring tissue. When studying cortical regions without clearly demarcated boundaries, e.g. the dorsolateral prefrontal cortex (DLPFC), it is unclear how representative a larger voxel is of a smaller volume within it. To determine if a large voxel is representative of a small voxel placed within it, this study quantified total N-Acetylaspartate (tNAA), choline, glutamate, Glx (glutamate and glutamine combined), myo-inositol, and creatine in two overlapping MRS voxels in the DLPFC, a large (30×30x30 mm) and small (15×15x15 mm) voxel. Signal-to-noise ratio (SNR) and tissue type factors were specifically investigated. With water-referencing, only myo-inositol was significantly correlated between the two voxels, while all metabolites showed significant correlations with creatine-referencing. SNR had a minimal effect on the correspondence between voxels, while tissue type showed substantial influence. This study demonstrates substantial variability of metabolite estimates within the DLPFC. It suggests that when small anatomical structures are of interest, it may be valuable to spend additional acquisition time to obtain specific, localized data.

Brain metabolites measured with magnetic resonance spectroscopy in pediatric concussion and orthopedic injury: An Advancing Concussion Assessment in Pediatrics (A-CAP) study.

Millions of children sustain a concussion annually. Concussion disrupts cellular signaling and neural pathways within the brain but the resulting metabolic disruptions are not well characterized. Magnetic resonance spectroscopy (MRS) can examine key brain metabolites (e.g., N-acetyl Aspartate (tNAA), glutamate (Glx), creatine (tCr), choline (tCho), and myo-Inositol (mI)) to better understand these disruptions. In this study, we used MRS to examine differences in brain metabolites between children and adolescents with concussion versus orthopedic injury. Children and adolescents with concussion (n = 361) or orthopedic injury (OI) (n = 184) aged 8 to 17 years were recruited from five emergency departments across Canada. MRS data were collected from the left dorsolateral prefrontal cortex (L-DLPFC) using point resolved spectroscopy (PRESS) at 3 T at a mean of 12 days post-injury (median 10 days post-injury, range 2-33 days). Univariate analyses for each metabolite found no statistically significant metabolite differences between groups. Within each analysis, several covariates were statistically significant. Follow-up analyses designed to account for possible confounding factors including age, site, scanner, vendor, time since injury, and tissue type (and interactions as appropriate) did not find any metabolite group differences. In the largest sample of pediatric concussion studied with MRS to date, we found no metabolite differences between concussion and OI groups in the L-DLPFC. We suggest that at 2 weeks post-injury in a general pediatric concussion population, brain metabolites in the L-DLPFC are not specifically affected by brain injury.

Atypical Tactile Perception in Early Childhood Autism.

We assessed different aspects of tactile perception in young children (3-6 years) with autism. Autistic and neurotypical children completed vibrotactile tasks assessing reaction time, amplitude discrimination (sequential and simultaneous) and temporal discrimination (temporal order judgment and duration discrimination). Autistic children had elevated and more variable reaction times, suggesting slower perceptual-motor processing speed and/or greater distractibility. Children with autism also showed higher amplitude discrimination and temporal order judgement thresholds compared to neurotypical children. Tactile perceptual metrics did not associate with social or tactile sensitivities measured by parent-reports. Altered tactile behavioral responses appear in early childhood, can be quantified but appear dissociated from sensitivity. This implies these measures are complementary, but not necessarily related, phenomena of atypical tactile perception in autism.

Development and validation of the Social Reward Questionnaire-Early Childhood.

Social interactions like group inclusion, receiving praise, or treating others kindly can be motivating and enjoyable. Social reward sensitivity, including motivation and enjoyment, varies between individuals. In early childhood, this variation may relate to differences in social experience and development. Social reward questionnaires have been developed to measure individual differences in social enjoyment for adolescents and adults, but no early childhood measure currently exists. Here, we describe the development and validation of the parent/caregiver report Social Reward Questionnaire-Early Childhood (SRQ-EC) for children aged 3-7 years. The SRQ-EC was developed to quantify both wanting (motivation) and liking (enjoyment) of social rewards, which were considered in separate factor models. For wanting and liking models, exploratory (N = 126) and confirmatory (N = 344) factor analyses identified that three subscales best represented early childhood social reward sensitivity, which were: Sociability (large groups), Admiration (praise and positive attention), and Prosocial Interactions and Compliance (kindness and rule following). SRQ-EC subscales were internally consistent (ω = 0.76-0.91, α = 0.75-0.88, mean interitem correlations = 0.38-0.60) with high test-retest reliability over 2-weeks (r = 0.66-0.85, all p < .001). Subscales differentially associated with other social behavior and personality measures, suggesting construct validity. SRQ-EC subscale scores further showed differential and significant associations with autistic-like traits in nonautistic children. These results suggest that SRQ-EC subscale scores are reliable for assessing social reward sensitivity during early childhood, which could offer key developmental insight regarding interindividual variation in early social behavior. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Repetitive transcranial magnetic stimulation (rTMS) combined with multi-modality aphasia therapy for chronic post-stroke non-fluent aphasia: A pilot randomized sham-controlled trial.

