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      Transcranial Magnetic Stimulation Markers of Antidepressant Treatment in Adolescents With Major Depressive Disorder

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          Abstract

          Background

          The goal of this study was to examine baseline transcranial magnetic stimulation measures of cortical inhibition and excitability in depressed patients and characterize their longitudinal posttreatment changes.

          Methods

          Fifteen adolescents (age 13–17 years) with moderate to severe major depressive disorder and 22 healthy controls (age 9–17) underwent single- and paired-pulse transcranial magnetic stimulation and clinical assessments. Transcranial magnetic stimulation measures included short-interval intracortical inhibition (2 and 4 milliseconds), long-interval intracortical inhibition (100, 150, and 200 milliseconds), cortical silent period, and intracortical facilitation (10, 15, and 20 milliseconds). Ten participants with major depressive disorder initiated antidepressant treatment or had dose adjustments. These participants were reassessed after treatment. Depression symptom severity was measured with the Children’s Depression Rating Scale, Revised. Robust regression modeling compared healthy and depressed adolescents at baseline. Relationships between changes in cortical inhibition and changes in depressive symptom severity were assessed in the depressed adolescents receiving antidepressant treatment.

          Results

          Our results revealed that at baseline, short-interval intracortical inhibition-2 was significantly reduced ( P adj = .01) in depressed participants, suggesting impaired cortical inhibition compared with healthy controls. At follow-up, improvement in Children’s Depression Rating Scale, Revised scores correlated with improvement in short-interval intracortical inhibition-4 amplitude (greater inhibition) after antidepressant treatment ( R 2 = 0.63; P = .01).

          Conclusions

          These results suggest that cortical inhibition measures may have promise as biomarkers in adolescents treated for depression.

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          Most cited references65

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          Childhood and adolescent depression: a review of the past 10 years. Part I.

          To qualitatively review the literature of the past decade covering the epidemiology, clinical characteristics, natural course, biology, and other correlates of early-onset major depressive disorder (MDD) and dysthymic disorder (DD). A computerized search for articles published during the past 10 years was made and selected studies are presented. Early-onset MDD and DD are frequent, recurrent, and familial disorders that tend to continue into adulthood, and they are frequently accompanied by other psychiatric disorders. These disorders are usually associated with poor psychosocial and academic outcome and increased risk for substance abuse, bipolar disorder, and suicide. In addition, DD increases the risk for MDD. There is a secular increase in the prevalence of MDD, and it appears that MDD is occurring at an earlier age in successive cohorts. Several genetic, familial, demographic, psychosocial, cognitive, and biological correlates of onset and course of early-onset depression have been identified. Few studies, however, have examined the combined effects of these correlates. Considerable advances have been made in our knowledge of early-onset depression. Nevertheless, further research is needed in understanding the pathogenesis of childhood mood disorders. Toward this end, studies aimed at elucidating mechanisms and interrelationships among the different domains of risk factors are needed.
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            Differential effects on motorcortical inhibition induced by blockade of GABA uptake in humans.

            1. Blockade of uptake carriers of gamma-aminobutyric acid (GABA) has been shown to modulate inhibition in cortical slices of experimental animals, although little is known about this mechanism in vivo and, in particular, in humans. 2. The effects of blockade of GABA uptake were studied using transcranial magnetic stimulation (TMS) in humans. In eight healthy volunteers several measures of cortical excitation and inhibition were obtained before and approximately 2 h after ingestion of 5-15 mg of tiagabine (TGB). 3. After TGB ingestion, the duration of the TMS-induced silent period observable in the electromyogram of the voluntarily contracted target muscle was prolonged. Similarly, paired-pulse inhibition of the motor-evoked potential (MEP), as tested by delivering two magnetic shocks of equal suprathreshold intensities at 160 ms interstimulus interval (ISI), was more pronounced. In apparent contradistinction, paired-pulse inhibition of the MEPs produced by a subthreshold conditioning stimulus delivered 3 ms prior to a suprathreshold stimulus was reduced. Paired-pulse facilitation elicited by the same double-shock protocol at an ISI of 10 ms was increased. 4. The prolongation of the GABAB receptor-mediated component of the inhibitory postsynaptic potential observed with TGB in in vitro studies probably underlies the increase in cortical silent period duration. The reduction of the paired-pulse inhibition at 3 ms, in turn, probably reflects inhibition of GABAA receptor-mediated inhibition via presynaptic GABAB receptors. 5. These data provide in vivo evidence of differential modulation of cortical inhibition by blockade of GABA uptake. Presynaptic GABA autoreceptors may be involved in modulating cortical inhibition in the human motor cortex.
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              The role of GABA(B) receptors in intracortical inhibition in the human motor cortex.

              While GABA(B) receptors are thought to have an important role in mediating long interval intracortical inhibition (LICI) in the human motor cortex, the effect of a selective GABA(B) receptor agonist on this measure has not been directly tested. Nine healthy volunteers ingested either 50 mg baclofen (BAC) or placebo (PBO) in a randomized, double blind crossover design, with the second session one week later. We used transcranial magnetic stimulation to assess motor threshold, motor evoked potential (MEP) amplitude, cortical silent period (CSP) duration, short interval intracortical inhibition (SICI) and LICI before and 90 min following drug intake. There was no specific effect of drug on motor threshold, MEP amplitude or CSP duration. BAC resulted in a significant increase in LICI (P=0.002) and a significant decrease in SICI (P=0.046) while PBO had no effect. Our findings demonstrate that the enhanced GABA(B) receptor activation results in differential effects on these two measures of intracortical inhibition in the human motor cortex. The increase in LICI is likely to be a result of increased GABA(B) receptor mediated inhibitory post-synaptic potentials, while the reduction in SICI may relate to the activation of pre-synaptic GABA(B) receptors reducing GABA release.
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                Author and article information

                Journal
                Int J Neuropsychopharmacol
                Int. J. Neuropsychopharmacol
                ijnp
                International Journal of Neuropsychopharmacology
                Oxford University Press (US )
                1461-1457
                1469-5111
                July 2019
                16 May 2019
                16 May 2019
                : 22
                : 7
                : 435-444
                Affiliations
                [1 ]Department of Psychiatry and Psychology, Mayo Clinic, Rochester, Minnesota
                [2 ]Temerty Centre for Therapeutic Brain Intervention, Centre for Addiction and Mental Health, Department of Psychiatry, University of Toronto, Ontario, Canada
                Author notes
                Correspondence: Paul E. Croarkin, DO, MS, Department of Psychiatry and Psychology, Mayo Clinic, 200 First St SW, Rochester, MN 55905 ( croarkin.paul@ 123456mayo.edu ).
                Article
                pyz021
                10.1093/ijnp/pyz021
                6600470
                31095686
                2ca6ac01-34cf-42e3-a685-00a0d6177668
                © The Author(s) 2019. Published by Oxford University Press on behalf of CINP.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com

                History
                : 24 September 2018
                : 01 April 2019
                : 14 May 2019
                Page count
                Pages: 10
                Funding
                Funded by: Brain and Behavior Research Foundation 10.13039/100000874
                Award ID: 20883
                Funded by: Mayo Clinic Foundation
                Funded by: National Institute of Mental Health 10.13039/100000025
                Award ID: K23 MH100266
                Award ID: R01MH113700
                Categories
                Regular Research Articles

                Pharmacology & Pharmaceutical medicine
                adolescent,cortical inhibition,mood disorders,paired-pulse transcranial magnetic stimulation,short-interval intracortical inhibition

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