Transcranial magnetic stimulation potentiates glutamatergic neurotransmission in depressed adolescents

Highlights

• Aberrant glutamate neurotransmission may play a role in adolescent depression.

• rTMS is a promising new treatment.

• Ten adolescents undergoing rTMS were assessed with 1 H-MRS.

• Gln/Glu ratios increased in the ACC and LDLFPC.

Abstract

Abnormalities in glutamate neurotransmission may have a role in the pathophysiology of adolescent depression. The present pilot study examined changes in cortical glutamine/glutamate ratios in depressed adolescents receiving high-frequency repetitive transcranial magnetic stimulation. Ten adolescents with treatment-refractory major depressive disorder received up to 30 sessions of 10-Hz repetitive transcranial magnetic stimulation at 120% motor threshold with 3000 pulses per session applied to the left dorsolateral prefrontal cortex. Baseline, posttreatment, and 6-month follow-up proton magnetic resonance spectroscopy scans of the anterior cingulate cortex and left dorsolateral prefrontal cortex were collected at 3 T with 8-cm³ voxels. Glutamate metabolites were quantified with 2 distinct proton magnetic resonance spectroscopy sequences in each brain region. After repetitive transcranial magnetic stimulation and at 6 months of follow-up, glutamine/glutamate ratios increased in the anterior cingulate cortex and left dorsolateral prefrontal cortex with both measurements. The increase in the glutamine/glutamate ratio reached statistical significance with the TE-optimized PRESS sequence in the anterior cingulate cortex. Glutamine/glutamate ratios increased in conjunction with depressive symptom improvement. This reached statistical significance with the TE-optimized PRESS sequence in the left dorsolateral prefrontal cortex. High-frequency repetitive transcranial magnetic stimulation applied to the left dorsolateral prefrontal cortex may modulate glutamate neurochemistry in depressed adolescents.

Introduction

Major depressive disorder (MDD) frequently presents in adolescence and is often recalcitrant to treatment (Brent, 2009) which leads to substantial morbidity, mortality, and a societal financial burden (Blazer et al., 1994, Greenberg et al., 2015). Suicide is a leading cause of death in adolescents and a stark reminder that the current mechanistic understanding of depression is underdeveloped (Vitiello et al., 2011). Unfortunately, antidepressant medications, cognitive-behavioral therapy, and combined treatment are either ineffective or have minimal durability for most depressed adolescents (March et al., 2009).

Noninvasive brain stimulation technologies such as repetitive transcranial magnetic stimulation (rTMS) may have promise as enduring therapeutic interventions in young people (Donaldson et al., 2014). Prior research has shown that rTMS applied to the left dorsolateral prefrontal cortex (L-DLPFC) is a safe and effective treatment for MDD in adults who fail to benefit from antidepressant medications (O'Reardon et al., 2007, George et al., 2010). Initial open-label studies of rTMS for MDD in adolescents suggest that it may be effective and well-tolerated in younger people, as well (Donaldson et al., 2014). Although rTMS treatment has US Food and Drug Administration clearance for adults, little is known about its mechanism of action and target engagement, especially in adolescents. Further research focused on understanding the underlying pathophysiology of MDD and how rTMS changes a patient's underlying neurophysiology would facilitate precision medicine approaches to brain stimulation treatments.

Glutamate (Glu) is the primary excitatory neurotransmitter, with roles in neurogenesis, synaptogenesis, neuronal migration, cognition, learning, and memory. Following release into the synaptic cleft, Glu is taken up by adjacent astrocytes and converted to glutamine (Gln) which is then transported back to the neuron. The glutamate–glutamine neurotransmitter recycling system is essential for normal neurotransmission (Yuksel and Ongur, 2010) and drives a large fraction of cerebral oxidative metabolism.

Prior research implicates dysregulated glutamatergic neurotransmission in mood disorders (Krystal et al., 2002, Sanacora et al., 2012) and suggests that rTMS may modulate glutamatergic circuitry (Michael et al., 2003). Initial preclinical (Yue et al., 2009) and clinical work (Michael et al., 2003) suggests that multiple sessions of rTMS increase cortical Glu concentrations in the brain.

Many previous proton magnetic resonance spectroscopy (¹H-MRS) studies have examined Glu+Gln (so-called Glx) levels in psychiatric disorders, while contemporary studies at higher field strength (3 T and above) have been able to separately measure Glu and Gln. While it is relatively easy to quantify brain Glu (in part due to its higher concentration of approximately 10 mM), accurate measurement of brain Gln remains difficult due to its relatively low brain concentration (estimated at 2–4 mM) and large spectral overlap with other brain metabolites (Hancu and Port, 2011). To mitigate this measurement difficulty and improve sensitivity for detecting glutamate-glutamine cycle dysfunction, recently investigators have used the Gln/Glu ratio (Brennan et al., 2010, Ongur et al., 2011) or the Glu/Gln ratio (Hermann et al., 2012) for detecting neurotransmission abnormalities in patients with psychiatric disorders.

In this study, we assumed that depressed adolescents have glutamate–glutamine cycle dysfunction. The study objective was to examine changes in Gln/Glu ratios in the anterior cingulate cortex and left dorsolateral prefrontal cortex of depressed adolescents receiving high-frequency rTMS. We hypothesized that the Gln/Glu ratio would increase over time as Gln levels would increase and Glu levels would stay the same or decrease following treatment (Yuksel and Ongur, 2010). We also hypothesized that this change would relate to symptom improvement.