Repetitive transcranial magnetic stimulation (rTMS) shows promise in improving speech production in post-stroke aphasia. Limited evidence suggests pairing rTMS with speech therapy may result in greater improvements. Twenty stroke survivors (>6 months post-stroke) were randomized to receive either sham rTMS plus multi-modality aphasia therapy (M-MAT) or rTMS plus M-MAT. For the first time, we demonstrate that rTMS combined with M-MAT is feasible, with zero adverse events and minimal attrition. Both groups improved significantly over time on all speech and language outcomes. However, improvements did not differ between rTMS or sham. We found that rTMS and sham groups differed in lesion location, which may explain speech and language outcomes as well as unique patterns of BOLD signal change within each group. We offer practical considerations for future studies and conclude that while combination therapy of rTMS plus M-MAT in chronic post-stroke aphasia is safe and feasible, personalized intervention may be necessary.

Brain total creatine differs between primary progressive aphasia (PPA) subtypes and correlates with disease severity.

Primary progressive aphasia (PPA) is comprised of three subtypes: logopenic (lvPPA), non-fluent (nfvPPA), and semantic (svPPA). We used magnetic resonance spectroscopy (MRS) to measure tissue-corrected metabolite levels in the left inferior frontal gyrus (IFG) and right sensorimotor cortex (SMC) from 61 PPA patients. We aimed to: (1) characterize subtype differences in metabolites; and (2) test for metabolite associations with symptom severity. tCr differed by subtype across the left IFG and right SMC. tCr levels were lowest in lvPPA and highest in svPPA. tCr levels predicted lvPPA versus svPPA diagnosis. Higher IFG tCr and lower Glx correlated with greater disease severity. As tCr is involved in brain energy metabolism, svPPA pathology might involve changes in specific cellular energy processes. Perturbations to cellular energy homeostasis in language areas may contribute to symptoms. Reduced cortical excitatory capacity (i.e. lower Glx) in language regions may also contribute to symptoms. Thus, tCr may be useful for differentiating between PPA subtypes, and both tCr and Glx might have utility in understanding PPA mechanisms and tracking progression.

Multimodal magnetic resonance imaging of youth sport-related concussion reveals acute changes in the cerebellum, basal ganglia, and corpus callosum that resolve with recovery.

Magnetic resonance imaging (MRI) can provide a number of measurements relevant to sport-related concussion (SRC) symptoms; however, most studies to date have used a single MRI modality and whole-brain exploratory analyses in attempts to localize concussion injury. This has resulted in highly variable findings across studies due to wide ranging symptomology, severity and nature of injury within studies. A multimodal MRI, symptom-guided region-of-interest (ROI) approach is likely to yield more consistent results. The functions of the cerebellum and basal ganglia transcend many common concussion symptoms, and thus these regions, plus the white matter tracts that connect or project from them, constitute plausible ROIs for MRI analysis. We performed diffusion tensor imaging (DTI), resting-state functional MRI, quantitative susceptibility mapping (QSM), and cerebral blood flow (CBF) imaging using arterial spin labeling (ASL), in youth aged 12-18 years following SRC, with a focus on the cerebellum, basal ganglia and white matter tracts. Compared to controls similar in age, sex and sport (N = 20), recent SRC youth (N = 29; MRI at 8 ± 3 days post injury) exhibited increased susceptibility in the cerebellum (p = 0.032), decreased functional connectivity between the caudate and each of the pallidum (p = 0.035) and thalamus (p = 0.021), and decreased diffusivity in the mid-posterior corpus callosum (p < 0.038); no changes were observed in recovered asymptomatic youth (N = 16; 41 ± 16 days post injury). For recent symptomatic-only SRC youth (N = 24), symptom severity was associated with increased susceptibility in the superior cerebellar peduncles (p = 0.011) and reduced activity in the cerebellum (p = 0.013). Fewer days between injury and MRI were associated with reduced cerebellar-parietal functional connectivity (p < 0.014), reduced activity of the pallidum (p = 0.002), increased CBF in the caudate (p = 0.005), and reduced diffusivity in the central corpus callosum (p < 0.05). Youth SRC is associated with acute cerebellar inflammation accompanied by reduced cerebellar activity and cerebellar-parietal connectivity, as well as structural changes of the middle regions of the corpus callosum accompanied by functional changes of the caudate, all of which resolve with recovery. Early MRI post-injury is important to establish objective MRI-based indicators for concussion diagnosis, recovery assessment and prediction of outcome.

