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 by ¹H-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 completed ¹H-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.

Keywords: child and adolescent; cortical excitability; depression; glutamate; proton magnetic resonance spectroscopy; transcranial magnetic stimulation.

Figure 1

Proton magnetic resonance spectrum from the anterior cingulate cortex (ACC). Spectroscopic data were acquired via a TE-optimized PRESS sequence (TE 80 ms) at 3 T. Quantitative analysis was performed by LCModel (Provencher, 1993). Note the dominant glutamate (Glu) peak at 2.34 ppm. Also shown are signal peaks of choline (Cho), creatine (Cr) and n-acetylaspartate (NAA).

Figure 2

Electromyography (EMG) of unconditioned, inhibited and facilitated motor evoked potentials (MEPs). (A) Following a single transcranial magnetic stimulation (TMS) pulse (at time = 0) to the primary motor cortex at an intensity above the resting motor threshold (RMT), an MEP is detected by EMG in the corresponding muscle. (B) In the short-interval intracortical inhibition (SICI) paradigm, a subthreshold conditioning stimulus (at time = 0) is administered to the primary motor cortex. After a 2-ms or 4-ms interstimulus interval (4-ms shown), a second, suprathreshold test stimulus is delivered. The resulting MEP is diminished in amplitude, i.e., inhibited. (C) In the intracortical facilitation (ICF) paradigm, a subthreshold conditioning stimulus (at time = 0) and a subsequent suprathreshold test stimulus are administered to the primary motor cortex, separated by a 10-ms, 15-ms, or 20-ms interstimulus interval (15-ms shown). This results in an MEP that is facilitated, or increased in amplitude.

Figure 3

EMG of the cortical silent period (CSP). In a muscle exhibiting tonic motor activity (A), a single TMS pulse at 140% of the RMT (B) is delivered to the corresponding area of the primary motor cortex. This is followed by the CSP (C), a quiescent interval that ends with resumption of motor activity (D).

Figure 4

Location of proton magnetic resonance spectroscopy (¹H-MRS) voxels. (A) Axial localizer slice indicating the location of the midline anterior cingulate voxel. This voxel encompasses the pregenual ACC of both cerebral hemispheres. (B) Coronal localizer slice indicating the location of the left primary motor cortex voxel. The arrowhead indicates the vitamin E capsule which was placed directly over the abductor pollicis brevis (APB) point as determined by TMS. (C) Axial oblique localizer slice showing another view of the left primary motor cortex voxel. The center of the voxel is located immediately beneath the vitamin E capsule, encompassing the hand knob area of the primary motor cortex.