title: An Exploratory Study of Spectroscopic Glutamatergic Correlates of Cortical Excitability in Depressed Adolescents.
abstract: Introduction: Transcranial magnetic stimulation (TMS) research has suggested dysfunction in cortical glutamatergic systems in adolescent depression, while proton magnetic resonance spectroscopy (1H-MRS) studies have demonstrated deficits in concentrations of glutamatergic metabolites in depressed individuals in several cortical regions, including the anterior cingulate cortex (ACC). However, few studies have combined TMS and MRS methods to examine relationships between glutamatergic neurochemistry and excitatory and inhibitory neural functions, and none have utilized TMS-MRS methodology in clinical populations or in youth. This exploratory study aimed to examine relationships between TMS measures of cortical excitability and inhibition and concentrations of glutamatergic metabolites as measured by1H-MRS in depressed adolescents.Methods: Twenty-four adolescents (aged 11-18 years) with depressive symptoms underwent TMS testing, which included measures of the resting motor threshold (RMT), cortical silent period (CSP), short-interval intracortical inhibition (SICI), and intracortical facilitation (ICF). Fourteen participants from the same sample also completed1H-MRS in a 3 T MRI scanner after TMS testing. Glutamate + glutamine (Glx) concentrations were measured in medial ACC and left primary motor cortex voxels with a TE-optimized PRESS sequence. Metabolite concentrations were corrected for cerebrospinal fluid (CSF) after tissue segmentation. Pearson product-moment and Spearman rank-order correlations were calculated to assess relationships between TMS measures and [Glx].Results: In the left primary motor cortex voxel, [Glx] had a significant positive correlation with the RMT. In the medial ACC voxel, [Glx] had significant positive correlations with ICF at the 10-ms and 20-ms interstimulus intervals (ISIs).Conclusion: These preliminary data implicate glutamate in cortical excitatory processes measured by TMS. Limitations included small sample size, lack of healthy control comparators, possible age- and sex-related effects, and observational nature of the study. Further research aimed at examining the relationship between glutamatergic metabolite concentrations measured through MRS and the excitatory and inhibitory physiology measured through TMS is warranted. Combined TMS-MRS methods show promise for future investigations of the pathophysiology of depression in adults as well as in children and adolescents.
authors.affiliation: Mayo Clinic Depression Center, Department of Psychiatry and Psychology, Mayo Clinic Rochester, MN, USA.
authors.forename: Charles P
authors.initials: CP
authors.lastname: Lewis
authors.affiliation: Mayo Clinic Depression Center, Department of Psychiatry and Psychology, Mayo ClinicRochester, MN, USA; Department of Radiology, Mayo ClinicRochester, MN, USA.
authors.forename: John D
authors.initials: JD
authors.lastname: Port
authors.affiliation: Mayo Clinic Depression Center, Department of Psychiatry and Psychology, Mayo Clinic Rochester, MN, USA.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Frye
authors.affiliation: Mayo Clinic Depression Center, Department of Psychiatry and Psychology, Mayo Clinic Rochester, MN, USA.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Vande Voort
authors.affiliation: Faculty of Medicine, Department of Psychiatry, University of TorontoToronto, ON, Canada; Temerty Centre for Therapeutic Brain Intervention, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, University of TorontoToronto, ON, Canada; The Margaret and Wallace McCain Centre for Child, Youth and Family Mental Health, Campbell Family Mental Health Research Institute, The Centre for Addiction and Mental Health, University of TorontoToronto, ON, Canada.
authors.forename: Stephanie H
authors.initials: SH
authors.lastname: Ameis
authors.affiliation: Department of Psychiatry, University of Texas Southwestern Medical CenterDallas, TX, USA; Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical CenterDallas, TX, USA; Department of Psychiatry and Behavioral Sciences, Duke University School of MedicineDurham, NC, USA.
authors.forename: Mustafa M
authors.initials: MM
authors.lastname: Husain
authors.affiliation: Faculty of Medicine, Department of Psychiatry, University of TorontoToronto, ON, Canada; Temerty Centre for Therapeutic Brain Intervention, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, University of TorontoToronto, ON, Canada.
authors.forename: Zafiris J
authors.initials: ZJ
authors.lastname: Daskalakis
authors.affiliation: Mayo Clinic Depression Center, Department of Psychiatry and Psychology, Mayo Clinic Rochester, MN, USA.
authors.forename: Paul E
authors.initials: PE
authors.lastname: Croarkin
mesh_terms: D000293:Adolescent; D002648:Child; D003866:Depressive Disorder / Q000000981:diagnostic imaging / Q000378:metabolism / Q000503:physiopathology; D019054:Evoked Potentials, Motor / Q000502:physiology*; D005260:Female; D018698:Glutamic Acid / Q000378:metabolism*; D005973:Glutamine / Q000378:metabolism*; D006179:Gyrus Cinguli / Q000000981:diagnostic imaging / Q000378:metabolism / Q000503:physiopathology; D006801:Humans; D009682:Magnetic Resonance Spectroscopy / Q000379:methods*; D008297:Male; D009044:Motor Cortex / Q000000981:diagnostic imaging / Q000378:metabolism / Q000503:physiopathology; D009433:Neural Inhibition / Q000502:physiology*; D050781:Transcranial Magnetic Stimulation / Q000379:methods*
chemical_list: D005973:Glutamine; D018698:Glutamic Acid
keywords: child and adolescent; cortical excitability; depression; glutamate; proton magnetic resonance spectroscopy; transcranial magnetic stimulation