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Objective: Compared to typically developing (TD) peers, children with attention deficit hyperactivity disorder (ADHD) manifest reduced short interval cortical inhibition (SICI) in the dominant motor cortex measured with transcranial magnetic stimulation (TMS). This multimodal study investigates the inhibitory neurophysiology and neurochemistry by evaluating the relationship between SICI and γ-amino butyric acid (GABA+) levels, measured with magnetic resonance spectroscopy (MRS)., Methods: Across two sites, 37 children with ADHD and 45 TD children, ages 8-12 years, participated. Single and paired pulse TMS to left motor cortex quantified SICI during REST and at times of action selection (GO) and inhibition (STOP) during a modified Slater-Hammel stop signal reaction task. MRS quantified GABA+ levels in the left sensorimotor cortex. Relationships between SICI and GABA+, as well as stopping efficiency and clinical symptoms, were analyzed with correlations and repeated-measure, mixed-models., Results: In both groups, higher GABA+ levels correlated with less SICI. In TD children only, higher GABA+ levels correlated with larger TMS motor evoked potentials (MEPs) at REST. In GO and STOP trials, higher GABA+ was associated with smaller MEP amplitudes, for both groups. Overall, GABA+ levels did not differ between groups or correlate with ADHD clinical symptoms., Conclusions: In children with higher motor cortex GABA+, motor cortex is less responsive to inhibitory TMS (SICI). Comparing the relationships between MRS-GABA+ levels and responses to TMS at REST vs. GO/STOP trials suggests differences in inhibitory neurophysiology and neurotransmitters in children with ADHD. These differences are more prominent at rest than during response inhibition task engagement., Significance: Evaluating relationships between GABA+ and SICI may provide a biomarker useful for understanding behavioral diagnoses., Competing Interests: Declaration of Competing Interest Dr. Gilbert has received honoraria and/or travel support from the Tourette Association of America/ Centers for Disease Control and Prevention, the American Academy of Pediatrics, the Child Neurology Society, the Texas Neurological Society, and the American Academy of Neurology. He has received compensation for expert testimony for the U.S. National Vaccine Injury Compensation Program, through the Department of Health and Human Services, and for the US Armed Services/US Attorney’s Office of VA. Dr. Gilbert has received research support from the NIH (NIMH, NINDS). He has received funding for work as a clinical trial site investigator fromEcopipam Pharmaceuticals (clinical trial, Tourette Syndrome) and EryDel (clinical trial, Ataxia Telangiectasia). He has received book royalties from Elsevier and Wolters Kluwer. Dr. Edden has received grants from Siemens., (Copyright © 2021 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Efficient practice organization maximizes learning outcome. Although randomization of practice as compared to blocked practice damages training performance, it boosts retention performance, an effect called contextual interference. Motor learning modulates the GABAergic (gamma-aminobutyric acid) system within the sensorimotor cortex (SM); however, it is unclear whether different practice regimes differentially modulate this system and whether this is impacted by aging. Young and older participants were trained on 3 variations of a visuomotor task over 3 days, following either blocked or random practice schedule and retested 6 days later. Using magnetic resonance spectroscopy, SM and occipital cortex GABA+ levels were measured before and after training during the first and last training days. We found that (1) behavioral data confirmed the contextual interference effects, (2) within-day occipital cortex GABA+ levels decreased in random and increased in blocked group. This effect was more pronounced in older adults; and (3) baseline SM GABA+ levels predicted initial performance. These findings indicate a differential modulation of GABA levels across practice groups that is amplified by aging., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Purpose: While PRESS is often employed to measure glutamate concentrations, MEGA-PRESS enables simultaneous Glx (glutamate and glutamine) and GABA measurements. This study aimed to compare validation, repeatability, and concordance of different approaches for glutamate quantification at 3T to aid future studies in their selection of the appropriate sequence and quantification method., Materials and Methods: Nine phantoms with different glutamate and glutamine concentrations and five healthy participants were scanned twice to assess respectively the validation and repeatability of measurements with PRESS and MEGA-PRESS. To assess concordance between the different methods, results from 95 human participants were compared. PRESS, MEGA-PRESS (i.e. difference), and the MEGA-PRESS OFF spectra were analyzed with both LCModel and Gannet., Results: In vitro, excellent agreement was shown between actual and measured glutamate concentrations for all measurements (r>0.98). In vivo CVs were better for PRESS (2.9%) than MEGA-PRESS (4.9%) and MEGA-PRESS OFF (4.2%). However, the concordance between the sequences was low (PRESS and MEGA-PRESS OFF, r=0.3) to modest (MEGA-PRESS versus MEGA-PRESS OFF, r=0.8)., Conclusion: Both PRESS and MEGA-PRESS can be employed to measure in vivo glutamate concentrations, although PRESS shows a better repeatability. Comparisons between in vivo glutamate measures of different sequences however need to be interpreted cautiously., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Edited magnetic resonance spectroscopy (MRS) and transcranial magnetic stimulation (TMS) have often been used to study the integrity of the GABAergic neurotransmission system in healthy aging. To investigate whether the measurement outcomes obtained with these 2 techniques are associated with each other in older human adults, gamma-aminobutyric acid (GABA) levels in the left sensorimotor cortex were assessed with edited MRS in 28 older (63-74 years) and 28 young adults (19-34 years). TMS at rest was then