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Original Article |

Evidence for Increased Glutamatergic Cortical Facilitation in Children and Adolescents With Major Depressive Disorder

Paul E. Croarkin, DO, MSCS; Paul A. Nakonezny, PhD; Mustafa M. Husain, MD; Tabatha Melton, BA; Jeylan S. Buyukdura, BS; Betsy D. Kennard, PsyD; Graham J. Emslie, MD; F. Andrew Kozel, MD, MSCR; Zafiris J. Daskalakis, MD, PhD, FRCPC
JAMA Psychiatry. 2013;70(3):291-299. doi:10.1001/2013.jamapsychiatry.24.
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Context  Converging lines of evidence implicate the glutamate and γ-aminobutyric acid neurotransmitter systems in the pathophysiology of major depressive disorder. Transcranial magnetic stimulation cortical excitability and inhibition paradigms have been used to assess cortical glutamatergic and γ-aminobutyric acid–mediated tone in adults with major depressive disorder, but not in children and adolescents.

Objective  To compare measures of cortical excitability and inhibition with 4 different paradigms in a group of children and adolescents with major depressive disorder vs healthy controls.

Design  Cross-sectional study examining medication-free children and adolescents (aged 9-17 years) with major depressive disorder compared with healthy controls. Cortical excitability was assessed with motor threshold and intracortical facilitation measures. Cortical inhibition was measured with cortical silent period and intracortical inhibition paradigms.

Setting  University-based child and adolescent psychiatry clinic and neurostimulation laboratory.

Patients  Twenty-four participants with major depressive disorder and 22 healthy controls matched for age and sex. Patients with major depressive disorder were medication naive and had moderate to severe symptoms based on an evaluation with a child and adolescent psychiatrist and scores on the Children's Depression Rating Scale–Revised.

Main Outcome Measures  Motor threshold, intracortical facilitation, cortical silent period, and intracortical inhibition.

Results  Compared with healthy controls, depressed patients had significantly increased intracortical facilitation at interstimulus intervals of 10 and 15 milliseconds bilaterally. There were no significant group differences in cortical inhibition measures.

Conclusions  These findings suggest that major depressive disorder in children and adolescents is associated with increased intracortical facilitation and excessive glutamatergic activity.

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Figure 1. Intracortical facilitation. These tracings are averaged electromyographic waveforms from cortical excitability testing in an adolescent patient. A, A suprathreshold test stimulus produces motor evoked potentials with a near 1-mV peak-to-peak amplitude. B, In the intracortical facilitation paradigm, a subthreshold conditioning stimulus precedes the test stimulus with an interstimulus interval of 10 to 20 milliseconds. This paired stimulation culminates in a motor evoked potential with an increased amplitude compared with that of the test stimulus alone (A). Differences in motor evoked potential amplitudes are expressed as a percentage of the unconditioned motor evoked potential. Prior work suggests that this measure indexes cortical glutamatergic N -methyl-D-aspartate receptor functioning.

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Figure 2. Increased cortical excitability in childhood depression. This illustration presents a theoretical model regarding the impact of increased glutamatergic intracortical facilitation in child and adolescent depression. Increased intracortical facilitation in depressed children and adolescents indicates increased cortical glutamatergic N -methyl-D-aspartate (NMDA) receptor functioning. At this stage, γ-aminobutyric acid (GABA) ionotropic receptor family A (GABAA) receptor–mediated and GABA metabotropic receptor family B (GABAB) receptor–mediated neurotransmission is unchanged because GABAergic interneurons are functioning normally. However, increased NMDA activity is thought to play a key role in excitotoxic effects. The impact is likely widespread and could subsequently impair or damage GABAergic interneurons. AMPA indicates α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid.

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Figure 3. Adult consequences of glutamatergic excitotoxic effects. This illustration presents a theoretical model that attempts to reconcile divergent findings in transcranial magnetic stimulation neurophysiological studies of childhood and adult depression. Our findings suggest that depressed children and adolescents have increased cortical glutamatergic N -methyl-D-aspartate receptor functioning. Across the lifespan, this excess N -methyl-D-aspartate activity could eventually impair or damage γ-aminobutyric acid (GABA)–ergic interneuronal functioning through excitotoxic effects. Hence, adults with depression might be expected to have deficits in GABAergic functioning as demonstrated in previous neurophysiological research.

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