Glutamate Alterations Associated With Transcranial Magnetic Stimulation in Youth Depression

Yang, Xinmin; Kirton, Adam; Wilkes, T. Christopher; Pradhan, Sarah; Liu, Irene; Jaworska, Natalia; Damji, Omar; Keess, Jamie; Langevin, Lisa Marie; Rajapakse, Thilinie; Lebel, R. Marc; Sembo, Mariko; Fife, Marilyn; MacMaster, Frank P.

doi:10.1097/yct.0000000000000094

Cited by 62 publications

(65 citation statements)

References 42 publications

(62 reference statements)

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“…Our findings in a small sample of depressed adolescents undergoing six weeks of high-frequency rTMS also suggest that cortical glutamate metabolites are modulated with rTMS treatment. In the present study, 1 H-MRS methodology and the directionality of glutamate changes diverged from the work of Yang and colleagues (Yang et al, 2014). Both studies should be viewed as preliminary and interpreted judiciously.…”

Section: Discussioncontrasting

confidence: 67%

“…The authors posited that high-frequency rTMS sessions may modulate aberrant glial function in depressed patients (Zheng et al, 2010). Yang and colleagues (Yang et al, 2014) recently examined short-echo 1 H-MRS measures of the L-DLPFC in 6 young patients before and after three weeks of high-frequency rTMS. Those responding to treatment demonstrated an increase in Glu quantification in the L-DLPFC, whereas nonresponders showed a decrease.…”

Section: Discussionmentioning

confidence: 99%

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Transcranial magnetic stimulation potentiates glutamatergic neurotransmission in depressed adolescents

Croarkin

Nakonezny

Wall³

et al. 2016

Psychiatry Research: Neuroimaging

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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 3,000 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 3T 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.

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Section: Discussioncontrasting

confidence: 67%

Section: Discussionmentioning

confidence: 99%

Transcranial magnetic stimulation potentiates glutamatergic neurotransmission in depressed adolescents

Croarkin

Nakonezny

Wall³

et al. 2016

Psychiatry Research: Neuroimaging

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“…However, one found an association between clinical response and increased post-treatment glutamate levels in dorsolateral prefrontal cortex (DLPFC) (Grimm et al, 2012). By contrast, increased glutamate and Glx levels in multiple brain regions including pgACC and DLPFC have been associated with response following extended courses of both ECT (Michael et al, 2003; Njau et al, 2016; Pfleiderer et al, 2003; Zhang et al, 2013) and repetitive transcranial magnetic stimulation (rTMS) (Luborzewski et al, 2007; Yang et al, 2014), with two exceptions (Dubin et al, 2016; Merkl et al, 2011). Notably, ECT failed to show acute glutamatergic effects after only two sessions (Njau et al, 2016; Zhang et al, 2013), which may have been too early to see effects.…”

Section: Discussionmentioning

confidence: 99%

“…Several studies have used 1 H-MRS in this context (Croarkin et al, 2016; Dubin et al, 2016; Godlewska et al, 2015; Grimm et al, 2012; Jarnum et al, 2011; Luborzewski et al, 2007; Merkl et al, 2011; Michael et al, 2003; Njau et al, 2016; Pfleiderer et al, 2003; Taylor et al, 2012; Yang et al, 2014; Zhang et al, 2013), but are characterized by important methodological limitations. First, many of these studies measured Glx – a composite measure containing both glutamate and glutamine – making them difficult to interpret.…”

Section: Introductionmentioning

confidence: 99%

Acute change in anterior cingulate cortex GABA, but not glutamine/glutamate, mediates antidepressant response to citalopram

Brennan

Admon

Perriello

et al. 2017

Psychiatry Research: Neuroimaging

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Little is known about the acute effects of antidepressant treatments on brain glutamate and gamma-amino-butyric acid (GABA) levels, and their association with clinical response. Using proton magnetic resonance spectroscopy (1H-MRS) we examined longitudinally the effects of citalopram on glutamine/glutamate ratios and GABA levels in the pregenual anterior cingulate cortex (pgACC) of individuals with major depressive disorder (MDD). We acquired 1H-MRS scans at baseline and at days 3, 7, and 42 of citalopram treatment in nineteen unmedicated individuals with MDD. Ten age- and sex-matched non-depressed comparison individuals were scanned once. The association between 1) baseline metabolites and 2) change in metabolites from baseline to each time point and clinical response (change in Montgomery-Åsberg Depression Rating Scale (MADRS) score from baseline to day 42) was assessed by longitudinal regression analysis using generalized estimating equations. Contrary to our hypotheses, no significant associations emerged between glutamate metabolites and clinical response; however, greater increases (or smaller decreases) in pgACC GABA levels from baseline to days 3 and 7 of citalopram treatment were significantly associated with clinical response. These findings suggest that an acute change in GABA levels in pgACC predicts, and possibly mediates, later clinical response to citalopram treatment in individuals with MDD.