Efficacy of Adjunctive D-Cycloserine to Intermittent Theta-Burst Stimulation for Major Depressive Disorder: A Randomized Clinical Trial.

Importance: The antidepressant effects of transcranial magnetic stimulation protocols for major depressive disorder (MDD) are thought to depend on synaptic plasticity. The theta-burst stimulation (TBS) protocol synaptic plasticity is known to be N-methyl-D-aspartate (NMDA)-receptor dependent, yet it is unknown whether enhancing NMDA-receptor signaling improves treatment outcomes in MDD. Objective: To test whether low doses of the NMDA-receptor partial-agonist, D-cycloserine, would enhance intermittent TBS (iTBS) treatment outcomes in MDD. Design, Setting, and Participants: This was a single-site 4-week, double-blind, placebo-controlled, randomized clinical trial conducted from November 6, 2019, to December 24, 2020, including 50 participants with MDD. Participants were recruited via advertisements and referral. Inclusion criteria were as follows: age 18 to 65 years with a primary diagnosis of MDD, a major depressive episode with score of 18 or more on the 17-item Hamilton Depression Rating Scale, a Young Mania Rating Scale score of 8 or less, and normal blood work (including complete blood cell count, electrolytes, liver function tests, and creatinine level). Interventions: Participants were randomly assigned 1:1 to either iTBS plus placebo or iTBS plus D-cycloserine (100 mg) for the first 2 weeks followed by iTBS without an adjunct for weeks 3 and 4. Main Outcomes and Measures: The primary outcome was change in depressive symptoms as measured by the Montgomery-Åsberg Depression Rating Scale (MADRS) at the conclusion of treatment. Secondary outcomes included clinical response, clinical remission, and Clinical Global Impression (CGI) scores. Results: A total of 50 participants (mean [SD] age, 40.8 [13.4] years; 31 female [62%]) were randomly assigned to treatment groups: iTBS plus placebo (mean [SD] baseline score, 30.3 [4.2]) and iTBS plus D-cycloserine (mean [SD] baseline score, 30.4 [4.5]). The iTBS plus D-cycloserine group had greater improvements in MADRS scores compared with the iTBS plus placebo group (mean difference, -6.15; 95% CI, -2.43 to -9.88; Hedges g = 0.99; 95% CI, 0.34-1.62). Rates of clinical response were higher in the iTBS plus D-cycloserine group than in the iTBS plus placebo group (73.9% vs 29.3%), as were rates of clinical remission (39.1% vs 4.2%). This was reflected in lower CGI-severity ratings and greater CGI-improvement ratings. No serious adverse events occurred. Conclusions and Relevance: Findings from this clinical trial indicate that adjunctive D-cycloserine may be a promising strategy for enhancing transcranial magnetic stimulation treatment outcomes in MDD using iTBS requiring further investigation. Trial Registration: ClinicalTrials.gov Identifier: NCT03937596.

Glutamate, GABA and glutathione in adults with persistent post-concussive symptoms.

Persistent post-concussive symptoms (PPCS) are debilitating and endure beyond the usual recovery period after mild traumatic brain injury (mTBI). Altered neurotransmission, impaired energy metabolism and oxidative stress have been examined acutely post-injury but have not been explored extensively in those with persistent symptoms. Specifically, the antioxidant glutathione (GSH) and the excitatory and inhibitory metabolites, glutamate (Glu) and γ-aminobutyric acid (GABA), are seldom studied together in the clinical mTBI literature. While Glu can be measured using conventional magnetic resonance spectroscopy (MRS) methods at 3 Tesla, GABA and GSH require the use of advanced MRS methods. Here, we used the recently established Hadamard Encoding and Reconstruction of MEGA-Edited Spectroscopy (HERMES) to simultaneously measure GSH and GABA and short-echo time point resolved spectroscopy (PRESS) to measure Glu to gain new insight into the pathophysiology of PPCS. Twenty-nine adults with PPCS (mean age: 45.69 years, s.d.: 10.73, 22 females, 7 males) and 29 age- and sex-matched controls (mean age: 43.69 years, s.d.: 11.00) completed magnetic resonance spectroscopy scans with voxels placed in the anterior cingulate and right sensorimotor cortex. Relative to controls, anterior cingulate Glu was significantly reduced in PPCS. Higher anterior cingulate GABA was significantly associated with a higher number of lifetime mTBIs, suggesting GABA may be upregulated with repeated incidence of mTBI. Furthermore, GSH in both regions of interest was positively associated with symptoms of sleepiness and headache burden. Collectively, our findings suggest that the antioxidant defense system is active in participants with PPCS, however this may be at the expense of other glutamatergic functions such as cortical excitation and energy metabolism.