used to measure intracortical inhibition (short-interval intracortical inhibition/long-interval intracortical inhibition), intracortical facilitation, interhemispheric inhibition from left to right primary motor cortex (M1) and recruitment curves of left and right M1. Our observations showed that short-interval intracortical inhibition and long-interval intracortical inhibition in the left M1 were reduced in older adults, while GABA levels did not significantly differ between age groups. Furthermore, MRS-assessed GABA within left sensorimotor cortex was not correlated with TMS-assessed cortical excitability or inhibition. These observations suggest that healthy aging gives rise to altered inhibition at the postsynaptic receptor level, which does not seem to be associated with MRS-assessed GABA+ levels., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Sensory processing abnormalities are among the most common behavioral phenotypes seen in autism spectrum disorder (ASD), typically characterized by either over- or under-responsiveness to stimulation. In this review, we focus on tactile processing dysfunction in ASD. We firstly review clinical studies wherein sensitivity to tactile stimuli has traditionally been assessed by self-, parent- and experimenter-reports. We also discuss recent investigations using psychophysical paradigms that gauge individual tactile thresholds. These more experimentally rigorous studies allow for more objective assessments of tactile abnormalities in ASD. However, little is understood about the neurobiological mechanisms underlying these abnormalities, or the link between tactile abnormalities and ASD symptoms. Neurobiological research that has been conducted has pointed toward dysfunction in the excitation/inhibition balance of the central nervous system of those with ASD. This review covers recent efforts that have investigated tactile dysfunction in ASD from clinical and behavioral perspectives, and some of the efforts to link these to neurobiology. On the whole, findings are inconsistent, which can be ascribed to the subjectivity of clinical assessments, the heterogeneity of ASD cohorts, and the diversity of tactile sensitivity measures. Future endeavors into understanding tactile processing differences in ASD will greatly benefit from controlled experiments driven by neurobiological hypotheses., (Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Standardization of results is an important milestone in the maturation of any truly quantitative methodology. For instance, a lack of measurement agreement across imaging platforms limits multisite studies, between-study comparisons based on the literature, and inferences based on and the generalizability of results. In GABA-edited MEGA-PRESS, two key sources of differences between implementations are: differences in editing efficiency of GABA and the degree of co-editing of macromolecules (MM). In this work, GABA editing efficiency κ and MM-co-editing μ constants are determined for three widely used MEGA-PRESS implementations (on the most common MRI platforms; GE, Philips, and Siemens) by phantom experiments. Implementation-specific κ,μ-corrections were then applied to two in vivo datasets, one consisted of 8 subject scanned on the three platforms and the other one subject scanned eight times on each platform. Manufacturer-specific κ and μ values were determined as: κ GE =0.436, κ Siemens =0.366 and κ Philips =0.394 and μ GE =0.83, μ Siemens =0.625 and μ Philips =0.75. Applying the κ,μ-correction on the Cr-referenced data decreased the coefficient of variation (CV) of the data for both in vivo data sets (multisubjects: uncorrected CV=13%, κ,μ-corrected CV=5%, single subject: uncorrected CV=23%, κ,μ-corrected CV=13%) but had no significant effect on mean GABA levels. For the water-referenced results, CV increased in the multisubject data (uncorrected CV=6.7%, κ,μ-corrected CV=14%) while it decreased in the single subject data (uncorrected CV=24%, κ,μ-corrected CV=21%) and manufacturer was a significant source of variance in the κ,μ-corrected data. Applying a correction for editing efficiency and macromolecule contamination decreases the variance between different manufacturers for creatine-referenced data, but other sources of variance remain., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Stimulants are the main pharmacological treatment for patients with attention-deficit/hyperactivity disorder (ADHD). Their current prescription rates are rising, both in children, adolescents and adults. Related to the impulse control phenotype, both preclinical and clinical studies have demonstrated lower γ-amino butyric acid (GABA) levels in prefrontal brain regions in ADHD. Whereas stimulant treatment increases GABA levels, preclinical studies have suggested that stimulant treatment effects may be age-dependent. As the long-term consequences of stimulant use in ADHD children and adolescents have so far been poorly studied, we used magnetic resonance spectroscopy to assess GABA+ and glutamate + glutamine (Glx) levels in the medial prefrontal cortex (mPFC) of adult ADHD patients, both before and after an oral methylphenidate (MPH) challenge. Three groups were studied: 1) ADHD patients who were first treated with stimulants before 16 years of age, i.e. during periods of ongoing brain development (early-stimulant-treated, EST); 2) patients first treated with stimulants in adulthood (i.e. > 23 years) (late-stimulant-treated, LST), and 3) stimulant-treatment-naive (STN) ADHD patients. Reduced basal GABA+ levels were found in EST compared to LST patients (p = 0.04), while after an MPH challenge, only the EST patients showed significant increases in GABA+ (p = 0.01). For Glx, no differences were found at baseline, nor after an MPH challenge. First stimulant exposure at a young age is thus associated with lower baseline levels of GABA+ and increased responsivity in adulthood. This effect could not be found in patients that started treatment at an adult age. Hence, while adult stimulant treatment seems to exert no major effects on GABA+ levels in the mPFC, MPH may induce long-lasting alterations in the adult mPFC GABAergic system when treatment was started at a young age.