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“…32 and amygdala after ECT; 31 in the DLPFC after TMS for pediatric depression; 33 and in the anterior cingulate cortex in healthy individuals after TMS. 34 The difference between our findings and those previously reported in healthy individuals after TMS may reflect a difference in Glx homeostasis in the MPFC in patients with depression.…”

Section: Mpfcmentioning

confidence: 99%

Elevated prefrontal cortex GABA in patients with major depressive disorder after TMS treatment measured with proton magnetic resonance spectroscopy

Dubin

Mao

Banerjee

et al. 2016

jpn

119

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IntroductionTranscranial magnetic stimulation (TMS) is an effective treatment for major depressive disorder (MDD), particularly in individuals resistant to first-line antidepressants.1-3 Effect sizes of TMS from recent meta-analyses range from 0.39 to 0.55. 4,5 Less is known about the neurobiological mechanisms of antidepressant response to TMS. Emerging evidence suggests that in addition to its effects on the dorsolateral prefrontal cortex (DLPFC), TMS also affects structures to which the DLPFC projects, including the medial prefrontal cortex (MPFC). 6 The MPFC is overactive in individuals with MDD,7 and functional connectivity between the DLPFC and MPFC predicts response to TMS. [8][9][10] Little is known about how connectivity between the DLPFC and MPFC gives rise to the antidepressant effect of TMS.Other antidepressants appear to act in part by modulating the excitability of cortical circuits. Levels of γ-aminobutyric acid (GABA), the primary inhibitory neurotransmitter in the brain, which are generally decreased in depressed individuals, 11 have been reported to increase after treatment with selective serotonin reuptake inhibitors (SSRIs) 12 and electroconvulsive therapy (ECT).13 Although TMS affects the balance of excitation and inhibition in cortical circuits, 14 it is unknown whether changes in excitation-inhibition balance mediate antidepressant response.In this naturalistic study, we tested whether TMS alters the levels of GABA and those of the combined resonance of glutamate and glutamine (Glx) in patients with MDD. Specifically, the standard J-edited spin echo difference proton magnetic resonance spectroscopy ( 1 H MRS) technique was implemented at 3 T to measure levels of MPFC GABA and Background: GABAergic and glutamatergic neurotransmitter systems are central to the pathophysiology of depression and are potential targets of repetitive transcranial magnetic stimulation (rTMS). We assessed the effect of 10-Hz rTMS over the left dorsolateral prefrontal cortex (DLPFC) of patients with major depressive disorder on the levels of medial prefrontal cortex (MPFC) γ-aminobutyric acid (GABA) and the combined resonance of glutamate and glutamine (Glx) as assessed in vivo with proton magnetic resonance spectroscopy ( 1 H MRS). Methods: Currently depressed individuals between the ages of 23 and 68 years participated in a 5-week naturalistic, open-label treatment study of rTMS, with 1 H MRS measurements of MPFC GABA and Glx levels at baseline and following 5 weeks of the rTMS intervention. We applied rTMS pulses over the left DLPFC at 10 Hz and 80%-120% of motor threshold for 25 daily sessions, with each session consisting of 3000 pulses. We assessed therapeutic response using the 24-item Hamilton Rating Scale for Depression (HAMD24). The GABA and Glx levels are expressed as ratios of peak areas relative to the area of the synchronously acquired and similarly fitted unsuppressed voxel water signal (W). Results: Twenty-three currently depressed individuals (7 men) participated in the study. GABA/W in the MPFC i...

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Glutamate Alterations Associated With Transcranial Magnetic Stimulation in Youth Depression

Abstract: Repetitive transcranial magnetic stimulation is feasible and possibly efficacious in adolescents with MDD. In responders, rTMS may act by induced elevations in elevating DFPLC glutamate levels in the left DLPFC, thereby leading to symptom improvement.

Cited by 62 publications

References 42 publications

Transcranial magnetic stimulation potentiates glutamatergic neurotransmission in depressed adolescents

Transcranial magnetic stimulation potentiates glutamatergic neurotransmission in depressed adolescents

Acute change in anterior cingulate cortex GABA, but not glutamine/glutamate, mediates antidepressant response to citalopram

Elevated prefrontal cortex GABA in patients with major depressive disorder after TMS treatment measured with proton magnetic resonance spectroscopy

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